AU2016202615B2 - Pacemaker for Unilateral Vocal Cord Autoparalysis - Google Patents

Abstract

A method of treating a human subject having unilateral vocal cord autoparalysis, the method comprising: providing a stimulating electrode configured to directly contact a recurrent laryngeal nerve or vagus nerve of the subject; sensing electrical activity of a synkinetically reinnervated dysfunctional muscle of the subject; generating at least one stimulation parameter, using a processor, based on the sensed electrical activity; and stimulating the recurrent laryngeal nerve or vagus nerve, using the stimulating electrode, based on the at least one stimulation parameter. A stimulation system is also provided. VOCAL CORD OPENING TETANIC ADDUCTOR CONTRACTION 60hZ 90 50hZ 30hZ 20hZ 10hZ 0 -v - t(ms) VOCAL CORD CLOSING SINGLE TWITCH ADDUCTION 60hZ 80hZ 90hZ 100hZ TETANIC ADDUCTOR CONTRACTION

Description

PACEMAKER FOR UNILATERAL VOCAL CORD AUTOPARALYSIS 2016202615 20 Sep 2016

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application is divided from Australian Patent Application No. 2015221540 filed 4 September 2015, itself divided from Australian Patent Application No. 2012347519 filed 7 December 2012, which claims priority to U.S. Provisional Patent Application No. 61/567,664 filed 7 December 2011, U.S. Provisional Patent Application No. 61/567,666 filed 7 December 2011, U.S. Patent Application No. 13/708,129 filed 7 December 2012 and U.S. Patent Application No. 13/708,146 filed 7 December 2012, the disclosures of which are incorporated by reference herein in their entirety. Australian Patent Application No. 2015221540 also claims priority to U.S. Patent Application No. 14/703,486 filed 4 May 2015, the disclosure of which is also incorporated by reference herein in its entirety.

TECHNICAL FIELD

[0002] The present invention relates to the treatment of spasmodic dysphonia, and in particular, to devices and methods for stimulating the recurrent laryngeal nerve (RLN) or the glottic closure reflex of a human subject to treat the spasmodic dysphonia

BACKGROUND ART

[0003] Voicing occurs when air is expelled from the lungs through the glottis, creating a pressure drop across the larynx. When this drop becomes sufficiently large, the vocal folds start to oscillate. The minimum pressure drop required to achieve phonation is called the phonation threshold pressure, and for humans with normal vocal folds, it is approximately 2-3 cm H20. The motion of the vocal folds during oscillation is mostly laterally, though there is also some superior component as well. However, there is almost no motion along the length of the vocal folds. The oscillation of the vocal folds serves to modulate the pressure and flow of 1 8215113_1 (GHMatters) P07141.AU.2 20/09/2016 the air through the larynx, and this modulated airflow is the main component of the sound of most voiced phones. 2016202615 26 Apr 2016 [0004] The vocal folds will not oscillate if they are not sufficiently close to one another, are not under sufficient tension or under too much tension, or if the pressure drop across the larynx is not sufficiently large. In linguistics, a phone is called voiceless if there is no phonation during its occurrence. In speech, voiceless phones are associated with vocal folds that are elongated, highly tensed, and placed laterally (abducted) when compared to vocal folds during phonation.

[0005] Fundamental frequency, the main acoustic cue for the percept pitch, can be varied through a variety of means. Large scale changes are accomplished by increasing the tension in the vocal folds through contraction of the cricothyroid muscle. Smaller changes in tension can be effected by contraction of the thyroarytenoid muscle or changes in the relative position of the thyroid and cricoid cartilages, as may occur when the larynx is lowered or raised, either volitionally or through movement of the tongue to which the larynx is attached via the hyoid bone. In addition to tension changes, fundamental frequency is also affected by the pressure drop across the larynx, which is mostly affected by the pressure in the lungs, and will also vary with the distance between the vocal folds. Variation in fundamental frequency is used linguistically to produce intonation and tone.

[0006] The voicing mechanism that is specifically designed for voice production is the larynx. The larynx is between the pharynx and the trachea. It communicates with the mouth and the nose though the laryngeal and oral parts of the pharynx. Although the larynx is part of the air passages, the larynx normally acts as a valve for preventing swallowed food and foreign bodies from entering the lower respiratory passages. The larynx is located in the anterior portion of the neck.

[0007] The laryngeal skeleton comprises nine cartilages that are joined by various ligaments and membranes. Three of the cartilages are single (thyroid, cricoid and epiglottis), 2 7670913.1 (GHMatters) P97141.AU.2 26/04/2016 and three are paired (arytenoid, comiculate, and cuneiform). 2016202615 26 Apr 2016 [0008] The extrinsic muscles of the larynx move the larynx as a whole. The infrahyoid muscles (omohyoid, sternohyoid, and sternothyroid) are depressors of the hyoid bone and the larynx, whereas the suprahyoid muscles (stylohyoid, digastric, mylohyoid and geniohyoid) and the stylopharyngeus are elevators of the hyoid bone and larynx.

[0009] The intrinsic muscles of the larynx are concerned with the movements of the laryngeal parts, making alterations in the length and tension of the vocal folds and in the size and shape of the rima glottidis in voice production. All intrinsic muscles of the larynx are supplied by the recurrent laryngeal nerve (RLN), a branch of the vagus nerve (CN X) except the cricothyroid muscle, which is supplied by the external laryngeal nerve.

[0010] The adductors of the vocal folds include the lateral cricoarytenoid muscles which arise from the lateral portions of the cricoid cartilage and insert into the muscular processes or the arytenoid cartilages. These muscles pull the muscular processes anteriorly, rotating the arytenoid cartilages so that their vocal processes swing medially. These movements adduct the vocal folds and close the rima glottidis.

[0011] The principle abductors of the vocal folds are the posterior cricoarytenoid muscles. These muscles arise on each side from the posterior surface of the lamina of the cricoid cartilage and pass laterally and superiorly to insert into the muscular processes of the arytenoid cartilages. They rotate the arytenoid cartilages, thereby deviating them laterally and widening the rima glottidis.

[0012] The main tensors of the vocal folds are the triangular cricothyroid muscles. These are located on the external surface of the larynx between the cricoid and thyroid cartilages. The muscle on each side arises from the anterolateral part of the cricoid cartilage and inserts into the inferior margin and anterior aspect of the inferior horn of the thyroid cartilage. These muscles tilt the thyroid cartilage anteriorly on the cricoid cartilage, increasing the distance between the thyroid and arytenoid cartilages. As a result, the vocal ligaments are 3 7670913_1 (GHMatters) P97141.AU.2 26/04/2016 elongated and tightened and the pitch of the voice is raised. 2016202615 26 Apr 2016 [0013] The principle relaxers of the vocal folds are the broad thyroarytenoid muscles. They arise from the posterior surface of the thyroid cartilage near the median plane and insert into the anterolateral surfaces of the arytenoid cartilages. One band of its inferior deep fibers, called the vocalis muscle, arises from the vocal ligament and passes to the vocal process of the arytenoid cartilages anteriorly. The thyroarytenoid muscles pull the arytenoid cartilages anteriorly, thereby slackening the vocal ligaments. The vocalis muscles produce minute adjustments of the vocal ligaments (e.g., as occurs during whispering). They also relax parts of the vocal folds during phonation and singing.

[0014] The laryngeal nerves are derived from the vagus nerve (CN X) through the superior laryngeal nerve and the RLN. All intrinsic muscles, except cricothyroid, are innervated by the RLN with fibers from the accessory nerve (CN XI). The external laryngeal nerve supplies the cricothyroid muscle. The supraglottic portion of the laryngeal mucosa is supplied by the internal laryngeal nerve, a branch of the superior laryngeal nerve. The infraglottic portion of the laryngeal mucosa is supplied by the RLN.

[0015] Dystonia is a movement disorder that can affect a single muscle group or the entire body. Dystonia is typically characterized by sustained muscular contraction that is forceful and inappropriate. Although dystonia has been linked to malfunction in certain areas of the brain, such as the basal ganglia, the precise cause of the disease remains unknown. Dystonias are generally classified into two groups, generalized and focal. Generalized (non-focal) dystonia involves a large number of muscle groups. Focal dystonia involves a single muscle group. The most common types of focal dystonia are blepharospasm, torticollis, writer's cramp, and laryngeal. Laryngeal dystonia, also called spasmodic dysphonia, is a focal, primary dystonia, affecting the muscles of the larynx.

[0016] Spasmodic dysphonia is an extremely disabling form of dystonia that is often misdiagnosed. Patients with spasmodic dysphonia have severely diminished vocal capacity. 4 7670913_1 (GHMatters) P97141.AU.2 26/04/2016

The voice can range from strangled and pressed to breathy and barely perceptible. 2016202615 26 Apr 2016

SUMMARY

[0017] In accordance with one embodiment of the invention, there is provided a method of treating a human subject having unilateral vocal cord autoparalysis, the method comprising: providing a stimulating electrode configured to directly contact a recurrent laryngeal nerve or vagus nerve of the subject; sensing electrical activity of a synkinetically reinnervated dysfunctional muscle of the subject; generating at least one stimulation parameter, using a processor, based on the sensed electrical activity; and stimulating the recurrent laryngeal nerve or vagus nerve, using the stimulating electrode, based on the at least one stimulation parameter.

[0018] In related embodiments, the stimulating electrode may be configured to sense the electrical activity of the synkinetically reinnervated dysfunctional muscle. The stimulating electrode may be configured to be central to an insertion point of the recurrent laryngeal nerve or vagus nerve into innervated muscle; central to the insertion point may be where the recurrent laryngeal nerve passes an aortic arch. The synkinetically reinnervated dysfunctional muscle may be a vocalizing muscle that opens or closes a vocal fold; the vocalizing muscle may be selected from the group consisting of thyroarytenoid muscles, vocalis muscles, posterior cricoarytenoid muscle, lateral cricoarytenoid muscles, and combinations thereof.

[0019] Additionally, stimulating the recurrent laryngeal nerve or vagus nerve may stimulate the abductor muscle. Stimulating the recurrent laryngeal nerve or vagus nerve may stimulate the adductor muscles. Stimulating the recurrent laryngeal nerve or vagus nerve may stimulate the abductor muscle and the adductor muscles.

[0020] Sensing may include detecting electromyographic (EMG) activity of a vocalizing muscle, detecting movement related to voice production, or both. The method may further comprise: determining when the sensed electrical activity has reached a predetermined 5 7670913_1 (GHMatters) P07141.AU.2 26/04/2016 level; and generating the at least one stimulation parameter when the predetermined level is reached. 2016202615 26 Apr 2016 [0021] The method may further comprise activating a glottic closure reflex, using the stimulating electrode, based on the at least one stimulation parameter. The method may further comprise activating a glottic closure reflex based on the at least one stimulation parameter, wherein activating includes electrical stimulation, mechanical stimulation, or a combination thereof.

[0022] The at least one stimulation parameter may include a stimulation voltage that is above a threshold for activation of vocal cord adductor muscles of the subject and below a threshold for activation of vocal cord abductor muscles of the subject. The at least one stimulation parameter may include a stimulation voltage that is above a threshold for activation of vocal cord adductor muscles of the subject and above a threshold for activation of vocal cord abductor muscles of the subject.

[0023] In accordance with another embodiment of the invention, there is provided a stimulation system for a human subject having unilateral vocal cord autoparalysis, the system comprising: a stimulating electrode configured to directly contact a recurrent laryngeal nerve or vagus nerve of the subject and configured to sense electrical activity of a synkinetically reinnervated dysfunctional muscle of the subject; and a processor configured to receive the sensed electrical activity of the synkinetically reinnervated dysfunctional muscle and configured to generate at least one stimulation parameter based on the sensed electrical activity, the stimulating electrode configured to stimulate the recurrent laryngeal nerve or vagus nerve of the subject based on the at least one stimulation parameter.

[0024] In related embodiments, the processor is configured to detect when the sensed electrical activity has reached a predetermined level and configured to generate the at least one stimulation parameter when the predetermined level is reached. The stimulation system may further comprise a manual activator configured to cause the processor to generate the at least 6 7670913.1 (GHMatters) P97141.AU.2 26/04/2016 one stimulation parameter. 2016202615 26 Apr 2016 [0025] The stimulating electrode may be a nerve cuff electrode, a rod electrode, or combinations thereof. The stimulating electrode may be configured to be around the recurrent laryngeal nerve or vagus nerve, configured to be fixed to the recurrent laryngeal nerve or vagus nerve, configured to be inserted into the recurrent laryngeal nerve or vagus nerve, or combinations thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The invention and its foregoing features will be more readily understood by reference to the following detailed description of exemplary embodiments, taken with reference to the accompanying drawings, in which: [0027] FIG. 1 is a graphical illustration of the underlying principle of frequency-dependent movement of the vocal cords in accordance with an embodiment of the present invention; [0028] FIG. 2 is a graphical illustration of the frequency-dependent motion of the vocal cords in accordance with the embodiment of FIG. 1; [0029] FIG. 3 is an illustration of a stimulation system for spasmodic dysphonia, in accordance with an embodiment of the invention, and FIG. 3A is an exploded view of the circled region in FIG. 3; [0030] FIG. 4 is a flow chart illustrating a method for stimulating a vocalizing nerve in a human subject having spasmodic dysphonia in accordance with an embodiment of the invention; [0031] FIG. 5 is a flow chart illustrating a method for pacing laryngeal activity of a human subject having spasmodic dysphonia in accordance with an embodiment of the invention; and 7 7670913_1 (GHMatters) P07141.AU.2 26/04/2016 [0032] FIG. 6 is a flow chart illustrating a method for pacing laryngeal activity of a human subject using a manual activator in accordance with an embodiment of the invention. 2016202615 26 Apr 2016

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0033] Spasmodic dysphonia is a central disease in which muscle spindles residing within the adductor and abductor muscles normally “report” to the brain the voltage state of their respective muscular tissue by use of afferent nerve signals. If these spindles are damaged or impaired they “report” the wrong signals and, consequently, the brain sends wrong nerve signals back, by use of efferent nerve fibers, to the peripheral anatomical structures, the adductor and abductor muscles. Typically, the impairment causes a spasm-like behavior of the vocal folds, e g., like stuttering. Thus, even though the nerve and corresponding muscle are functional and intact, the end result is that both vocal folds are closed spasm-like.

[0034] There are two prominent types among a variety of different forms of spasmodic dysphonia: abductory spasmodic dysphonia and adductory spasmodic dysphonia. In abductory spasmodic dysphonia a spasm-like behavior of the abductor muscles occurs whereas in adductory spasmodic dysphonia a spasm-like behavior of the adductor muscles occurs.

[0035] Embodiments of the present invention recognized the benefit of treating spasmodic dysphonia by stimulating the RLN or vagus nerve or by activating the glottic closure reflex by electrical and/or mechanical stimulation in order to selectively activate the abductor muscle, the adductor muscles or both. The advantages of nerve stimulation or reflex activation over intramuscular stimulation are less interference of the stimulation electrode from movement of the muscle, the placement of the implanted electrode is distant from the risky, delicate location of nerve muscle endplates, less invasive surgery is required for implanting the stimulation electrode, etc.

[0036] The benefits of using embodiments of the present invention allow the opening and closing of the vocal folds to be activated by the same stimulation electrode based on the 8 7670913_1 (GHMatters) P07141.AU.2 26/04/2016 stimulation parameters selected due to the differences between the abductor (the opener) and the adductor (the closer) muscles (e.g., frequency-dependent, different thresholds or difference of net forces of adductor and abductor muscles). Exploiting these differences allows for a stimulation system that provides for the selective activation of vocal fold closing muscles, without activation of vocal fold opening muscles, the selective activation of vocal fold opening muscles, without activation of vocal fold closing muscles, and/or the tensioning of vocal folds by graded balanced activation of both opening and closing muscles. In addition, activation of the vocal folds closure has the effect of (1) glottis closure during episodes of abductory spasmodic dysphonia and glottis opening during episodes of adductory spasmodic dysphonia, (2) reducing the spasmodic effects by conditioning/relaxing activation of the spasmodic muscle, and (3) reducing the spasmodic effects by inhibiting spasmodic muscle by activating the (non-spasmodic) antagonistic muscle of the spasmodic muscle. 2016202615 26 Apr 2016 [0037] Embodiments of the present invention are directed to a system and method of sensing the vocal activity of a vocalizing muscle contraction in the larynx and/or pharynx and stimulation of the RLN or vagus nerve innervating the vocalizing muscle, e.g., without the electrical stimulation of the muscle fibers directly, based on the sensed activity. This would allow the surgeon to choose the optimum accessibility to the nerve. In contrast, US Patent No. 5,111,814 by Goldfarb, incorporated herein by reference, teaches sensing of electrical activity of normally functioning muscle tissue and stimulating of reinnervated muscle tissue of the larynx.

[0038] Embodiments of the present invention are also directed to a system and method of sensing the vocal activity of a vocalizing muscle contraction in the larynx and/or pharynx and activating the glottic closure reflex. This reflex may be activated by stimulation of a nerve, such as the superior laryngeal nerve, the internal or external superior nerve, and/or the glossopharyngeal nerve. It may also be elicited by stimulating mechanoreceptors and/or mucosa of the larynx and/or pharynx, or by the slap reflex. Stimulation may occur by electric 9 7670913_1 (GHMatters) P97141.AU.2 26/04/2016 currents and/or by mechanical movement or vibration. This variety of stimulation sites may allow a surgeon to choose the optimum treatment for the patient. The glottic closure reflex, in turn, activates the natural fiber tissue which innervates the vocalizing muscles that control the closure of the vocal folds. 2016202615 26 Apr 2016 [0039] In spasmodic dysphonia, it may be beneficial to stimulation the RLN or vagus nerve and to activate the glottic closure reflex at the same time. For example, the RLN or vagus nerve may stimulate the opening muscles while the glottic closure reflex activates the closing muscles. Operating both systems at the same time might allow for better control of the counteracting signals. In addition, mechanical stimulation of the glottic closure reflex and electrical stimulation of the RLN or vagus nerve may be advantageous in order to avoid interference of two electrical stimulation signals. However, electrical stimulation of both the glottic closure reflex and RLN may be used because the locations of stimulation are separated. In either case, two stimulators may be used, e.g., one for electrical stimulation (e.g., stimulation electrode) and one for mechanical stimulation (e.g., mechanical actuator).

[0040] In some embodiments, the system and method may further include a sensing electrode configured to sense the electrical activity of a vocalizing muscle contraction in the larynx and/or pharynx and stimulating the RLN or vagus nerve innervating the vocalizing muscle, or activating the glottic closure reflex, based on the sensed activity. In this case, the glottis is closed by active electrical sensing/stimulation or electrical sensing and electrical/mechanical stimulation in order to increase the quality of the voice. In contrast, US Patent No. 5,111,814 is employed to stimulate muscles which open the glottis in order to increase the amount of inspired air. Similarly, US Patent Publication No. 2006/282127 by Zealear, incorporated herein by reference, is employed to open the vocal folds for the same reason. Thus, embodiments of the present method and device are directed to the sensing activity of vocalizing muscle contraction and not respiratory muscle contraction as, e.g., in US

Patent Publication No. 2006/282127 by Zealear. 10 7670913_1 (GHMatters) P07141.AU.2 26/04/2016 [0041] In some embodiments, a manual activator may be used, rather than a sensing electrode, that senses a vocalizing muscle contraction. The manual activator activates the RLN, the vagus nerve, or glottic closure reflex, e.g., by causing stimulation parameters to be sent to the appropriate locations via the stimulation electrode(s). The manual activator allows the stimulation system to be inactive during periods in which vocalization would not be needed, e.g., during sleep or while eating, but allows it to be manually activated when vocalization is desired. 2016202615 26 Apr 2016 [0042] After active sensing of the vocalizing muscle contraction or manual activation, various stimulation parameters may be used in order to take advantage of the differences between the abductor (the opener) and the adductor (the closer) muscles in terms of the threshold voltage for activation, the contraction time, and the number of fibers. Thus, the stimulation parameters include varying amplitude, frequency and/or threshold. For example, the applied voltage and the stimulation frequency may be chosen such that the desired muscles are activated. In general, the stimulation voltage should be directly proportional to the threshold values and the stimulation frequency indirectly proportional to the contraction times.

[0043] Embodiments of the present invention may use the frequency-dependent movement of the vocal cords, as shown in FIG. 1. Such movement occurs as a result of the difference in contraction times between the abductor and adductor muscles. The contraction time of the only existing abductor of the vocal cords, the posterior cricoarytenoid (PCA) muscle, is significantly longer than that of the adductor muscles. The RLN contains the nerve fibers to all muscles that act on the vocal cords (except the cricothyroid (CT) muscle which is innervated by the superior laryngeal nerve (SLN)), randomly distributed over the whole nerve. Consequently, an action potential generated by an electrical stimulation always reaches both abductor and adductor muscles. Thus, the glottis first closes due to the faster adductors, then it opens, and ends with relaxation which leads to a vibration of the vocal cords.

[0044] When stimulated at a frequency approximately reciprocal to the contraction 11 7670913.1 (GHMatters) P97141.AU.2 26/04/2016 time of the vocal cord abductor, the action potentials arrive at the muscles at a time when the adductor muscles will have just relaxed from the last activation when the next pulse arrives (as shown below the zero-line on the graph). The abductor, in contrast, has just reached its maximal contraction when the incoming initiation for the next contraction causes their temporal summation (shown above the zero-line). Consequently, resulting tetanic abductor tension overcomes the weaker single twitch adduction. 2016202615 26 Apr 2016 [0045] For stimulation at a frequency approximately reciprocal to the contraction time of the vocal cord adductor, the adductor muscles also reach tetanic contraction, and due to their greater number (4:1) the vocal cords are closed.

[0046] Embodiments of the present invention may use the different thresholds for selective activation of the nerves innervating the abductor and adductor muscles. The threshold for activation for abduction is higher than the threshold for adduction because the contraction time of the PCA muscle is significantly longer than that of the adductor muscles. Therefore, the PCA muscle is innervated by nerve fibers of smaller mean nerve fiber diameter which have a threshold for electrical activation higher than for nerve fibers of higher mean nerve fiber diameter, such as innervating the adductor muscles.

[0047] When stimulated by a stimulation voltage above the threshold for activation of the nerve fibers innervating the adductor muscle but below the threshold for activation of the nerve fibers innervating the abductor muscle, the abductor muscle fibers will not be activated and therefore relaxed. In contrast, nerve fibers innervating the adductor muscle fibers will be activated, leading to a contraction of the adductor muscles, and the vocal cords will close. When the stimulation voltage is above the respective thresholds for activation for both abductor and adductor muscles, then both sets of muscles will be stimulated. The larger the stimulation amplitude (i.e., the injected amount of charge), the stronger both the abductor and adductor muscles are activated independent of the chosen stimulation frequency, provided the stimulation voltage is above each respective threshold. 12 7670913_1 (GHMatters) P97141.AU.2 26/04/2016 [0048] Embodiments of the present invention may use the difference of net forces of adductor and abductor muscles due to electrical activation for the nerves innervating the abductor and adductor muscles. The net force for activation of adductor muscles is higher than the net force for activation of abductor muscles due to their greater number (4 adductor muscles versus 1 abductor muscle per side). 2016202615 26 Apr 2016 [0049] When stimulated by a stimulation voltage above the threshold for activation of the nerve fibers innervating the adductor muscles and above the threshold for activation of the nerve fibers innervating the abductor muscle, the abductory (vocal fold opening) net force of the abductor muscle fibers will be lower than the adductory (vocal fold closing) net force of the adductor muscle fibers, as a sum of forces leading to a closing of the vocal folds.

[0050] Thus, the stimulation parameters should be selected based on the desired application and selective activation. In summary, when the stimulation voltage is below the threshold value for activation of the adductors, then no stimulation occurs regardless of the stimulation frequency or amplitude used. When the stimulation voltage is above the threshold value for activation of the adductors, but below the threshold value for activation of the abductors, then the vocal folds are closed, regardless of the stimulation frequency or amplitude used, which should benefit abductory spasmodic dysphonia. When the stimulation voltage is above the threshold value for activation of the abductors (and thus above the threshold value for activation of the adductors as well), then the vocal folds may be opened or opening due to tetanic contraction of the abductor muscle when the stimulation frequency is approximately the stimulation frequency of the abductor muscle and the amplitude is low or high, which should compensate for adductory spasmodic dysphonia. If an even higher amplitude is used such that the force of tetanically contracted abductor muscle is less than the twitch contractions of the adductor muscles, then the vocal folds may be closing (although there may be a ripple or vibration depending on the stimulation frequency) because the higher applied amplitude overrules tetanic contraction of the abductor muscle. When the stimulation voltage is above the 13 7670913_1 (GHMatters) P97141.AU.2 26/04/2016 threshold value for activation of the abductors and the stimulation frequency is approximately the stimulation frequency of the adductor muscle, then the vocal folds are closed, regardless of the amplitude used, which should compensate for abductory spasmodic dysphonia. For example, depending on the stimulation parameters, a low amplitude may be less than approximately 1.5mA, a high amplitude may be about 1 to 3mA, and a very high amplitude may be greater than about 2.5mA, for a pulse duration of about 0.5 ms. 2016202615 26 Apr 2016 [0051] Consequently, based on the stimulation parameters used (such as described above, as well as other combinations), there may be various switching scenarios for the adductor and abductor muscles that are beneficial to selectively activate the vocalizing muscles in order to exercise or train the muscles. For example, with the selection of a stimulation frequency approximately equal to the stimulation frequency of the abductor muscle, a low amplitude, and a stimulation voltage greater than the stimulation voltage for the adductor muscles, the stimulation voltage may be switched between a voltage less than the stimulation voltage of the abductor muscle to a stimulation voltage greater than the stimulation voltage of the abductor muscle, which causes the vocal cords to switch between a closed and an open state. Similarly, with the selection of a stimulation frequency approximately equal to the stimulation frequency of the abductor muscle and the stimulation voltage to greater than the stimulation voltage for the abductor muscles, the amplitude may be switched between a low value and a high value (or very high value), which causes the vocal cords to switch between an opened and an opening (or closing) state. Likewise, with the selection of a stimulation frequency approximately equal to the stimulation frequency of the abductor muscle and a low amplitude, the stimulation frequency may be switched between the stimulation frequency of the abductor muscle and the adductor muscles, which causes the vocal cords to switch between an opened and a closed state.

[0052] Embodiments of the present invention include stimulation electrode(s) that are configured to provide various stimulation voltages, frequencies and/or amplitudes, so that the 14 7670913_1 (GHMatters) P97141.AU.2 26/04/2016 various stimulation parameters may be implemented. 2016202615 26 Apr 2016 [0053] In embodiments of the present invention, the RLN or vagus nerve is stimulated directly or indirectly (via the glottic closure reflex), and the muscle is not simulated directly, because more than 10 times less power is necessary for activation of a nerve than of the muscle itself. Additionally, a nerve-cufl-electrode can be positioned along the nerve far from moving muscles and tissue and far from sensitive receptors, which would produce unwanted reactions.

[0054] FIG. 2 is a graphical illustration of the frequency-dependent motion of the vocal cords. Stimulation at 10 to 30 Hz causes a graded abduction 201 of the vocal cords. Above 30 Hz graded cord adduction occurs 202, with total airway occlusion 203 at 100 Hz by bilateral stimulation.

[0055] FIGS. 3 and 3A are illustrations of a stimulation system according to one embodiment of the present invention. The stimulation system for spasmodic dysphonia includes one or more stimulating (efferent) electrodes 301 and optionally may include one or more sensing (afferent) electrodes (not visible) or a manual activator that may be activated by the user, e g., a switch or toggle, instead of, or in addition to, the sensing electrodes. Alternatively, the one or more stimulating electrodes 301 may be used as both the sensing and stimulating electrode(s). The stimulation system also includes a processor 303, which may include a pulse generator. The processor 303 may be implanted in the patient’s chest, and the stimulating electrodes 301 may be wrapped around or placed near or in contact with the vagus nerve or RLN 302 along with the electrode leads 304 and safety loops 305. For example, one or more stimulating electrode 301 may be provided at an insertion point of the vocalizing nerve into an innervated muscle, such as a synkinetically reinnervated dysfunctional muscle. In this way, a single electrode 301, or more than one electrode 301, may be used to sense the electrical activity of the synkinetically reinnervated dysfunctional muscle and to send the sensed electrical activity to the processor 303, which generates at least one stimulation parameter. The single electrode 301 may then receive the stimulation parameters from the 15 7670913_1 (GHMatters) P97141.AU.2 26/04/2016 processor 303 and stimulate the RLN or vagus nerve based on the received stimulation parameters. Alternatively, the stimulation electrodes 301 may be used indirectly to stimulate the RLN or vagus nerve by activating the glottic closure reflex, by stimulation of a nerve, such as the superior laryngeal nerve, the internal or external superior nerve, and/or the glossopharyngeal nerve. The stimulation electrodes 301 may be used to stimulate the glottic closure reflex by stimulating mechanoreceptors and/or mucosa of the larynx and/or pharynx, or by the slap reflex. As mentioned above, the stimulation may be electrical and/or mechanical or vibratory stimulation. 2016202615 26 Apr 2016 [0056] Embodiments of the present system may be totally or partially implanted in a human subject. For example, the stimulator may include a housing that can be very small with all of the implant's electronic components contained in a robust and compact hermetically sealed case. Energy and necessary information may be inductively or optically transferred through the skin of the subject. This can be achieved by either enclosing the electronic circuitry inside a metallic case with a secondary coil placed aside or around the case. Similarly, this may be achieved by enclosing the electric circuitry and a secondary coil inside a dielectric case.

[0057] Referring also to FIG. 4, the optional sensing (afferent) part of the closed loop system may include one or more sensing electrodes, or the stimulating electrodes as mentioned above, that detect the voice activities of the infrahyoidal muscles or signals recorded by the alternative sensors (step 101). For example, the sensing electrode(s) or stimulating electrodes(s) may be configured to detect electromyographic (EMG) activity of a vocalizing muscle and/or to detect movement related to voice production. The sensing electrode may be a microphone that detects acoustic signals related to voice production, an impedance sensor that detects changes of impedances related to voice production, and/or a pressure sensor that detects changes in pressure related to voice production. The sensing electrode or stimulating electrode may generate a first signal in response to the activity that has been detected. 16 7670913_1 (GHMatters) P97141.AU.2 26/04/2016

[0058] The first signal is received (step 102) at a processor 303. The processor 303 may include a pulse generator. The processor 303 receives the first signal from the sensing electrode or stimulating electrode and generates at least one stimulation parameter (step 103) that is based on the first signal. The stimulation parameter or second signal may be a biphase current pulse, and the biphase current pulse may have a duration of about 0.001 ms to 50 ms, in most subjects from about 0.1 msec to 5 msec, and a magnitude in the range of about 0.05 mA to 20 mA, in most subjects from about 0.5 mA to 5 m A 2016202615 26 Apr 2016 [0059] The stimulation parameter from the processor 303 is received by one or more stimulating electrodes 301 (step 104), and the stimulating electrode(s) 301 stimulate a vocalizing nerve, such as the RLN or the vagus nerve directly (from which the RLN originates and which is easier to handle surgically), in accordance with the stimulation parameter. Alternatively, the stimulating electrode(s) 301 may stimulate the RLN or the vagus nerve indirectly by activating the glottic closure reflex(es) (step 105), which then activate the RLN or vagus nerve. In accordance with an embodiment of the invention, the stimulation is limited to the time periods of voice production or swallowing or valsalva maneuver. Outside these activities, the synkinetic reinnervated vocal fold passively relaxes to the paramedian position.

[0060] The stimulating electrodes and the sensing electrodes may be either bipolar or tripolar. Similarly, one electrode may be bipolar and one electrode may be tripolar. The electrode leads 304 should be sufficiently damage-resistant. The lead body should be arranged in a way, so that the nerve and the stimulator are influenced as little as possible by movements of the muscles, the neck and the head.

[0061] Embodiments can be used to activate the vocal cord adduction in patients with spasmodic dysphonia by stimulating the whole innervating RLN or alternatively, the vagus nerve, from which the RLN originates. This treatment is effective with respect to patients having spasmodic dysphonia because it is based on muscle characteristics and not on nerve or muscle/nerve characteristics only. 17 7670913J (GHMatters) P97141.AU.2 26/04/2016 [0062] FIG. 5 is a flow chart illustrating a method of training therapy of a human subject in accordance with one embodiment of the invention. Electrical activity of a vocalizing muscle (such as the infrahyoidal muscles) of a human subject is sensed (step 110), and a vocalizing nerve (such as the RLN or the vagus nerve) of the subject is directly stimulated with an electrical signal based on the sensed electrical activity. Alternatively, after electrical activity is sensed, the RLN or the vagus nerve may be indirectly stimulated by the activation of the glottic closure reflex(es) (step 120). The stimulation/activation parameters may include stimulating the RLN or vagus nerve with an electrical signal at a stimulation frequency above the reciprocal value of the contraction time of the vocal cord adductor of the subject. Stimulating the vocalizing nerve of the subject with an electrical signal may include stimulating the nerve with an electrical signal at a frequency approximately reciprocal to the contraction time of the vocal cord adductor of the subject and above the reciprocal of the contraction time of the vocal cord abductor of the subject. 2016202615 26 Apr 2016 [0063] FIG. 6 is a flow chart illustrating a method of pacing laryngeal activity of a human subject using a manual activator in accordance with one embodiment of the invention. The stimulation system is manually activated in step 130. The manual activator may send a first signal to the processor 303, which may include a pulse generator. The processor 303 receives the first signal from the manual activator and generates at least one stimulation parameter that is based on the first signal. A glottic closure reflex is then activated (step 140) based on the stimulation parameter, which in turn stimulates the RLN or vagus nerve of the subject. The stimulation may be electrical and/or mechanical or vibratory stimulation.

[0064] Some embodiments of the processor 303 may be implemented as hardware, software (e.g., a computer program product), or a combination of both software and hardware. For example, embodiments may be implemented as a computer program product for use with a computer system. Such implementation may include a series of computer instructions or program code fixed either on a tangible medium, such as a computer readable medium (e.g., a 18 7670913_1 (GHMatters) P07141.AU.2 26/04/2016 2016202615 26 Apr 2016 diskette, CD-ROM, ROM, or fixed disk) or transmittable to a computer system, via a modem or other interface device, such as a communications adapter connected to a network over a medium. The medium may be either a tangible medium (e.g., optical or analog communications lines) or a medium implemented with wireless techniques (e g., microwave, infrared or other transmission techniques). The series of computer instructions may embody all or part of the functionality previously described herein with respect to the processor. Those skilled in the art should appreciate that such computer instructions may be written in a number of programming languages for use with many computer architectures or operating systems. Furthermore, such instructions may be stored in any memory device, such as semiconductor, magnetic, optical or other memory devices, and may be transmitted using any communications technology, such as optical, infrared, microwave, or other transmission technologies. It is expected that such a computer program product may be distributed as a removable medium with accompanying printed or electronic documentation (e.g., shrink wrapped software), preloaded with a computer system (e.g., on system ROM or fixed disk), or distributed from a server or electronic bulletin board over the network (e.g., the Internet or World Wide Web).

[0065] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modification. This application is intended to cover any variation, uses, or adaptions of the invention and including such departures from the present disclosure as come within known or customary practice in the art to which the invention pertains.

[0066] In the claims that follow and in the preceding description of the invention, except where the context requires otherwise owing to express language or necessary implication, the word “comprise” or variations such as “comprises” or “comprising” is used in an inclusive sense, that is, to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention. 19 7670913.1 (GHMatters) P97141.AU.2 26/04/2016 2016202615 26 Apr 2016 [0067] Further, any reference herein to prior art is not intended to imply that such prior art forms or formed a part of the common general knowledge in any country. 20 7670913_1 (GHMatters) P97141.AU.2 26/04/2016

Claims (20)

1. THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

   1. A method of treating a human subject having unilateral vocal cord autoparalysis, the method comprising: providing a stimulating electrode configured to directly contact a recurrent laryngeal nerve or vagus nerve of the subject; sensing electrical activity of a synkinetically reinnervated dysfunctional muscle of the subject; generating at least one stimulation parameter, using a processor, based on the sensed electrical activity; and stimulating the recurrent laryngeal nerve or vagus nerve, using the stimulating electrode, based on the at least one stimulation parameter.
2. 2. The method of claim 1, wherein the stimulating electrode is configured to sense the electrical activity of the synkinetically reinnervated dysfunctional muscle.
3. 3. The method of claim 1, wherein the stimulating electrode is configured to be central to an insertion point of the recurrent laryngeal nerve or vagus nerve into innervated muscle.
4. 4. The method of claim 3, wherein central to the insertion point is where the recurrent laryngeal nerve passes an aortic arch.
5. 5. The method of claim 1, wherein the synkinetically reinnervated dysfunctional muscle is a vocalizing muscle that opens or closes a vocal fold.
6. 6. The method of claim 5, wherein the vocalizing muscle is selected from the group consisting of thyroarytenoid muscles, vocalis muscles, posterior cricoarytenoid muscle, lateral cricoarytenoid muscles, and combinations thereof.
7. 7. The method of claim 1, wherein stimulating the recurrent laryngeal nerve or vagus nerve stimulates the abductor muscle.
8. 8. The method of claim 1, wherein stimulating the recurrent laryngeal nerve or vagus nerve stimulates the adductor muscles.
9. 9. The method of claim 1, wherein stimulating the recurrent laryngeal nerve or vagus nerve stimulates the abductor muscle and the adductor muscles.
10. 10. The method of claim 1, wherein sensing includes detecting electromyographic (EMG) activity of a vocalizing muscle, detecting movement related to voice production, or both.
11. 11. The method of claim 1, further comprising: determining when the sensed electrical activity has reached a predetermined level; and generating the at least one stimulation parameter when the predetermined level is reached.
12. 12. The method of claim 1, further comprising activating a glottic closure reflex, using the stimulating electrode, based on the at least one stimulation parameter.
13. 13. The method of claim 1, further comprising activating a glottic closure reflex based on the at least one stimulation parameter, wherein activating includes electrical stimulation, mechanical stimulation, or a combination thereof.
14. 14. The method of claim 1, wherein the at least one stimulation parameter includes a stimulation voltage that is above a threshold for activation of vocal cord adductor muscles of the subject and below a threshold for activation of vocal cord abductor muscles of the subject.
15. 15. The method of claim 1, wherein the at least one stimulation parameter includes a stimulation voltage that is above a threshold for activation of vocal cord adductor muscles of the subject and above a threshold for activation of vocal cord abductor muscles of the subject.
16. 16. A stimulation system for a human subject having unilateral vocal cord autoparalysis, the system comprising: a stimulating electrode configured to directly contact a recurrent laryngeal nerve or vagus nerve of the subject and configured to sense electrical activity of a synkinetically reinnervated dysfunctional muscle of the subject; and a processor configured to receive the sensed electrical activity of the synkinetically reinnervated dysfunctional muscle and configured to generate at least one stimulation parameter based on the sensed electrical activity, the stimulating electrode configured to stimulate the recurrent laryngeal nerve or vagus nerve of the subject based on the at least one stimulation parameter.
17. 17. The stimulation system of claim 16, wherein the processor is configured to detect when the sensed electrical activity has reached a predetermined level and configured to generate the at least one stimulation parameter when the predetermined level is reached.
18. 18. The stimulation system of claim 16, further comprising a manual activator configured to cause the processor to generate the at least one stimulation parameter.
19. 19. The stimulation system of claim 16, wherein the stimulating electrode is a nerve cuff electrode, a rod electrode, or combinations thereof.
20. 20. The stimulation system of claim 16, wherein the stimulating electrode is configured to be around the recurrent laryngeal nerve or vagus nerve, configured to be fixed to the recurrent laryngeal nerve or vagus nerve, configured to be inserted into the recurrent laryngeal nerve or vagus nerve, or combinations thereof.