Patent Publication Number: US-2021187288-A1

Title: Stimulator systems and methods for selectively recruiting fascicles in hypoglossal nerve trunk

Description:
CROSS-REFERENCE TO RELATED APPLICATION(S) 
     The present application is a continuation of U.S. patent application Ser. No. 16/118,348, filed Aug. 30, 2018, which claims the benefit of priority to U.S. Provisional Application Ser. No. 62/522,266, filed on Aug. 30, 2017. The contents of the aforementioned patent applications are hereby expressly incorporated by reference in their entirety. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to systems and methods for the treatment of obstructive sleep apnea (OSA), and more specifically for the treatment of OSA by stimulating the hypoglossal nerve (HGN) trunk. 
     BACKGROUND 
     Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder that is caused by the collapse of or increase in the resistance of the pharyngeal airway, often resulting from tongue obstruction. The obstruction of the upper airway is mainly caused by reduced genioglossus muscle activity during the deeper states of NREM sleep. Obstruction of the upper airway causes breathing to pause during sleep. Cessation of breathing causes a decrease in the blood oxygen saturation level, which is eventually corrected when the person wakes up and resumes breathing. The long-term effects of OSA include high blood pressure, heart failure, strokes, diabetes, headaches, and general daytime sleepiness and memory loss, among other symptoms. 
     OSA is extremely common, having a similar prevalence as diabetes or asthma. Over 100 million people worldwide suffer from OSA, with about 25% of those being treated. Continuous Positive Airway Pressure (CPAP) is the usual established therapy for people who suffer from OSA. More than five million patients own a CPAP machine in North America, but many do not comply with use of these machines, because they cover the mouth and nose and, hence, are cumbersome and uncomfortable. 
     The use of neurostimulators to open the upper airway has been explored by several companies as a treatment for alleviating apneic events. Such therapy involves stimulating the nerve fascicles of the hypoglossal nerve (HGN) that innervate the intrinsic and extrinsic muscles of the tongue in a manner that prevents retraction of the tongue, which would otherwise close the upper airway during inspiration of the respiratory cycle. 
     ImThera Medical is currently in FDA clinical trials for a stimulator system that is used to stimulate the trunk of the HGN with a nerve cuff electrode. The stimulation system does not provide a sensor or sensing, and therefore, the stimulation delivered to the HGN trunk is not synchronized to the respiratory cycle. Thus, the tongue and other muscles that are innervated by nerve fascicles of the HGN trunk are stimulated irrespective of the respiratory cycle. 
     The rationale for this treatment method appears to be that it is enough simply to tone the tongue muscle and other nearby muscles, so that the tongue muscle does not retract in a manner that would cause obstructive sleep apnea. The belief is that it is not necessary to specifically target the protraction (i.e., anterior movement) of the tongue muscle and to synchronize the occurrence of tongue protraction when it is most needed, i.e., during inspiration. The nerve cuff electrode of the ImThera Medical system has multiple electrode contacts helically surrounding the proximal part of the HGN nerve trunk. So, instead, each electrode contact delivers stimulation in a sequential order to the HGN trunk. For example, if a three-electrode contact nerve cuff is used, electrode contact #1 stimulates, then stops, electrode contact #2 stimulates, then stops, electrode contact #3 stimulates, then stops, then electrode contact #1 stimulates, then stops and so on. Since all or most electrode contacts deliver stimulation, there is no selection process to choose the best one or two electrode contact or contacts that is finally used to deliver the best stimulation to alleviate sleep apnea. 
     However, because the HGN trunk contains nerve fascicles that innervate muscles other than the muscle that extend the tongue, the Imthera Medical method of stimulation at the HGN trunk does not just target the specific protrusor tongue muscles, but may stimulate other tongue muscles that are not targeted. 
     Another company, Inspire Medical Systems, Inc., does offer a stimulation system with a sensor, and therefore does attempt to time the onset of stimulation to the breathing cycle. This system, which is FDA approved for sale in the United States since April 2010, uses a simple, bipolar electrode (two electrode contacts only) within a nerve cuff electrode and implants the electrode at the branch of the HGN that is responsible for protruding the tongue. A simple, two-electrode contact cuff electrode can be used at the branch nerve, unlike the HGN trunk, because at the distal branch location, the nerve fascicles generally innervate the specific tongue protrusor muscle and not other muscles. 
     However, implanting the electrode at a branch of the HGN takes additional surgery time, which increases trauma to the patient and increases the substantial expense of operating room time. By attaching the nerve cuff electrode to the proximal section of the main trunk of the HGN, compared to placing the nerve cuff electrode at the more distal end of the HGN, it estimated that the surgical time will be reduced by approximately one hour. Even more importantly, because the branch nerve is small and more difficult to isolate than the HGN trunk, implanting a nerve cuff electrode at the branch site demands heightened expertise from the otolaryngologist/Ear Nose and Throat (ENT) surgeon or neurosurgeon, which significantly increases the chance for error and surgical risks. Furthermore, because the distal location of the HGN has a smaller diameter of nerves, and hence the required electrode contacts need to be smaller, the smaller nerve cuff electrode may be more difficult to manufacture. 
     Thus, it is desirable to implant the nerve cuff electrode at the trunk of the hypoglossal nerve. However, one must then deal with the fact that the target nerve fascicles are not easily isolated and stimulated, while at the same time avoiding stimulating other fascicles in the same nerve trunk. 
     There, thus, remains a need for improved systems and methods for selectively recruiting only specific fascicles of the hypoglossal nerve, while minimizing the surgery time and effort required to implant the neurostimulation components in the patient. 
     SUMMARY 
     In accordance with a first aspect of the present inventions, an electrode lead comprises an elongated lead body having a proximal end and a distal end, an array of connector contacts affixed to the proximal end of the lead body, and a biologically compatible, elastic, electrically insulative cuff body affixed to the distal end of the lead body. The electrode lead further comprises an array of electrode contacts (which may number at least three, and preferably at least six) circumferentially disposed along the cuff body when in the furled state, such that at least one of the electrode contacts is located on the inner surface of the cuff body, and at least another of the electrode contacts is located between the overlapping inner and outer cuff regions. The electrode lead further comprises a plurality of electrical conductors extending through the lead body respectively between the array of connector contacts and the array of electrode contacts. 
     The cuff body is pre-shaped to transition from an unfurled state to a furled state, wherein the cuff body, when in the furled state has an inner surface for contacting a nerve and an overlapping inner cuff region and an outer cuff region. The inner surface of the furled cuff body may have a diameter in the range of 2.5 mm to 4.0 mm. In one embodiment, only one of the electrode contacts is located between the overlapping inner and outer cuff regions. In another embodiment, when the cuff body is in the unfurled state, a center-to-center spacing of each pair of adjacent ones of electrode contacts is equal to or less than twice a width of each electrode contact of the respective pair of electrode contacts. 
     In accordance with a second aspect of the present inventions, a neurostimulation system comprises the afore-described electrode lead, and a neurostimulator comprising a connector configured for receiving the proximal contacts of the electrode lead, and stimulation circuitry configured for generating and delivering an electrical stimulation pulse train to at least one of the electrode contacts of the electrode lead. 
     In accordance with a third aspect of the present inventions, a method of using the afore-described electrode lead comprises maintaining the cuff body in the unfurled state while placing the cuff body in contact with the nerve (which may be, e.g., a trunk of a hypoglossal nerve (HGN)), and placing the cuff body from the unfurled state into the furled state, such that the cuff body wraps around the nerve. In one method, the size of the nerve allows the cuff body to wrap upon itself, such that the one electrode contact(s) are in contact with the nerve, and the other electrode contact(s) are between the overlapping inner and outer cuff regions without contacting the nerve. In another method, the size of the nerve may prevent the cuff body from wrapping upon itself, such that all of the electrode contacts are in contact with the nerve. When the cuff body is wrapped around the nerve, a center-to-center spacing of each pair of adjacent ones of electrode contacts is equal to or less than twice a width of each electrode contact of the respective pair of electrode contacts. Still another method further comprises delivering electrical stimulation energy to one or more of the electrode contacts to stimulate the nerve. For example, the electrical stimulation energy may be delivered between a pair of adjacent ones of the electrode contacts to stimulate the nerve in a bipolar mode. 
     In accordance with a fourth aspect of the present inventions, a method of implanting an electrode lead in a patient is provided. The electrode lead comprises a biologically compatible, elastic, electrically insulative cuff body and an array of electrode contacts (which may number at least three, and preferably at least six) disposed along the cuff body. The method comprises wrapping the cuff body upon itself around a nerve (which may be, e.g., a trunk of a hypoglossal nerve (HGN) and may be in the range of 2.5 mm to 4.0 mm) of the patient, such that there exists an inner surface that contacts the nerve and an overlapping inner cuff region and an outer cuff region, at least one of the electrode contacts being on the inner surface in contact with the nerve, and at least another of the electrode contacts being between the inner and outer overlapping regions of the cuff body without contacting the nerve. In one method, only one of the electrode contacts is located between the overlapping inner and outer cuff regions. 
     The cuff body may be pre-shaped to transition from an unfurled state to a furled state, in which case, the method may further comprise maintaining the cuff body in the unfurled state while placing the cuff body in contact with the nerve, and placing the cuff body from the unfurled state into the furled state, such that the cuff body wraps upon itself around the nerve. The cuff body may be wrapped around itself around the nerve, in which case, a center-to-center spacing of each pair of adjacent ones of electrode contacts is equal to or less than twice a width of each electrode contact of the respective pair of electrode contacts. 
     Other and further aspects and features of the invention will be evident from reading the following detailed description of the preferred embodiments, which are intended to illustrate, not limit, the invention. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The drawings illustrate the design and utility of preferred embodiments of the present invention, in which similar elements are referred to by common reference numerals. In order to better appreciate how the above-recited and other advantages and objects of the present inventions are obtained, a more particular description of the present inventions briefly described above will be rendered by reference to specific embodiments thereof, which are illustrated in the accompanying drawings. Understanding that these drawings depict only typical embodiments of the invention and are not therefore to be considered limiting of its scope, the invention will be described and explained with additional specificity and detail through the use of the accompanying drawings in which: 
         FIG. 1  is a cut-away anatomical drawing of the head and neck area illustrating the muscles that control movement of the tongue and the hypoglossal nerve and its branches that innervate these muscles; 
         FIG. 2  is a plan view of a stimulation system constructed in accordance with one embodiment of the present inventions; 
         FIG. 3  is a block diagram of the internal components of an implantable pulse generator of the stimulation system of  FIG. 2 ; 
         FIG. 4  is a perspective view of a lead electrode used in the stimulation system of  FIG. 2 ; 
         FIG. 5  is a plan view of a nerve cuff electrode of the lead electrode of  FIG. 4 , particularly shown in an unfurled state; 
         FIG. 6  is an end view of the nerve cuff electrode of  FIG. 5 , particularly shown in a furled state; 
         FIGS. 7 a -7 c    are cross-sectional views of the nerve cuff electrode of  FIGS. 5 and 6  wrapped around differently sized HGN trunks; 
         FIG. 8  is a profile view of an alternative nerve cuff electrode of the lead electrode of  FIG. 4 , particularly shown in an unfurled state; 
         FIG. 9  is an end view of the nerve cuff electrode of  FIG. 8 , particularly shown in a furled state; 
         FIGS. 10 a -10 c    are cross-sectional views of the nerve cuff electrode of  FIGS. 8 and 9  wrapped around differently sized HGN trunks; and 
         FIG. 11  is a flow diagram illustrating one method of implanting and fitting the stimulation system to a patient. 
     
    
    
     DETAILED DESCRIPTION 
     It is believed that obstruction to the upper airways is primarily caused by reduced genioglossus muscle activity during the deeper stages of NREM sleep. The present invention provides a system and method for moving the glossus (tongue) anteriorly using electrical stimulation to prevent the obstruction of the airway during sleep. 
     Referring first to  FIG. 1 , it is desirable to locate a nerve cuff electrode  10  around a trunk  14  of a hypoglossal nerve (HGN)  12  for purposes of stimulating the muscles that anteriorly move the tongue  16 , and in particular, the fascicles of the HGN  12  that innervate the tongue protrusor muscles, such as the genioglossus  18  and/or the geniohyoid muscles  20 . As shown, the nerve cuff electrode  10  is positioned on the HGN trunk  14  immediately before it branches out, and hence at a proximal position  22  to the HGN branches  24 . As briefly discussed above, the implantation of the nerve cuff electrode  10  at this proximal position  22  reduces the surgical time and effort, allows more surgeons to perform the surgery, reduces the risk and trauma to the patient, and reduces engineering design complexity and cost. However, it introduces the problem of inadvertently stimulating other fascicles of the HGN trunk  14  that innervate muscles in opposition to the genioglossus  18  and/or the geniohyoid muscles  20 , i.e., the tongue retractor muscles, e.g., the hyoglossus  26  and styloglossus muscles  28 , as well as the intrinsic muscles of the tongue  16 . 
     Referring to  FIG. 2 , one embodiment of a stimulation system  50  that selectively stimulates the fascicles of the trunk  14  of the HGN  12  that innervate the genioglossus  18  and/or the geniohyoid  20  muscles for treating obstructive sleep apnea will now be described. The system  50  generally comprises an implantable device  52 , an electrode lead  54 , a clinician programmer  56 , and a patient programmer  58 . The implantable device  52 , or alternatively, an implantable pulse generator (“IPG”) or equivalently a “stimulator” can be implanted within a patient. 
     The electrode lead  54  comprises the aforementioned nerve cuff electrode  10 , a lead body  60  coupling the nerve cuff electrode  10  to the implantable device  52  via a proximal lead connector  62  and a corresponding connector receptacle  64 . Although the lead body  60  can be straight, in the illustrated embodiment, the lead body  60  may have one or more S-shaped sections in order to provide strain relief in order to accommodate body movement at the location where the lead body  60  is implanted. This strain relief feature is advantageous, since the lead body  60  is intended to be implanted in a body location such as the neck, where the lead body  60  is subjected to frequent movement and stretching. Thus, the S-shape of the lead body  60  can help prevent damage to the HGN trunk  14 , resulting from sometimes, unavoidable pulling of the nerve cuff electrode  10  as a result of neck movements. As will be described in further detail, the nerve cuff electrode  10  comprises an array of circumferentially disposed electrode contacts. 
     Although only a single electrode lead  54  is shown in  FIG. 2 , some embodiments of the present system may have an IPG  52  having two receptacles  64  (not shown) for attaching two electrode leads, each electrode lead having a nerve cuff electrode  10 . In such a two-electrode lead system, each nerve cuff electrode  10  can be implanted bilaterally to each of the HGN trunks  14 . However, it has been determined that only a single nerve cuff electrode  10  implanted at the HGN trunk  14  on either side (unilaterally) can provide sufficiently effective stimulation to protrude the tongue to control obstructive sleep apnea. A unilateral stimulation system is advantageous, since it is simpler in numbers of components used and requires only half the surgery to implant only a single nerve cuff electrode  10 , instead of two. 
     The IPG  52  comprises an outer case  66  for housing the electronic and other components (described in further detail below). In one embodiment, the outer case  66  is composed of an electrically conductive, biocompatible material, such as titanium, and forms a hermetically sealed compartment wherein the internal electronics are protected from the body tissue and fluids. In some cases, the outer case  66  may serve as an electrode. As briefly discussed above, the IPG  52  further comprises a receptacle  64  to which the proximal end of the lead body  60  mates in a manner that electrically couples the nerve cuff electrode  10  to the internal electronics (described in further detail below) within the outer case  66 . 
     Referring further to  FIG. 3 , the components and circuitry housed in the outer case  66  may comprise stimulation circuitry  68 , control circuitry  70 , communication circuitry  72 , memory  74 , and sensing circuitry  76 . The stimulation circuitry  68 , control circuitry  70 , communication circuitry  72 , memory  74 , and sensing circuitry  76  may be conveniently mounted on a printed circuit board (PCB) (not shown). 
     In one embodiment, the sensing circuitry  76  comprises one or more sensor(s) (not shown) that are contained in the outer case  66 , although in alternative embodiments, the sensor(s) may be affixed to the exterior of the outer case  66 . In other alternative embodiments, the sensor(s) can be positioned at a site remote from the IPG  52  coupled by a connecting lead, e.g., as described in U.S. patent application Ser. No. 15/093,495, filed on Apr. 7, 2016, entitled “Upper Airway Stimulator Systems for Obstructive Sleep Apnea,” which is expressly incorporated herein by reference in its entirety. 
     The sensing circuitry  76  can detect physiological artifacts that are caused by respiration (e.g., motion or ribcage movement), which are proxies for respiratory phases, such as inspiration and expiration or, if no movement occurs, to indicate when breathing stops. For example, the sensing circuitry  76  may sense movement of the thoracic cavity and/or detect changes in pressure/force in the thoracic cavity. Thus, the sensing circuitry  76  is configured for acquiring, conditioning, and processing signals related to respiration. The sensor(s) of the sensing circuitry  76  can take the form of, e.g., inertial sensors (e.g., accelerometers), bioimpedance sensors, pressure sensors, gyroscopes, ECG electrodes, temperature sensors, GPS sensors, or some combination thereof. 
     The stimulation circuitry  68  is coupled to the nerve cuff electrode  10  via the lead body  60 , and is configured for delivering stimulation to the HGN trunk  14 . The control circuitry  70  is coupled to the stimulation circuitry  68  and controls when, and for how long, the stimulation circuitry  68  applies stimulation to the HGN trunk  14 . The control circuitry  70  may also control the intensity of the stimulation applied by the stimulation circuitry  68  to the HGN trunk  14 , e.g., by varying the amplitude, pulse width, or frequency of the stimulation. The control circuitry  70  may select the optimal electrode contact(s) of the nerve cuff electrode  10  used for stimulating the HGN trunk  14 , and in particular, the electrode contacts that stimulate the fascicles of the HGN  14  innervating the genioglossus  18  or geniohyoid  20  protrusor muscles over the fascicles innervating the tongue retractor muscles, e.g., the hyoglossus  26  and styloglossus muscles  28 , as well as the intrinsic muscles of the tongue  16 , thereby preventing or alleviating obstructive apneic events. 
     The memory  74  is configured for storing specific data gathered by the sensing circuitry  76  and programming instructions and stimulation parameters. The control circuitry  70  may recall the sensed data from the memory  74  and analyze it to determine when stimulation should be delivered to synchronize the stimulation delivery with the respiratory cycle. In some embodiments, the sensor data may be analyzed to predict the onset of the next inspiratory phase of the breathing cycle and to deliver stimulation right before, at, or slightly after the predicted onset of the inspiratory phase. 
     Thus, when the patient is in the inspiratory portion of the respiratory cycle—where the patient is breathing in or attempting to breath in, the control circuitry  70  may condition the application of stimulation upon the patient being in this inspiratory phase of respiration, thereby causing anterior displacement of the tongue, and causing the upper airway to remain un-obstructed during inspiration while sleeping. The control circuitry  70  causes the stimulation circuitry  68  to apply stimulation in the form of a train of stimulation pulses during these inspiratory phases of the respiratory cycle (or applying stimulation starting slightly before the inspiration and ending at the end of inspiration), and not the remainder of the respiration cycle, when all other conditions for stimulation are met. The train of stimulus pulses may be set to a constant time duration or it may be adaptive, meaning that duration of the train of pulses can change dynamically based on a predictive algorithm that determines the duration of the inspiratory phase of the respiratory cycle. The communication circuitry  72  is configured for wirelessly communicating transcutaneously (through the patient&#39;s skin) with the clinician programmer  56  and patient programmer  58  using radio frequency (RF) signals, e.g., via an Off The Shelf (OTS) inductive/Bluetooth/MICS radio link. 
     The clinician programmer  56  may be used to program the IPG  52  and query the IPG  52  for status. For example, the clinician programmer  56  can be used to configure certain programs and processes used by the control circuitry  70  in the IPG  52  to determine when the stimulation pulses are to be delivered to electrode contacts of the nerve cuff electrode  10 . The clinician programmer  56  can also be used to program specific stimulus parameters, such as stimulus pulse width, stimulus frequency, duration of a train pulses and pulse amplitude. The amplitude may be expressed in current, for example, milliamperes, or it could be expressed in volts, such as 0.3 volts. The choice between milliamperes or volts to express stimulus amplitude will depend on whether the design of the stimulation circuitry  68  provides stimulus pulses that are constant voltage or constant current. Another important function of the clinician programmer  56  is the ability to select modes of stimulation. For example, the IPG  52  may operate in a monopolar stimulation mode (also sometimes referred to as a “unipolar” mode) and in a bipolar stimulation mode. 
     As used in this present disclosure, a monopolar stimulation mode means that one of the electrode contacts used is at least a portion of the outer case  66  that will function as an indifferent/anode electrode. The indifferent electrode is part of the electrical circuit with at least one electrode contact of the nerve cuff electrode  10  as the active/cathode electrode contact that stimulates the HGN trunk  14 . Generally, that part of the outer case  66  that is acting as the indifferent electrode does not stimulate any tissue or nerve, but merely functions as a return electrode and may be a biocompatible, conductive metal such as a titanium alloy, as discussed above. 
     A bipolar stimulation mode means, for purposes of this disclosure, that the outer case  66  is not part of the stimulation circuit. At least two electrode contacts of the nerve cuff electrode  10  must be selected and will be part of the bipolar mode electrical stimulation circuit. Sometimes a stimulation circuit can have three or even more electrode contacts functioning together. This may also be referred to as “bipolar” stimulation mode even though there are sometimes more than two active electrode contacts in the stimulation circuit. Sometimes a three-electrode contact system may be referred to as a tripolar circuit. For purposes of this disclosure and application, we will consider a three or more electrode-contact stimulation circuit (if it excludes the outer case  66 ) as variants of a bipolar stimulation mode and will be included as within a “bipolar” stimulation mode. The present stimulation system in its various embodiments, thus, may operate in either monopolor or bipolar stimulation modes. 
     In addition to choosing stimulation modes, the clinician programmer  56  also can choose which electrode contacts of the nerve cuff electrode  10  or the indifferent electrode of the outer case  66  are to be in the stimulation circuit. It may be possible, for example, to have three electrode contacts active simultaneously, where a middle electrode contact is delivering a cathodic phase of stimulus pulse, while the two surrounding electrode contacts are anodes in the anodic phase of the stimulus. The clinician programmer  56  may also be able to query the status of the IPG  52  for a number of status functions, such as battery status. Another query may be whether the IPG  52  is in an ON mode or an OFF mode. In the ON mode, the stimulation circuitry  68  within the IPG  52  is enabled and stimulation pulses can be delivered via the selected electrode contact or contacts of the nerve cuff electrode  10 . When the patient is awake, the IPG may be placed automatically or by choice into the OFF position or mode, and the stimulation circuitry  68  is not enabled and no stimulation can occur. 
     The patient programmer  58  offers more limited programming options than the clinician programmer  56 . The patient programmer  58  may provide the option to toggle the IPG  52  into the OFF mode or into the ON mode. Also, the stimulus pulse amplitudes may be adjusted for a limited range of up and down. Often the patient programmer  58 , because of limited functionality, may be in a package or form that is much smaller in size than the clinician programmer  56 . The clinician programmer  56  and patient programmer  58  may take the form of commercial electronic smart devices on which there are installed customized applications for performing the afore-described functions. 
     In an optional embodiment, the IPG  52  may have a magnetic reed switch (not shown) contained within the outer case  66  that can sense a magnetic field from an external magnet. An external magnet may be used to toggle the IPG  52  to the OFF position or alternatively to an ON position. Often, patients may need to undergo an MRI scan. A reed switch in the IPG  52  may make it MRI incompatible. In another embodiment, the IPG may contain a sensor (not shown) that is sensitive to movement, such as an inertial sensor or an accelerometer, and can be toggled between an ON position and an OFF position by tapping the implanted IPG  52 , for example, with the hand; for example, one tap to switch the IPG  52  from an ON position to an OFF position, and one tap to switch the IPG  52  from an OFF position to an ON position. In a particularly preferred embodiment, the IPG  52  can be toggled between an ON position and an OFF position in response to multiple quick successive taps, as opposed to a single tap, which may occur by accidental bumping and cause an inadvertent turn off of the IPG; for example, two taps to switch the IPG  52  from an ON position to an OFF position, and two taps to switch the IPG  52  from an OFF position to an ON position. As a redundancy, the patient programmer  58  or the clinician programmer  56  may also be configured to be able to toggle the IPG  52  from ON to OFF and from OFF to ON. 
     Referring further to  FIGS. 4-6 , the electrode lead  54  will now be described in further detail. The proximal lead connector  62  comprises a linear array of connector contacts  78   a - 78   f  (in this case, six) for connecting to the connector receptacle  64  of the IPG  52  when the proximal lead connector  62  is inserted into the connector receptacle  64 . The nerve cuff electrode  10  comprises a nerve cuff body  80  that is capable of substantially or completely encircling the HGN trunk  14 , and an array of electrode contacts  82   a - 82   f  (in this case, six) affixed to inside of the cuff body  80 , such that when the cuff body  80  encircles the HGN trunk  14 , the electrode contacts  82   a - 82   f  are in contact with the HGN trunk  14 . 
     To facilitate selective activation of the fascicles of the HGN trunk  14  that innervate the protrusor muscles, the electrode contacts  82  are affixed to the cuff body  80  in a manner, such that when the cuff body  80  encircles the HGN trunk  14 , the electrode contacts  82  are circumferentially disposed about the HGN trunk  14 . In this case, the electrode contacts  82  span the cuff body  80  circumferentially around the HGN trunk  14 . 
     Although in some embodiments, the nerve cuff electrode  10  may be operated in a monopolar stimulation mode, requiring that only one electrode contact  82  of the nerve cuff electrode  10  be activated at any given time, as will be described in further detail below, it is desirable that the nerve cuff electrode  10  be operated in a bipolar stimulation mode, requiring that at least two electrode contacts  82  of the nerve cuff electrode  10  be activated at any given time. Although the exemplary nerve cuff electrode  10  comprises six electrode contacts  82   a - 82   f , other nerve cuff electrodes may have two to five electrode contacts  82  or more than six electrode contacts  82 . The preferred range, however, of the numbers of electrode contacts  82  on any particular nerve cuff electrode is between three to eight electrode contacts  82 , so as to surround the circumference of the HGN trunk  14 , and provide a sufficient number of independent electrode channels from which to select and to recruit the protrusor muscles without recruiting the retractor muscles. The connector contacts  78   a - 78   f  are respectively and independently electrically coupled to the electrode contacts  82   a - 82   f  via electrical conductors (not shown), such that the electrode contacts  82   a - 82   f  may be independently activated in either monopolar stimulation mode or bipolar stimulation mode. In the monopolar stimulation mode, one or more of the electrode contacts  82   a - 82   f  will preferably be activated as cathode(s), whereas in the bipolar stimulation mode, one or more of the electrode contacts  82   a - 82   f  will be activated as cathode(s), and one or more other electrode contacts  82   a - 82   f  will be activated as anode(s). 
     The nerve cuff electrode  10  may be manufactured to be self-curling. The material used for the electrode substrate can be typical implantable electrode materials such as silicone, polyurethane or other materials, such as liquid crystal polymers. The material consistency of the formed cuff body  80  should be pliable enough to allow the clinician to unfold the cuff, as shown in  FIG. 5 , and placed around the HGN trunk  14  and to have the nerve cuff electrode  10  curl back around itself, as shown in  FIG. 6 . The substrate material of the nerve cuff body  80 , therefore, should have a memory property to the extent that it will tend to return to its original curled shape. In one advantageous manufacturing process, the nerve cuff electrode  10 , lead body  60 , and proximal lead connector  62  may be constructed of a flexible circuit, as described in U.S. patent application Ser. Nos. 15/634,057 and 15/634,134, both filed on Jun. 27, 2017, and entitled “Nerve Cuff Electrodes Fabricated Using Over-Molded LCP Substrates,” which are expressly incorporated by reference in their entirety. 
     The nerve cuff electrode  10 , as shown, will also have some give, so that when the nerve swells during the inflammatory phase post-surgery, the inner lumen size of the nerve cuff electrode  10  can expand and accommodate to the nerve swelling. This capability of self-adjustment over time is important because once tissue has been dissected from around the nerve, there will be an inflammatory body response around the damaged tissue and also in response to the presence of foreign matter that may be introduced during the surgical implantation of the nerve cuff electrode  10 . Indeed, the nerve cuff electrode  10 , itself, is likely seen as a foreign matter contributing to inflammation. The inflammatory response may be ongoing over a period of months. During this period, the nerve, itself, may swell up and increase substantially in diameter, perhaps up to 50% more than before the surgery. Once past this inflammatory response, the nerve diameter may then decrease in size, closer to its original diameter. If the inner lumen size of the nerve cuff electrode  10  does not adjust in size to accommodate the increase in the nerve diameter, constriction of the target nerve can result in traumatic cell damage and nerve death. Further details describing various self-expanding nerve cuff electrodes are set forth in U.S. patent application Ser. No. 15/967,332, filed on Apr. 30, 2018, entitled “Nerve Cuff Electrode Locking Mechanism,” and U.S. patent application Ser. No. 15/967,468, filed on Apr. 30, 2018, “Self-Expanding Nerve Cuff Electrode,” which claim the benefit of priority to U.S. Provisional Patent Application Ser. No. 62/500,080, filed on May 2, 2017, entitled “Nerve Cuff Electrode Locking Mechanism,” and U.S. Provisional Patent Application Ser. No. 62/500,091, filed on May 2, 2017, entitled “Self-Expanding Nerve Cuff Electrode,” all of which are expressly incorporated herein by reference in their entirety. 
     As briefly discussed above, it is desirable to operate the nerve cuff electrode  10  in a bipolar mode in order to facilitate selective recruitment of the fascicles  15  in the HGN trunk  14 . That is, monopolar stimulation results in a more diffuse electrical field that will tend to recruit most fascicles  15  in the HGN trunk  14 , whereas bipolar stimulation results in a more specific and confined electrical field that will tend to recruit less non-targeted fascicles  15  in the HGN trunk  14 . Thus, the fascicles  15  in the HGN trunk  14  that innervate the tongue protrusor muscles can be more selectively activated via bipolar stimulation. Because the electrode contacts  82  will circumferentially surround the HGN trunk  14 , the electrical field generated by the nerve cuff electrode  10  in the bipolar stimulation mode can be selectively steered around the HGN trunk  14  to recruit the desired fascicles  15  within the HGN trunk  14 . It is further noted that, because the fascicles  15  innervating the tongue protrusor muscles are peripherally located at the proximal position  20  to the HGN branches  18 , it is desirable that adjacent electrode contacts  82  can be activated in the bipolar arrangement, such that the electrical field extends only peripherally into the HGN trunk  14 . Thus, with reference to  FIG. 6 , it may be desirable to activate electrode contact pair  82   a - 82   b , electrode contact pair  82   b - 82   c , electrode contact pair  82   c - 82   d , electrode contact combination  82   d - 82   e , electrode contact combination  82   e - 82   f , or electrode combination  82   f - 82   a . As shown in  FIG. 6 , electrode combination  82   a - 82   b  are shown to be activated to create a confined bipolar electrical field therebetween that recruits one or more of the peripherally located fascicles  15   a , as opposed to recruiting the centrally located fascicles  15   b . Of course, any of the other electrode combinations can be operated in a bipolar manner to recruit other peripherally located fascicles  15   a . The first one of the electrode contacts  82  in the combination can be a cathode, and the second one of the electrode contacts  82  in the combination can be an anode, or vice versa. 
     Notably, the strongest electrical field generated by the nerve cuff electrode  10  will be beneath an active an active electrode contact/cathode. Thus, in order to effectively employ bipolar stimulation, the nerve cuff electrode  10  may have the following design constraint: L≤2 W, where W is the width of each electrode contact  82 , and L is the center-to-center distance between two adjacent electrode contacts  82 , as illustrated in  FIG. 5 . This constraint is based on the commercial needs in neuromodulation therapies to cover the most distance with spatial separations L and using the fewest number of electrode contacts  82 . The width of the electrode contacts  82  will typically be based on the particular neural element that will be stimulated or the size of the cuff body  80 , or a combination thereof, and will set the strength ranges of the electric fields generated by the nerve cuff electrode  10 . As the center-to-center distance L exceeds the L≤2 W design constraint, the electric field generated by a bipolar pair of electrode contacts  82  quickly starts to resemble a monopolar electric field as if there as a remote anode (unless there is a dramatic increase in the electric field amplitude). The ability of perform current steering between two or more adjacent electrode contacts  82  also weakens. In contrast, if adjacent electrode contacts  82  are too close or touching each other, there may be bleeding of electrical fields across the active contacts  82  at a higher amplitude, thereby creating a short that changes the ability to spatially select fascicles. Thus, it is important that the center-to-center distance L between adjacent electrode contacts  82  and the width W of the electrode contacts  82  be constrained. 
     However, because the size of the HGN  12  varies within the human population (e.g., between 2.5 mm and 4.00 mm), the effective distance between the electrode contacts  82   a ,  82   f  of a nerve cuff electrode  10  when wrapped around a HGN trunk  14  may vary with the size of the HGN trunk  14 , thereby requiring nerve cuff electrodes to be made in different sizes. 
     For example, as shown in  FIGS. 7 a -7 c   , the distance between the electrode contacts  82   a ,  82   f  (shown to have widths W of 0.8 mm) will increase as the diameter of the HGN trunk  14  increases from 3.0 mm to 3.8 mm. However, it is desirable that the distance between the electrode contacts  82   a ,  82   f  be maintained in accordance with the L≤2W design constraint to ensure that bipolar stimulation using the electrode contacts  82   a ,  82   f  is effective. As illustrated in  FIG. 7 a   , the distance between electrode contacts  82   a ,  82   f  complies with the L≤2 W design constraint. That is, the center-to-center distance L a-f  between the electrode contacts  82   a ,  82   f  is shown to be 0.7 mm when the diameter of the HGN trunk  14  is 3.0 mm, thereby complying with the L≤2 W design constraint (0.7 is less than (2×0.8). However, as illustrated in  FIGS. 7 b  and 7 c   , the distance between electrode contacts  82   a ,  82   f  violates the L≤2 W design constraint, thereby causing the nerve cuff electrode  10  to have a “dead spot” between the electrode contacts  82   a ,  82   f  that would not be effective in bipolar stimulation. That is, the center-to-center distance L a-f  between the electrode contacts  82   a ,  82   f  is shown to be 2.0 mm when the diameter of the HGN trunk  14  is 3.4 mm, thereby violating the L≤2 W design constraint (2.0 is greater than (2×0.8)), and the center-to-center distance L a-f  between the electrode contacts  82   a ,  82   f  is shown to be 3.3 mm when the diameter of the HGN trunk  14  is 3.8 mm, thereby violating the L≤2 W design constraint (3.8 is greater than (2×0.8)). 
     In order to prevent the occurrence of a blind spot between the electrode contacts  82 , and because there is variation in HGN nerve diameters, in the operating room, many different sizes of nerve cuff electrodes would need to be readily available to the surgeon. For example, in order to cover the range of HGN nerve sizes in the general population, at least five different sizes of nerve cuff electrodes would have to be fabricated and supplied to the surgeon in the operating room. Unused nerve cuff electrodes, opened during surgery, may need to be discarded, thereby increasing the cost of the surgical procedure. Furthermore, a surgeon will have to measure every HGN size to determine the right size of the nerve cuff electrode to be placed onto the HGN, which increases the time in the operating room. Measuring the HGN size requires very delicate work and can be quite subjective as well. Hence, the process is not only cumbersome and prone to error, but most importantly, poses the risk of damaging the HGN during the process to precisely measure the HGN. 
     In accordance with the present inventions, one embodiment of a nerve cuff electrode  10 ′ accommodates a large range of HGN sizes without creating blind spots, thereby eliminating the need to fabricate differently sized nerve cuff electrodes. In this embodiment, the array of electrode contacts  82  is disposed on the cuff body  80 , and the cuff body  80  is pre-shaped to, in the absence of an external force, transition from an unfurled state ( FIG. 8 ) to a furled state ( FIG. 9 ). In one embodiment, the cuff body  80  will automatically transition from the unfurled state to the furled state in response to merely removing an external force from the cuff body  80 . In another embodiment, the cuff body  80  is pre-shaped to curve in two orthogonal directions (along a lateral axis and a longitudinal axis), such that the cuff body  80  has a bi-stable structure. In this embodiment, an external force must be exerted on the cuff body  80  to transition it between the unfurled and furled state. Further details describing a bi-stable cuff body  80  are set forth in U.S. patent application Ser. No. 15/634,057, filed on Jun. 27, 2017, entitled “Nerve Cuff Electrodes Fabricated Using Over-Molded LCP Substrates,” and Ser. No. 15/634,134, filed on Jun. 27, 2017, entitled “Nerve Cuff Electrodes Fabricated Using Over-Molded LCP,” which have been expressly incorporated by reference. 
     In the unfurled state, all pairs of adjacent electrode contacts  82  (i.e.,  82   a - 82   b ,  82   b - 82   c ,  82   c - 82   d ,  82   d - 82   e , and  82   e - 82   f ) nominally comply with L≤2 W design constraint. In the furled state, the cuff body  80  has an inner surface  84  capable of contacting the HGN trunk  14 , as well as an overlapping inner cuff region  86   a  and outer cuff region  86   b . Furthermore, when the cuff body  80  is in the furled state, the electrode contacts  82  are circumferentially disposed along the cuff body  80 , such that at least one of the electrode contacts  82  is located on the inner surface  84  of the cuff body  80 , and at least another one of the electrode contacts  82  is disposed between the overlapping inner and outer cuff regions  86   a ,  86   b . Since the nominal distances between the respective pairs of adjacent electrode contacts  82   a - 82   b ,  82   b - 82   c ,  82   c - 82   d ,  82   d - 82   e , and  82   e - 82   f  are fixed and therefore will not change, it is expected that these distances will comply with the L≤2 W design constraint when the cuff body  80  is in the furled state, and will therefore, provide effective bipolar stimulation as long as the respective electrode contact pairs are in contact with the HGN trunk  14 . However, as will be described in further detail below, the distance between the electrode contact  82   a  and the electrode contact  82   f  will vary in accordance with the diameter of the HGN trunk  14 . 
     Although only one electrode contact, and in this case the electrode contact  82   f , is shown as being disposed between the overlapping inner and outer cuff regions  86   a ,  86   b  in  FIG. 9 , more than one electrode contact  82  may be disposed between the overlapping inner and outer cuff regions  86   a ,  86   b . The number of electrode contacts  82  that are disposed between the overlapping inner and outer cuff regions  86   a ,  86   b  when the cuff body  80  is in the furled state can be selected by selecting the number of electrode contacts  82  and/or the nominal center-to-center distances between adjacent electrode contacts  82 . That is, the number of electrode contacts  82  that are disposed between the overlapping inner and outer cuff regions  86   a ,  86   b  will tend to increase as the number of electrode contacts  82  increases and/or the nominal center-to-center distance between adjacent electrode contacts  82  increases. In the example shown in  FIGS. 8 and 9 , the number of electrode contacts  82  relative to the embodiment shown in  FIGS. 5 and 6  remains the same (i.e., six total), but the nominal center-to-center distance L between adjacent electrode contacts  82  have been increased, resulting in one electrode contact  82  being disposed between the overlapping inner and outer cuff regions  86   a ,  86   b  when the cuff body  80  is in the furled state. Of course, if the nominal center-to-center distance L between adjacent electrode contacts  82  is increased and/or the number of electrode contacts  82  is increased, additional electrode contacts  82  may be disposed between the overlapping inner and outer cuff regions  86   a ,  86   b  when the cuff body  80  is in the furled state. 
     Advantageously, the nerve cuff electrode  10 ′ is capable of being used with differently sized HGN trunks  14  while still complying with the L≤2 W design constraint for all pairs of adjacent electrode contacts  82  that are in contact with the HGN trunk  14 . In particular, the extent that the cuff body  80  furls will adjust in accordance with the diameter of the HGN trunk  14 , such that one of the set of electrode contacts  82  at the end of the array of electrode contacts  82  (in this case, either the electrode contact  82   e  or the electrode contact  82   f ) will be in contact with the HGN trunk  14  adjacent to the next electrode contact  70  adjacent to this electrode contact  70  (in this case, the electrode contact  82   e  or the electrode contact  70   d ) in compliance with the L≤2 W design constraint. 
     For example, as shown in  FIGS. 10 a -10 c   , for smaller diameter HGN trunks  14 , the electrode contact  82   f  will be located between the overlapping inner and outer cuff regions  86   a ,  86   b , but the next electrode contact  82   e  will be in contact with the HGN trunk  14  in a bipolar relationship with the electrode contact  82  in compliance with the L≤2 W design constraint. However, as the diameter of the HGN trunk  14 , the cuff body  80  will partially unfurl, causing the electrode contact  82   f  to be displaced from between the overlapping inner and outer cuff regions  86   a ,  86   b  to a position that is contact with the HGN trunk  14  in a bipolar relationship with the electrode contact  82  in compliance with the L≤2 W design constraint. 
     Thus, as illustrated in  FIG. 10 a   , the electrode contact  82   f  is between the overlapping inner and outer cuff regions  86   a ,  86   b , such that it does not contact the HGN trunk  14 . However, the electrode contact  82   e  is in contact with the HGN trunk  14  in a bipolar relationship with electrode contact  82   a . The center-to-center distance L a-e  between the electrode contacts  82 ,  82   e  is shown to be 0.7 mm when the diameter of the HGN trunk  14  is 3.0 mm, thereby complying with the L≤2 W design constraint (0.7 is less than (2×0.8)). As illustrated in  FIG. 10 b   , as the cuff body  80  partially unfurls due to the increased diameter of the HGN trunk  14 , the electrode contact  82   f  is not between the overlapping inner and outer cuff regions  86   a ,  86   b , but instead is in contact with the HGN trunk  14  in a bipolar relationship with electrode contact  82 . The center-to-center distance L a-f  between the electrode contacts  82   a ,  82   f  is shown to be 0.7 mm when the diameter of the HGN trunk  14  is 3.4 mm, thereby complying with the L≤2 W design constraint (0.7 is less than (2×0.8)). As illustrated in  FIG. 10 c   , as the cuff body  80  further partially unfurls due to the increased diameter of the HGN trunk  14 , the center-to-center distance L a-f  between the electrode contact  82   f  and the electrode contact  82   a  increases. However, the center-to-center distance L between the electrode contacts  82   a ,  82   f  is shown to be 1.6 mm when the diameter of the HGN trunk  14  is 3.8 mm, thereby complying with the L≤2 W design constraint (1.6 is equal to (2×0.8)). 
     It should be appreciated that if it is desired to increase the range of diameter size of the HGN trunk  14  with which the nerve cuff electrode  10 ′ used, such nerve cuff electrode  10 ′ can be designed, such that more than one electrode contact  82  will be disposed between the overlapping inner and outer cuff regions  86   a ,  86   b  for the smallest designed diameter of the HGN trunk  14 . For example, the number of electrode contacts  82  may be increased (e.g., from six to seven) or the cuff body  80  may be pre-shaped to have a smaller diameter in the absence of an external force. 
     Having described the structure and function of the nerve cuff electrode  10 ′, one method  100  of implanting the nerve cuff electrode  10 ′ in a patient will now be described with reference to  FIG. 11 . First, the cuff body  80  is maintained in the unfurled state ( FIG. 8 ) while placing the cuff body  80  in contact with the HGN trunk  14  (step  102 ). For example, the unfurled cuff body  80  may be placed underneath the HGN trunk  14 . The cuff body  80  may be maintained in the unfurled state by, e.g., applying an external force to the cuff body  80  to prevent it from transitioning to the furled state, or if the cuff body  80  has a bi-stable structure, the cuff body  80  may be maintained in the unfurled state by not applying an external force to transition it to the furled state. 
     Next, the cuff body  80  is transitioned from the unfurled state into the furled state, such that the cuff body  80  wraps around the HGN trunk  14  (step  104 ). The cuff body  80  may be placed from the unfurled state into the furled state by, e.g., merely removing the external force from the cuff body  80 , such that the cuff body  80  automatically transitions from the unfurled state to the furled state, or if the cuff body  80  has a bi-stable structure, an external force may be exerted on the cuff body  80  to transition it from the unfurled state to the furled state. 
     If the size of the HGN trunk  14  is relatively small, the cuff body  80  may wrap upon itself, as shown in  FIG. 10 a   . In this case, there exists an inner surface  84  that contacts the HGN trunk  14  and an overlapping inner cuff region  86   a  and an outer cuff region  86   b , and the electrode contacts  82  that are on the inner surface  84  of the cuff body  80  is contact with the HGN trunk  14 , and at least another of the electrode contacts  82  is between the inner and outer overlapping regions  86   a ,  86   b  of the cuff body  80  without contacting the HGN trunk  14 . If the size of the HGN trunk  14  is relatively large, the cuff body  80  may be prevented from wrapping upon itself, as shown in  FIGS. 10 b  and 10 c   . In this case, all electrode contacts  82  will be in contact with the HGN trunk  14 . In all cases, the center-to-center spacing L of each respective pair of adjacent electrode contacts  82  is equal to or less than twice the width W of each electrode contact  82  of the respective pair of adjacent electrode contacts  82 . 
     Next, the IPG  52  is implanted within the patient (step  106 ), and the proximal lead connector  62  is mated with the receptacle  64  of the IPG  52  (step  108 ). Next, electrical stimulation energy is delivered to a pair of adjacent ones of the electrode contacts  82  to stimulate the HGN trunk  14  in a bipolar mode, and preferably, the fascicles of the HGN trunk  14  innervating the tongue protrusor muscles (step  110 ). Step  110  can be repeated for different pair of electrode contacts  82  to find the optimal electrode contact pairs in a fitting procedure. Lastly, the IPG  52  is programmed with the optimal electrode contact pair(s) using the clinician programmer  56  (step  112 ). 
     Although particular embodiments of the present inventions have been shown and described, it will be understood that it is not intended to limit the present inventions to the preferred embodiments, and it will be obvious to those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the present inventions. Thus, the present inventions are intended to cover alternatives, modifications, and equivalents, which may be included within the spirit and scope of the present inventions as defined by the claims.