(12) United States Patent
`Osorio et al.
`
`USOO6341236B1
`(10) Patent No.:
`US 6,341,236 B1
`(45) Date of Patent:
`Jan. 22, 2002
`
`(54) VAGAL NERVE STIMULATION
`TECHNIQUES FOR TREATMENT OF
`EPLEPTIC SEZURES
`
`(76) Inventors: Ivan Osorio, 4005 W. 124th St.,
`Leawood, KS (US) 66209; Mark G.
`Frei, 2513 via Linda Dr., Lawrence, KS
`(US) 66047
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(*) Notice:
`
`(21) Appl. No.: 09/302,516
`(22) Filed:
`Apr. 30, 1999
`(51) Int. Cl. .................................................. A61N 1/36
`(52) U.S. Cl. ......................................................... 607/45
`(58) Field of Search ............................................ 607/45
`(56)
`References Cited
`U.S. PATENT DOCUMENTS
`4,628,942 A 12/1986 Sweeney et al. ............ 128/784
`4,649.936 A 3/1987 Ungar et al. ......
`... 128/784
`4,702.254 A 10/1987 Zabara .........
`... 128/419
`4,867,164 A 9/1989 Zabara ......
`... 128/421
`5,025,807 A 6/1991 Zabara .........
`... 128/421
`5,052,388 A 10/1991 Sivula et al. ..
`... 128/419
`5.330,508 A
`7/1994 Gunderson ................... 607/14
`5,562,711 A 10/1996 Yerich et al. ................. 607/74
`5,713,923 A 2/1998 Ward et al. .................... 607/3
`5,928,272 A * 7/1999 Adkins et al. ................ 607/45
`5,995,868 A 11/1999 Dorfmeister et al.
`OTHER PUBLICATIONS
`Handforth et al., “Vagus Nerve Stimulation Therapy for
`Partial Onset Seizures: A Randomized Active Control Trial.”
`J.Neurology, vol. 5, pp. 48-55(1998).
`Han et al., “Probable Mechanisms of Action of Vagus Nerve
`Stimulation in Humans with Epilepsy: Is the Heart the
`Window into the Brain?” AES Processing, p. 83 (1997).
`
`Frei et al. “Effects of Vagal Stimulation on Human ECG,”
`Abstract from the Annual Meeting of the American Epilepsy
`Society, vol.39, Supp 6 (1998).
`Salinskey et al. “Vagus Nerve Stimulation Has No Effect on
`Awake EEG Rhythms in Humans, 'J. Epilespia, vol. 34 (2),
`pp. 229–304 (1993).
`Michael H. Chase et al., “Afferent Vagal Stimulation neuro
`graphic Correlates if Induced EEG Synchronization and
`Desynchronization,” Brain Research pp. 236-249 (1967).
`Chase et al., “Cortical and Subcortical Patterns of Response
`to Afferent Vagal Stimulation,” Experimental Neurology,
`vol. 16, pp. 36–49 (1966).
`(List continued on next page.)
`
`Primary Examiner William E. Kamm
`(74) Attorney, Agent, or Firm-Banner & Witcoff, Ltd.
`(57)
`ABSTRACT
`A System and method for using electrical Stimulation of the
`vagus nerve to treat epilepsy with minimized or no effect on
`the heart. Treatment is carried out by an implantable Signal
`generator, one or more implantable electrodes for electri
`cally Stimulating a predetermined Stimulation site of the
`vagus nerve, and a Sensor for Sensing characteristics of the
`heart Such as a heart rate. The heart rate information from the
`Sensor can be used to determine whether the vagus nerve
`Stimulation is adversely affecting the heart. Once threshold
`parameters are met, the vagus nerve Stimulation may be
`Stopped or adjusted. In an alternative embodiment, a modi
`fied pacemaker is used to maintain the heart in desired
`conditions during the vagus nerve Stimulation. In yet another
`embodiment, a modified pacemaker having circuitry that
`determines whether a vagus nerve is being Stimulated is
`used. In the event that the vagus nerve is being Stimulated,
`the modified pacemaker may control the heart to maintain it
`within desired conditions during the vagus nerve Stimula
`tion.
`
`6 Claims, 11 Drawing Sheets
`
`MICRO
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`Petitioner - Avation Medical, Inc.
`Ex. 1025, p. 1
`
`

`

`US 6,341,236 B1
`Page 2
`
`OTHER PUBLICATIONS
`Jalife J, Anzelecitch C., “Phase Resetting and annihilation of
`pacemaker activity in cardiac tissue,” Science 206:695-697
`(1979).
`Windfree AT, “Sudden Cardian Death: A Problem in Topol
`ogy,” Sci Am, 248:144-161 (1983).
`Ruda, Anti, “A Real-Time Microprocessor QRS Detector
`System with a 1-ms Timing Accuracy for the Measurement
`of Ambulatory HRV,” IEEE Transactions on Biomedical
`Engineering, vol. 44, No. 3, pp. 159-167 (Mar. 1997).
`Accornero et al. “Selective Activation of Peripheral Nerve
`Fibre Groups of Different Diameter by Triangular Shaped
`Pulses,” J. Physiol., pp. 539-560 (1977).
`Bures et al., “Electrophysiological Methods in Biological
`Research Academic Press New York, London pp. 338-339
`(3rd ed. 1967).
`
`Jones et al., "Heart Rate responses to Selective Stimulation of
`cardiac Vagal C Fibers in anaesthetized cats, rats and rab
`bits,” J. Physiol (London) 489.1:203-214 (1995).
`Jalife J. Antzelevitch C., “Pacemaker annihilation: diagnos
`tic and therapeutic implications,” Am Heart J 100:128-130
`(1980).
`Frei et al., “Effects of Vagal Stimulation on Human EEG,”
`AES Proceedings, p. 200 (1998).
`Asconape et al., Early Experience with Vagus Nerve Stimu
`lation for the Treatment of Epilepsy; Cardiac Complications,
`AES Proceeding, p. 193 (1998).
`Mark V. Kamath, “Neurocardiac Responses to Vagoafferent
`Electrostimulation in Humans”, PACE, vol. 15. Oct. (1992)
`p. 1581.
`* cited by examiner
`
`Petitioner - Avation Medical, Inc.
`Ex. 1025, p. 2
`
`

`

`U.S. Patent
`
`Jan. 22, 2002
`
`Sheet 1 of 11
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`US 6,341,236 B1
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`Jan. 22, 2002
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`Ex. 1025, p. 4
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`U.S. Patent
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`Jan. 22, 2002
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`Sheet 3 of 11
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`US 6,341,236 B1
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`Ex. 1025, p. 5
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`

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`U.S. Patent
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`Jan. 22, 2002
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`US 6,341,236 B1
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`Ex. 1025, p. 6
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`Jan. 22, 2002
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`Ex. 1025, p. 7
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`Petitioner - Avation Medical, Inc.
`Ex. 1025, p. 7
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`

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`U.S. Patent
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`Jan. 22, 2002
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`Jan. 22, 2002
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`Ex. 1025, p. 9
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`Jan. 22, 2002
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`Ex. 1025, p. 10
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`
`Jan. 22, 2002
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`Ex. 1025, p. 11
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`Petitioner - Avation Medical, Inc.
`Ex. 1025, p. 11
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`

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`U.S. Patent
`
`Jan. 22, 2002
`
`Sheet 10 of 11
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`US 6,341,236 B1
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`Ex. 1025, p. 12
`
`

`

`U.S. Patent
`
`Jan. 22, 2002
`
`Sheet 11 of 11
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`US 6,341,236 B1
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`
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`Petitioner - Avation Medical, Inc.
`Ex. 1025, p. 13
`
`

`

`US 6,341,236 B1
`
`1
`WAGAL NERVE STIMULATION
`TECHNIQUES FOR TREATMENT OF
`EPILEPTIC SEZURES
`
`2
`and Stimulation of the vagus nerve causes the heart to
`experience a significant drop in heart rate. For example, FIG.
`1A is graph illustrating the effects of vagus nerve Stimulation
`on the heart rate for a patient. In this Figure, the horizontal
`axis represents time and the vertical axis represents the
`normalized heart rate. A value of 1 in this graph indicates
`that the instantaneous heart rate (IHR) at that point in time
`is equal to the median IHR for the current vagus nerve
`stimulator (VNS) device cycle (i.e., for the current 5%
`minute window). The graph shows that during vagus nerve
`stimulation from time 0 to 50, the heart rate drops to as low
`as 0.8 of its background rate. Similarly, FIG. 1B is a graph
`of the instantaneous heart rates (defined herein) of a patient
`as a function of time over an 8 hour period. The Sharp drops
`that occur periodically along the bottom of the graphed line
`correspond to times when the vagus nerve Stimulation
`device is reset or turned “on”. These sharp drops illustrate
`the effect that vagus nerve Stimulation has on the heart.
`Notably, the Zabara patents recognize that the heart rate
`Slows as a result of the Stimulation. This effect that vagus
`nerve Stimulation has on the heart is undesirable due to
`negative short- or long-term effects on the patient. For
`example, the heart may become less adaptable to Stresses
`due to the vagus nerve Stimulation, which may lead to
`arrhythmia, asyStole (heart stoppage), and possibly even to
`Sudden death. See Asconape et al., “Early Experience with
`Vagus Nerve Stimulation for the Treatment of Epilepsy;
`Cardiac Complications, AES Proceedings, p. 193 (1998).
`The relative lack of efficacy and the adverse effects of the
`VNS are attributable in part to inadequate stimulation.
`Specifically, the NCP does not change the EEG. See Salin
`sky et al. “Vagus Nerve Stimulation Has No Effect on Awage
`EEG Rythms in Humans,” J. Epilespia, Vol. 34 (2),
`p.299-304 (1993). Adequate stimulation of the vagus nerve
`induces either Synchronization or desynchronization of brain
`rhythms depending on the Stimulation parameters used. See
`Michael H. Chase et al., “Afferent Vagal Stimulation: Neu
`rographic Correlates of Induced EEG Synchronization and
`Desynchronization.” Brain Research pp. 236-249 (1967);
`Chase et al., “Cotical and Subcortical Patterns of Response
`to Afferent Vagul Stimulation,” Experimental Neurology,
`Vol. 16, pp. 36-49 (1966). EEG desynchronization requires
`Selective activation of Slow conducting nerve fibers. This
`State of desynchronization does not favor the occurrence of
`Seizures and is therefore preferred for this specific therapeu
`tic purpose. The absence of EEG changes in humans during
`VNS Suggests Stimulation is inadequate and this in turn may
`explain its relatively low therapeutic value. See Handforth
`et. al., “Vagus Nerve Stimulation Therapy for Partial Onset
`Seizures: A Randomized Active Control Trial,” J.
`Neurology, Vol. 51, pp. 45–55 (1998).
`In addition, VNS provides non-selective bi-directional
`nerve fiber activation. In general, the VNS stimulation
`affects the brain (a desirable target) and also the viscera,
`including the heart (undesirable targets). Accordingly, VNS
`causes alterations in the heart EKG. Given the shape of the
`pulse, its biphasic nature and the intensity Settings available
`in the NCP, selective stimulation of slow conducting nerve
`fibers (a necessary condition for EEG desynchronization) is
`highly unlikely with this device.
`Further, the NCP provides indiscriminate timing for
`Stimulation of the heart. Cardiac arrest can result from
`Stimulation of the heart during Vulnerable phases of its cycle.
`See Jalife J, Anzelevitch C., “Phase resetting and annihila
`tion of pacemaker activity in cardiac tissue,” Science
`206:695-697 (1979); Jalife J, Anzelevitch C., “Pacemaker
`annihilation: diagnostic and therapeutic implications, Am.
`
`15
`
`25
`
`35
`
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`This invention relates to neural tissue Stimulation
`techniques, and more particularly relates to techniques for
`providing more effective vagus nerve Stimulation and for
`controlling or preventing epileptic Seizures with minimized
`effect on the heart.
`2. Description of Related Art
`Epileptic Seizures are the outward manifestation of exces
`Sive and/or hyperSynchronous abnormal activity of neurons
`in the cerebral cortex. Many types of Seizures occur. The
`behavioral features of a seizure reflect function of the
`portion of the cortex where the hyper activity is occurring.
`Seizures can be generalized and appearing to involve the
`entire brain Simultaneously. Generalized Seizures can result
`in the loSS of conscious awareneSS only and are then called
`absence Seizures (previously referred to as “petit mal').
`Alternatively, the generalized Seizure may result in a con
`Vulsion with tonic-clonic contractions of the muscles
`("grand mal’ seizure). Some types of Seizures, partial
`Seizures, begin in one part of the brain and remain local. The
`perSon may remain conscious throughout the Seizure. If the
`perSon loses awareness, the Seizure is referred to as a
`complex partial Seizure.
`A number of techniques are known to treat Seizures
`including, for example, drug therapy, drug infusion into the
`brain, electrical Stimulation of the brain, electrical Stimula
`tion of the nervous system, and even lesioning of the brain.
`U.S. Pat. No. 5,713,923 entitled Techniques of Treating
`Epilepsy by Brain Stimulation and Drug Infusion' generally
`discloses Such techniques in the background Section and
`Specifically discloses techniques for drug infusion and/or
`electrical Stimulation to treat epilepsy. This patent is incor
`porated herein by reference in its entirety.
`U.S. Pat. No. 5,025,807 entitled “Neurocybernetic Pros
`thesis” and its parentage (U.S. Pat. Nos. 4,867,164 and
`4,702,254) (all three patents are collectively referred to
`herein as the "Zabara patents”) disclose techniques for
`electrical Stimulation of the vagus nerve. These Zabara
`patents generally disclose a circuit-based device that is
`implanted near the axilla of a patient. Electrode leads are
`passed from the circuit device toward the neck and terminate
`in an electrode cuff or patch on the vagus nerve.
`The neuro-cybernetic prosthesis (NCP) is the primary
`vagus nerve stimulation (VNS) system that is presently
`available. This presently available VNS treatment technique
`for the treatment of epilepsy, however, has limited thera
`peutic efficacy and exerts clear but variable chronotropic
`effects on the human heart. See Handforth et. al., “Vagus
`Nerve Stimulation Therapy for Partial Onset Seizures: A
`55
`Randomized Active Control Trial,” J. Neurology, Vol. 51,
`pp. 45–55 (1998); Han et al., “Probable Mechanisms of
`Action of Vagus Nerve Stimulation in Humans with Epi
`lepsy: Is the Heart the Window into the Brain?” AES
`Proceedings, p. 83 (1997); Frei et al., “Effects of Vagal
`Stimulation on Human EEG, AES Poceedings, p. 200
`(1998). With regard to the heart, vagus nervestimulation has
`the side-effect of altering the heart rate. See Frei et al.
`“Effects of Vagal Stimulation on Human ECG, Abstract
`from the Annual Meeting of the American Epilepsy Society,
`Vol. 39, Supp. 6 (1998), which is incorporated herein by
`reference in its entirety. Typically, activation of the device
`
`50
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`40
`
`45
`
`60
`
`65
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`Petitioner - Avation Medical, Inc.
`Ex. 1025, p. 14
`
`

`

`3
`Heart J. 100:128-130 (1980); and Winfree AT, “Sudden
`Cardiac Death: A Problem in Topology,” Sci Am
`248:144-161 (1983). VNS can cause cardiac arrest because
`the timing of Stimulation does not take into account the
`phase or State of the cardiac cycle.
`Accordingly, it is an object of the invention to provide a
`technique for controlling or preventing epilepsy via Stimu
`lation of the vagus nerve with minimized effect on the heart
`rate. It is another object of the invention to provide a
`technique for adjusting the vagus nerve Stimulation to mini
`mize its affect on the heart rate. It is another object of the
`invention to provide Stimulation of the vagus nerve while
`maintaining the heart rate at a preset rate. It is a further
`object to minimize the risk of cardiac arrest in patients
`receiving VNS by delivering stimuli at times in the heart
`cycle which cause no or minimal adverse effects on rhythms
`generation or propagation. Other objects of the present
`invention will become apparent from the following disclo
`SUC.
`
`15
`
`SUMMARY OF THE INVENTION
`The present invention discloses techniques for treating
`epilepsy by providing electrical Stimulation of the vagus
`nerve to induce therapeutic EEG changes with little or no
`potentially Serious or life-threatening Side-effects, especially
`to the heart. Accordingly, the present invention discloses
`techniques for adjusting the vagus nerve Stimulation and/or
`controlling the heart rate during vagus nerve Stimulation to
`maintain the heart within desired parameters. In a preferred
`embodiment of the present invention, treatment is carried
`out by an implantable Signal generator, one or more implant
`able electrodes for electrically Stimulating a predetermined
`Stimulation site of the vagus nerve, and a sensor for Sensing
`characteristics of the heart Such as heart rate. The heart rate
`information from the Sensor can be used to determine
`whether the vagus nerve Stimulation is adversely affecting
`the heart. Once threshold parameters are met, the vagus
`nerve Stimulation may be stopped or adjusted. In an alter
`native embodiment, heart EKG signals may be monitored
`and applied to an EKG algorithm to detect epileptic Seizures
`and to responsively trigger the Signal generator to provide
`Stimulation to the vagus nerve.
`In an alternative embodiment, the invention may include
`a modified pacemaker to maintain the heart in desired
`conditions during the vagus nerve Stimulation. In yet another
`embodiment, the invention may be Simply a modified pace
`maker having circuitry that determines whether a vagus
`nerve is being Stimulated. In the event that the vagus nerve
`is being Stimulated, the modified pacemaker may control the
`heart to maintain it within desired conditions during the
`vagus nerve Stimulation.
`In yet another embodiment, EKG rhythms may be sensed
`So as to minimize EKG changes via cybernetic techniques.
`In another embodiment, the present invention may selec
`tively Stimulate certain fiber groups within the vagus nerve
`to block the propagation of impulses towards the Viscera,
`Such as the heart, using electrophysiologic techniques. In
`Still another embodiment, the present invention may Sense
`brain EEG to provide feedback on the vagal nerve stimula
`tion. Alternatively, heart EKG may be monitored to deter
`mine whether there is a risk of a possible Seizure onset to
`either adjust the VNS stimulation or to warn the patient.
`BRIEF DESCRIPTION OF THE DRAWINGS
`These and other advantages and features of the invention
`will become apparent upon reading the following detailed
`
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`US 6,341,236 B1
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`4
`description and referring to the accompanying drawings in
`which like numbers refer to like parts throughout and in
`which:
`FIG. 1A is graph illustrating the effects of vagus nerve
`Stimulation on the heart rate for a patient;
`FIG. 1B is a graph of the instantaneous heart rate of a
`patient as a function of time over an 8 hour period;
`FIG. 2 is a Schematic block diagram of the components of
`the present invention implanted within a patient in accor
`dance with a preferred embodiment of the present invention;
`FIG. 3 is a block diagram depicting the connection
`between the Sensor and the Signal generator;
`FIG. 4 is a Schematic block diagram of a microprocessor
`and related circuitry for utilizing the Sensor to control
`Stimulation administered to the vagus nerve,
`FIG. 5 is a graph of standard deviations of the instanta
`neous heart rate (IHR) of a patient as a function of the IHR;
`FIG. 6 is a flow chart depicting a control algorithm
`utilized to minimize the effect of vagus nerve Stimulation on
`the heart; and
`FIG. 7 is a graph depicting the IHR of a patient as a
`function of time,
`FIG. 8 depicts another embodiment of the present inven
`tion having a pacemaker or a like device implemented to
`affect the heart in the event that vagus nerve Stimulation
`causes the heart to beat outside of the acceptable ranges,
`FIG. 9 is a schematic diagram of yet another embodiment
`of the invention where a pacemaker is modified with a
`digital Signal processing algorithm to recognize whether the
`vagus nerve is being Stimulated;
`FIG. 10 is a block diagram of an algorithm for detecting
`whether a vagus nerve Stimulator is Stimulating the nerve
`based on heart EKG;
`FIGS. 11 A-C are graphs illustrating the EKG signal as it
`is processed by the algorithm of FIG. 10; and
`FIGS. 12A-B are schematic diagrams of one or more
`electrode pairs providing Stimulation to the vagus nerve in
`accordance with an embodiment of the present invention.
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`Referring to FIG. 2, a system 10 made in accordance with
`a preferred embodiment may be implanted below the skin of
`a patient. System 10 generally includes a sensor 15 for
`Sensing a characteristic of the heart 55 of the patient, a signal
`generator 20, and one or more Stimulation electrodes 25.
`System 10 may be a modified version of the devices dis
`closed in the Zabara patents and are incorporated herein by
`reference.
`Sensor 15 is implemented at or near the heart 55 to sense
`a characteristic of the heart 55, including the heart rate. A
`number of techniques may be used to Sense the heart rate
`including, but not limited to, QRS detection or R-wave
`detection techniques, for example, as disclosed in Antti
`Ruha et al., “A Real-Time Microprocessor QRS Detector
`System with a 1-ms Timing Accuracy for the Measurement
`of Ambulatory HRV,” IEEE Transactions on Biomedical
`Engineering, Vol. 44, No. 3, pp. 159–167 (March 1997).
`Another technique may use Standard analog techniques. In
`alternative embodiments, Sensor 15 may be physically
`located outside of the body and communicate with the
`implanted portion through telemetry.
`Sensor 15 is coupled to signal generator 20 via cable 17.
`Sensor 15 and Signal generator 20 may alternatively com
`
`Petitioner - Avation Medical, Inc.
`Ex. 1025, p. 15
`
`

`

`S
`municate via telemetry Such as, for example, radio
`frequency Signals. Alternatively, Sensor 15 and Signal gen
`erator 20 may be a Single device that may be part of a heart
`pacemaking or like device. Depending upon the Sensor 15
`used, the outputs of Sensor 15 may require the use of an
`analog-to-digital (A/D) converter 18 to be coupled between
`sensor 15 and signal generator 20 as shown in FIG. 3. The
`output of A/D converter 18 is connected to microprocessor
`200 as shown in FIG. 4. Alternatively, if an A/D converter
`18 is not required, the output from sensor 15 can be filtered
`by an appropriate electronic filter 19 prior to delivery of the
`Sensor Signal to Signal generator 20.
`When in operation to Stimulate the vagus nerve 60, Signal
`generator 20 receives the sensed information from sensor 15
`and adjusts the Stimulation therapy in response to the Sensed
`information in accordance with the present invention. Signal
`generator 20 is preferably capable of providing a range of
`Stimulation therapy with adjustable cycling parameters of
`the electrical pulse including but not limited to pulse shape,
`inter-Stimulus interval, pulse frequency, pulse width, pulse
`amplitude, and pulse phase. AS discussed herein, it is pre
`ferred that the Stimulation be accomplished So as to have
`minimal effect on the heart. Continuous Stimulation may
`also be provided. Preferably, signal generator 20 is of the
`type which is capable of ramping up to the Set pulsing
`parameters whenever the Signal generator 20 is activated.
`This technique helps eliminate involuntary twitching when
`the prosthesis is activated. Once implanted, Signal generator
`20 must be “tuned” to provide desired treatment therapy to
`the Specified nerve properties of the vagus nerve 60. Signal
`generator 20 accordingly is capable of varying before and
`after implant the pulsing parameters of the pulse signal.
`After implant, the pulsing parameters may be adjustable via
`telemetry which is known to those skilled in the art.
`AS shown in FIG. 3, Signal generator 20 may include a
`microprocessor 200 that is coupled to the output of A/D
`converter 18, filter 19 or directly to sensor 15. Micropro
`cessor 200 processes the sensor data in different ways
`depending on the type of transducer in use. Microprocessor
`200 may read the Sensor Signal and Stores one or more values
`in RAM 102a. Referring now to FIG. 4, memory 204 may
`be used to Store parameters for control of the Stimulation
`therapy based on the sensor signal. Microprocessor 200 is
`coupled to a peripheral buS 202 having address, data and
`control lines. Stimulation is delivered through an output
`driver 224.
`Signal generator 20 is Suited to provided Stimulation
`therapy with adjustable pulse frequency, pulse width and
`pulse amplitude. The Stimulus pulse frequency is controlled
`by programming a value to a programmable frequency
`generator 208 using bus 202. The programmable frequency
`generator 208 provides an interrupt Signal to microprocessor
`200 through an interrupt line 210 when each stimulus pulse
`is to be generated. The frequency generator 208 may be
`implemented by model CDP 1878 sold by Harris Corpora
`tion. The amplitude for each Stimulus pulse is programmed
`to a digital to analog converter 218 using bus 202. The
`analog output is conveyed through a conductor 220 to an
`output driver circuit 224 to control Stimulus amplitude.
`Microprocessor 200 also programs a pulse width control
`module 214 using bus 202. The pulse width control provides
`an enabling pulse of duration equal to the pulse width via a
`conductor 216. Pulses with the selected characteristics are
`then delivered from signal generator 20 through cable 22 to
`the electrodes 25 which are in communication with the
`vagus nerve 60. Electrical stimulation of the vagal nerve 60
`may be implemented by providing pulses to electrodes 25
`
`15
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`25
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`35
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`40
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`45
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`50
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`55
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`60
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`65
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`US 6,341,236 B1
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`6
`having amplitudes of 0.1 to 20 volts, pulse widths varying
`from 0.02 to 1.5 milliseconds, and repetition rates varying
`from 2 to 2500 Hz. The appropriate stimulation pulses are
`generated by Signal generator 20 based on the computer
`algorithm, parameters Set by the clinician, and the features
`of the present invention.
`Microprocessor 200 executes an algorithm to provide
`stimulation with closed loop feedback control based on the
`sensed conditions of the heart from sensor 15. At the time the
`Signal generator 20 is implanted, the clinician programs
`certain key parameters into the memory of the implanted
`device via telemetry. These parameters may be updated
`Subsequently as needed. Alternatively, the clinician may
`elect to use default values. The clinician must program the
`range of values for pulse width, amplitude and frequency
`which Signal generator 20 may use to optimize the therapy.
`The Stimulation may be applied continuously to prophy
`lactically prevent the onset of Seizures, manually by the
`patient, or it may turn on in response to a Signal on
`Secondary sensor 30 (discussed herein) indicating the begin
`ning of a Seizure. Stimulus parameters can be adjusted by the
`computer algorithm within a range specified by the clinician
`in an attempt to optimize the Seizure Suppression.
`Signal generator 20 is implanted in a human body in a
`Subclavicular, Subcutaneous pocket. Signal generator 20
`may also be implanted near the heart 55. For example, in one
`embodiment discussed herein, Signal generator 20 may be
`encased along with sensor 15 near the heart 55. Signal
`generator 20 may take the form of a modified neuro
`cybernetic prosthesis (NCP) device, a modified signal gen
`erator Model 7424 manufactured by Medtronic, Inc. under
`the trademark Itrel II, or any other signal generator Suited for
`stimulation of the vagus nerve 60. Signal generator 20 may
`also be similar to one disclosed in the Zabara patents, which
`are incorporated herein by reference, with the modification
`that it be adjustable and responsive to sensor 15.
`Signal generator 20 is coupled to the proximal end of at
`least one lead 22. The distal end of 22 terminates in one or
`more Stimulation electrodes 25 that can Stimulate neurons in
`the vagus nerve 60. The electrodes 25 are shown as an
`electrode patch, which is generally known in the art, though
`Single electrodes may also be used. Various other known
`electrodes may also be used Such as, for example, a tripolar
`cuff electrode. The electrodes 25 may be of the form
`disclosed in the Zabara patents and are incorporated herein
`by reference. Electrode patches include both positive and
`negative electrodes. Electrodes 25 may be placed anywhere
`along the length of the vagus nerve 60, above or below the
`inferior cardiac nerve depending upon the particular appli
`cation. Electrodes 25 are placed on or near the vagus nerve
`60 or in indirect contact with the vagus nerve 60.
`FIG. 12A shows an embodiment of the present invention
`having a pair of electrodes for use in different combinations.
`The electrode pair is positioned to Stimulate the vagus nerve
`60. As preferred, the anode is implanted to be closest to the
`heart So as to block passage of unwanted nerve impulses
`towards the Viscera, Such as the heart. The pulse is prefer
`ably a Saw-tooth wave as shown as having a steeply rising
`beginning followed by a slow exponential decay, although
`any other way may be used. The outward flow of current at
`the cathode, triggerS conducted impulses in larger and
`Smaller nerve fibers while the inward inflow at the anode
`inactivates the conduction of impulses in the Smaller or
`slower conduction fibers. The differential effect of anodal
`currents results form the greater internal conductances and
`greater conduction Velocity of larger (faster) conducting
`
`Petitioner - Avation Medical, Inc.
`Ex. 1025, p. 16
`
`

`

`US 6,341,236 B1
`
`15
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`7
`nerve fibers. See Accornero et al. “Selective Activation of
`Peripheral Nerve Fibre Groups of Different Diameter by
`Triangular Shaped Pulses,” J. Physiol., pp. 539-560 (1977).
`Simply Stated, anodal currents causes a functional nerve
`block.
`Alternatively, a modification of the above technique may
`be implemented which rests on the “law of independent
`conduction” of nerve fibers. Bures et al., “Electrophysiologi
`cal Methods in Biological Research,” Academic Press New
`York, London, pp 338-339 (3rd ed. 1967). This law gener
`ally States that larger fibers will conduct impulses faster than
`Smaller fibers. In this embodiment, impulses travelling in
`larger or myelinated fibers will reach the anode well before
`the smaller or slower conducting fibers and while the
`functional block is still active. See Jones et al., “Heart rate
`responses to Selective Stimulation of cardiac Vagal C fibers
`in anaesthetized cats, rats and rabbits,” J. Physiol (London)
`489.1:203-214 (1995). These fast impulses which are more
`likely to alter the heart than the Slow conducting ones, will
`be prevented from reaching the heart (Id.). The distance
`between the active electrodes should be sufficiently long so
`as to allow the differential conduction of impulses to fully
`take place or develop. The optimal distance betweeen these
`electrodes can be found during the implantation procedure.
`If the anodal current is maintained for a Sufficiently long
`period of time, the Slow traveling impulses can be also
`blocked from reaching the heart. The duration of anodal
`Stimulation necessary to attain this effect can be determined
`during the implantation procedure or at a later time. Those
`skilled in the art understand that more than one pair of
`electrodes and different impulse shapes, phases and time
`constants may be used to optimize blockage of impulses
`travelling towards the heart using collision techniques. See
`Jones et al., “Heart rate responses to Selective Stimulation of
`cardiac Vagal C fibers in anaesthetized cats, rats and
`rabbits,” J. Physiol (London) 489.1:203-214 (1995). Elec
`trodes can be used not only to transf