SYSTEM

Subject of the Invention

The invention relates to a system where the diseases and/or disorders are treated by electrical stimulation of the auricular vagus nerve, and to a method of operation for said system.

State of the Art

The autonomic nervous system is a system controlling all of the vital functions of the body. In other words, all of the functions of our organs that are not able to be controlled by ourselves are managed by the autonomic nervous system. The activity of the autonomic nervous system varies during the daily life, serving to enable our body to accommodate the changes in the internal and external environment. The impairments in the variable activity of the autonomic nervous system lead to the impairment in the body's ability to adapt to the variables in the internal and external environment, resulting in the emergence of the autonomic dysfunction and the associated diseases. Activation of the nerves by stimulation is employed for the treatment of the resulting disorders and diseases.

While the activities like sports, yoga, breathing exercises and massage are used for stimulating the nerves, the electrical stimulation of the nerves is also a frequently used method. The nerves may be stimulated by sending electrical signals to various nerves from various parts. The stimulation is realized via different parts of different nerves by means of the signals with different electrical properties for treating different disorders.

With the system according to the invention, the treatment of the diseases and disorders is enabled by noninvasive electrical stimulation of the auricular vagus nerve. Object of the Invention

An object of the invention is to develop a system where the treatment of the diseases and/disorders is enabled by the stimulation of the vagus nerve.

Another object of the invention is to develop a system where the treatment of diseases and/or disorders is enabled by the stimulation of the vagus nerve via the ear.

Another object of the invention is to develop a system where the treatment of diseases and/or disorders is enabled by the stimulation of the vagus nerve via both ears.

Another object of the invention is to develop a system where the treatment of diseases and/or disorders is enabled by the stimulation of the vagus nerve through the application of electricity to two different points of the ear.

Another object of the invention is to develop a system where the stimulation parameters may be set wirelessly via a mobile device or partly via the device itself.

Description of the Figures

Figure 1: An overall view of the system according to the invention

Figure 2: A view of the electrode and the electrode carrier

Figure 3: A view of the ear hook, the electrode and the electrode carrier

Figure 4: Another view of the ear hook, the electrode and the electrode carrier

Reference Numerals

S : Stimulator

51 : Visual warning member

52 : Setting component

E : Electrode El : Electrode carrier

E2 : Ear hook

E3 : Connection member

Detailed Description of the Invention

The invention relates to a system where the diseases and/or disorders are treated by electrical stimulation of the auricular vagus nerve, and to a method of operation for said system. More specifically, the invention relates to a system where the stimulation of the vagus nerve is enabled via the auricular branch of said nerve with the electrical parameters possible to be set according to the needs of the patient to thereby treat the diseases and/or disorders, and to a method of operation for said system.

With the system according to the invention, the bilateral symmetric stimulation of the auricular vagus nerve is performed. The performance of the stimulation of the auricular vagus nerve in a bilateral symmetric manner enables the efficacy to be increased. Owing to the fact that the stimulation is not applied simultaneously to both ears, the possible electric leakage between the two ears is reduced, thereby enabling the current to stay vagus-specific. The symmetric sequential bilateral stimulation enhances the efficacy of the treatment. This method is one of the practices preferred especially for the psychological/psychiatric disorders. Said method, which first started to be practiced in the form of EMDR (Eye Movement Desensitization and Reprocessing), was subsequently improved also for the other stimuli such as sound and touch. However, so far there is no such known application of the method for the stimulation of the auricular vagus nerve.

EMDR is a strong psychotherapeutic approach. Until the present, the method has enabled the successful treatment of different types of psychological disorders in about 2 million people from all ages. The development of EMDR began in 1987 when Dr. Francine Shapiro accidentally discovered that the eye movements could diminish the intensity of the disturbing thoughts. Dr. Shapiro conducted scientific studies about this effect in the individuals who experienced trauma and published her study demonstrating the success achieved in the treatment (Journal of Traumatic Stress, 1989). According to the EMDR protocol, the individual follows with his/her eyes the fingers of the therapist who moves his/her fingers in two directions. It is believed that a person's focusing his/her attention simultaneously on the thoughts in his/her mind and on his/her eye movements activates the relationship between the right and left cerebral hemispheres. Besides the bidirectional eye movements applied in EMDR, other stimulations are also used, such as the bidirectional auditory stimulation and bidirectional touch. It was found as a result of the controlled studies that EMDR effectively reduces or eliminates the post-traumatic stress syndromes in the majority of the patients and provides relief in the symptoms (such as anxiety) generally associated with the psychological problems. EMDR is found effective also by many international health and government institutions (World Health Organization (WHO), American Psychiatric Association, International Society for Traumatic Stress Studies, U.S. Department of Veterans Affairs, U.S. Department of Defense, United Kingdom Department of Health, and Israeli National Council for Mental Health) (EMDR Society, https://www.emdr-tr.org/emdr-nedir/).

The mechanism of EMDR basically comprises the rhythmic bilateral stimulation applied to both halves of the body sequentially. The rhythmic bilateral stimulation is indicated to provide relaxation. It is thought to increase the consistence and coordination between the cerebral hemispheres (NovoNavarro P, Landin-Romero R, Guardiola- Wanden-Berghe R, Moreno-Alcazar A, Valiente-Gomez A, Lupo W, Garcia F, Fernandez I, Perez V, Amann BL. 25 years of Eye Movement Desensitization and Reprocessing (EMDR): The EMDR therapy protocol, hypotheses of its mechanism of action and a systematic review of its efficacy in the treatment of post-traumatic stress disorder. Rev Psiquiatr Salud Ment. 2018 Apr-Jun; ll(2):101-114. doi: 10.1016/j.rpsm.2015.12.002. Epub 2016 Feb 11). The opinions that the EMDR further increases parasympathetic activity are also found in the literature (Landin-Romero R, Moreno-Alcazar A, Pagani M, Amann BL. How Does Eye Movement Desensitization and Reprocessing Therapy Work? A Systematic Review on Suggested Mechanisms of Action. Front Psychol. 2018 Aug 13; 9:1395.). It is suggested that the EMDR therapy may be useful for the disorders such as tinnitus, post-traumatic stress disorder, substance abuse, and anxiety (Phillips JS, Erskine S, Moore T, Nunney I, Wright C. Eye movement desensitization and reprocessing as a treatment for tinnitus. Laryngoscope. 2019 Oct; 129(10):2384-2390; Wilson G, Farrell D, Barron I, Hutchins J, Whybrow D, Kiernan MD. The Use of Eye Movement Desensitization Reprocessing (EMDR) Therapy in Treating Post-traumatic Stress Disorder-A Systematic Narrative Review. Front Psychol. 2018 Jun 6; 9:923; Pilz R, Hartleb R, Konrad G, Reininghaus E, Unterrainer HF. The role of eye movement desensitization and reprocessing (EMDR) in substance use disorders: A systematic review. Fortschr Neurol Psychiatr. 2017 Oct; 85(10):584-591; Yunitri N, Kao CC, Chu H, Voss J, Chiu HL, Liu D, Shen SH, Chang PC, Kang XL, Chou KR. The effectiveness of eye movement desensitization and reprocessing toward anxiety disorder: A meta-analysis of randomized controlled trials. J Psychiatr Res. 2020 Apr; 123:102-113). EMDR was found effective against phantom pain, headaches, chronic musculoskeletal pain as well as depression (Tesarz J, Leisner S, Gerhardt A, Janke S, Seidler GH, Eich W, Hartmann M. Effects of eye movement desensitization and reprocessing (EMDR) treatment in chronic pain patients: a systematic review. Pain Med. 2014 Feb; 15(2):247-63; Wood E, Ricketts T, Parry G. EMDR as a treatment for long-term depression: A feasibility study. Psychol Psychother. 2018 Mar; 91(l):63-78).

Although being referred to as Eye Movement Desensitization and Reprocessing, EMDR actually includes bilateral stimulation. The bilateral stimulation can occur in a variety of forms, including left-right eye movements, tapping on the knees, using headphones, or with handheld buzzers known as tappers (Gainer D, Alam S, Alam H, Redding H. A FLASH OF HOPE: Eye Movement Desensitization and Reprocessing (EMDR) Therapy. Innov Clin Neurosci. 2020 Jul 1; 17(7-9):12-20). A study protocol involving the combination of the EMDR method with transcranial electrical stimulation is also found in the literature (Gardoki-Souto I, Martin de la Torre O, Hogg B, Redolar-Ripoll D, Valiente-Gomez A, Martinez Sadurni L, Blanch JM, Lupo W, Perez V, Radua J, Amann BL, Moreno-Alcazar A. Augmentation of EMDR with multifocal transcranial current stimulation (MtCS) in the treatment of fibromyalgia: study protocol of a double-blind randomized controlled exploratory and pragmatic trial. Trials. 2021 Jan 29; 22(l):104). Another different form of the method could include the application of the transcranial stimulations in a manner similar to the EMDR principles. With such a method, the electrical stimulation may be applied in a bilateral symmetric manner (both temporal and spatial) and equally to both halves of the body sequentially.

Use of vagus nerve stimulation was approved by FDA (Food and Drug Administration) in 1997 for treatment-resistant epilepsy and in 2005 for treatment-resistant depression. The vagus nerve is the 10 ^th cranial nerve and the most important component of the parasympathetic nervous system. Although the mechanism of action for the vagus nerve stimulation is still not well understood, it is believed to affect the cerebral blood flow and neural activity through the afferent fibers. Since the invasive vagus stimulation also affects the efferent fibers via the cervical area, it is possible to perform the stimulation unilaterally, and in this case, the risk for side effects is greater compared to the afferent stimulations, besides the surgical complications. Hoarseness, sore throat/dysphagia, coughing and labored breathing are among the most frequently encountered side effects of the invasive cervical stimulation (Ohemeng KK, Parham K. Vagal Nerve Stimulation: Indications, Implantation, and Outcomes. Otolaryngol Clin North Am. 2020 Feb; 53(1):127-143). The studies reveal that the auricular vagus nerve stimulation is often performed unilaterally similar to the cervical application; however the simultaneous activation of the left and right auricular vagus nerve may potentially increase the effects of stimulation due to the increased sensory input to the brain stem (Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, Papa M, Kiss A, Podesser B, Cassara AM, Tanghe E, Samoudi AM, Tarnaud T, Joseph W, Marozas V, Lukosevicius A, Istuk N, Sarolic A, Lechner S, Klonowski W, Varoneckas G, Szeles JC. Current Directions in the Auricular Vagus Nerve Stimulation I - A Physiological Perspective. Front Neurosci. 2019 Aug 9; 13:854.). In a study by Kutlu et al., the simultaneous bilateral stimulation was applied to the patients with fibromyalgia (Kutlu N, Ozden AV, Alptekin HK, Alptekin JO. The Impact of Auricular Vagus Nerve Stimulation on Pain and Life Quality in Patients with Fibromyalgia Syndrome. Biomed Res Int. 2020 Feb 28; 2020:8656218). Laskiewicz et al. stated in their study that the impacts of stimulation of both vagus nerves on the final body weight and food intake are significantly greater than those obtained with the stimulation of only one vagus nerve (Laskiewicz J, Krolczyk G, Zurowski G, Sobocki J, Matyja A, Thor PJ. Effects of vagal neuromodulation and vagotomy on control of food intake and body weight in rats. J Physiol Pharmacol. 2003 Dec; 54(4):603-10.). There are studies in the literature indicating that the transcutaneous vagus nerve stimulation is beneficial for the disorders such as depression, tinnitus, migraine, and chronic pain (Yap JYY, Keatch C, Lambert E, Woods W, Stoddart PR, Kameneva T. Critical Review of Transcutaneous Vagus Nerve Stimulation: Challenges for Translation to Clinical Practice. Front Neurosci. 2020 Apr28; 14:284). We observe that the EMDR treatment is also beneficial for the similar disease groups. A method where the auricular vagus nerve stimulation is applied in a bilateral symmetric manner, but sequentially, in both ears is not available in the literature.

In the auricular vagus nerve stimulation (aVNS), various stimulation parameters may lead to different outcomes. Due to the complex physiology of the body, the strong and moderate levels of stimulation, in addition to the continuous and intermittent stimulation, may even cause negative physiological effects. It is alleged that the continuous vagus nerve stimulation (VNS) develops intense bradycardia and increased cardiac load conditions to an extent leading to the compensatory sympathetic reflexes. On the other hand, the intermittent VNS lacks a sufficient average intensity, and accordingly, the parasympathetic VNS is still able to antagonize the sympathetic system. Although it is clear that VNS or aVNS should be optimized according to a given dose and duty cycle, the principle of "as low as reasonably achievable" is valid for a certain therapeutic indication. Favorably, VNS or aVNS should not be chronic in order to attain sustainable therapeutic effects (Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, Papa M, Kiss A, Podesser B, Cassara AM, Tanghe E, Samoudi AM, Tarnaud T, Joseph W, Marozas V, Lukosevicius A, Istuk N, Lechner S, Klonowski W, Varoneckas G, Szeles JC, Sarolic A. Current Directions in the Auricular Vagus Nerve Stimulation II - An Engineering Perspective. Front Neurosci. 2019 Jul 24; 13:772).

Such sequential symmetric stimulation results in the combination of the benefits obtained from the EMDR technique and the effects provided by the vagus nerve stimulation. Applying the sequential and symmetric stimulation method instead of the continuous stimulation enhances the efficacy and reduces the adverse effects associated with the stimulation. The system according to the invention comprises in its most basic form at least one stimulator (S), which generates the electric current to be delivered for the stimulation of the nerves, and at least one electrode (E), which enables the electric current generated by the stimulator (S) to be applied to the vagus nerve in the ear.

In a preferred embodiment of the invention, the stimulation of the vagus nerve in both ears is performed. This embodiment of the system has at least two electrodes (E) for transmitting the electric signals delivered by the stimulator (S) to each ear separately and/or simultaneously. In other words, the system has at least two electrodes (E) for enabling the symmetric and sequential stimulation of the vagus nerve in the ear.

In another preferred embodiment of the invention, the electric signal is delivered to the vagus nerve from two different points of the ear. This embodiment comprises at least two electrodes (E), one positioned to contact the concha section of the ear and the other positioned to contact the tragus section of the ear. The embodiment where the vagus nerve stimulation is performed from two different points of the ear and where the vagus nerves located in both ears are stimulated comprises at least four electrodes (E).

In a preferred embodiment of the invention, the current is introduced from both ears via the system according to the invention. Preferably, the current is not simultaneously transmitted to ears and the sequential symmetric stimulation is performed.

In a preferred embodiment of the invention; o The current is biphasic/bipolar. o The pulse width of the current is in the range of 100 microseconds-500 microseconds. o The current is applied for 0 to 15s to the right or left ear and then for 0 to 15s to the other ear. o No current is applied to any ear for 0-30s. o The current application times are equal for both ears. o The current properties other than the application time, such as the pulse width, wave feature, and frequency range, may vary between the two ears. o The current frequency exhibits random or regular variation in the range of 1-30 Hz for both ears. o The current may have a sine, square, rectangular or triangular waveform.

A preferred embodiment of the invention comprises at least one ear hook (E2), which enables the electrode (E) to be positioned on the ear. The ear hook (E2) has a geometry wrapping around the ear lobe to enable the electrode (E) to hang on the ear.

A preferred embodiment of the invention comprises at least one electrode carrier (El), on which the electrode (E) is fixed and which enables the electrode (E) to be moveably secured on the ear hook (E2). The electrode carrier (El) is able to freely rotate around its own axis on the ear hook (E2) and thus, enables the electrodes (E) to be adjusted in the desired manner to suit the patient.

A preferred embodiment of the invention comprises at least one connection member (E3), which enables the electric current generated by the stimulator (S) to be conveyed to the electrodes (E). Said connection member (E3) is preferably a cable.

In a preferred embodiment of the invention, the stimulator (S) comprises at least one visual warning member (SI), which enables the user to be informed about the status of the system. In a preferred embodiment of the invention, said visual warning member (SI) is a luminescent member. A preferred embodiment of the invention comprises at least one visual warning member (SI), which indicates whether the system is on or off, and/or at least one visual warning member (SI), which indicates the wireless connection status of the system, and/or at least one visual warning member (SI), which indicates the status of the stimulation.

In a preferred embodiment of the invention, none of the visual warning members (SI) lights up while the system is off and at least one of said members flashes when the system assumes the on position. In a preferred embodiment of the invention, one of the visual warning members (SI) blinks while the wireless connection has not yet been established and the device to be connected is being searched and flashes when the connection has been established. In a preferred embodiment of the invention, one of the visual warning members (SI) flashes during the period where the treatment has started and the stimulation is occurring and does not light up during the period where the stimulation does not occur or the treatment is in the off state. A preferred embodiment of the invention comprises the visual warning member (SI), which indicates whether the system is on or off, and/or the visual warning member (SI), which indicates the wireless connection status of the system, and/or the visual warning member (SI), which indicates the status of the stimulation.

In a preferred embodiment of the invention, at least one setting component (S2) is present on the stimulator (S). Said setting component (S2) enables at least one variable of the stimulator (S) to be set. In a preferred embodiment of the invention, the switching on and off of the stimulator (S) is controlled via the setting component (S2).

In a preferred embodiment of the invention, the stimulator (S) is able to establish connection with at least one smart device. In a preferred embodiment of the invention, said connection is provided in a wireless manner. The parameters of the electric current generated by the stimulator (S) may be set through said smart device. In a preferred embodiment of the invention, the variables such as the pulse width and/or frequency of the electric current to be applied to the nerve and/or the time for which the nerve is to be stimulated during the treatment and/or the time to be allowed to elapse after a stimulation before the next stimulation will occur and/or the overall time for which the treatment is to continue after the stimulation is started and/or the density of the electric current may be controlled via the stimulator (S) itself or via a smart device to which the stimulator (S) is connected. The pulse width refers to the variable expressed in microseconds, the frequency refers to the variable expressed in hertz, the density refers to the variable expressed in milliamperes, and time refers to the variable expressed in seconds. In a preferred embodiment of the invention, the start and termination of the treatment are also controlled via the device itself or via a smart device. In a preferred embodiment of the invention, the time to the end of the treatment may also be monitored via the smart device.

In a preferred embodiment of the invention, the smart device is a mobile phone or any electronic device capable of wireless communication.

The method of operation for the system according to the invention comprises in its most basic form the steps of; bringing the stimulator (S) into the on state, activating the wireless connection of the stimulator (S) and realizing the connection with at least one smart device in the embodiment where the stimulator is to be controlled via a wireless device, setting the stimulation parameters via the smart device and/or the device itself, and starting the stimulation and therefore the treatment.

In a preferred embodiment of the invention, some data about the patient are recorded before and after the stimulation and are stored in a database. Said data are classified as pre-stimulation and post-stimulation data. In a preferred embodiment of the invention, said data are in the form of questionnaires and/or biological data and/or voice records for the patient.

Prior to the stimulation, the data about the patient are acquired through a questionnaire, and the patient is subjected to biological measurements and voice analysis. The same procedures are repeated after the stimulation. The data obtained prior to the stimulation, the personal data input and the database data are evaluated, the stimulation parameters are set according to the results obtained by running the artificial intelligence algorithms, and the stimulation is performed. After the stimulation, the data collected prior to the stimulation are measured again and said data are entered in the database as database data. In a preferred embodiment of the invention, the variables such as the pulse width and/or frequency of the electric current to be applied to the nerve and/or the time for which the nerve is to be stimulated during the treatment and/or the time to be allowed to elapse after a stimulation before the next stimulation will occur and/or the overall time for which the treatment is to continue after the stimulation is started and/or the density of the electric current are set in the step of setting the stimulation parameters. The pulse width refers to the variable expressed in microseconds, the frequency refers to the variable expressed in hertz, the density refers to the variable expressed in milliamperes, and time refers to the variable expressed in seconds.

In a preferred embodiment of the invention, the pre-stimulation data of the patient, the personal data of the patient, the data of the other patients available in the database, and the post-stimulation data of the patient are evaluated to customize the stimulation parameters to be applied to the patient, i.e. to revise said parameters specifically for the patient. More specifically, the pre-stimulation and post-stimulation data of the patient are compared to the data of other patients available in the database and the optimum stimulation parameters determined for the other patients with similar data or the estimated stimulation parameters obtained as a result of the use of various algorithms are applied to the current patient, thereby enabling the efficacy of the treatment to be enhanced.

In a preferred embodiment of the invention, the pre-stimulation and post-stimulation data of the patient are also stored in the database and said data or inferences to be made from said data are used for the subsequent treatments of the same patient and/or for the treatments of the other patients.

In a preferred embodiment of the invention, the termination of the treatment may be performed manually via the smart device and/or the stimulator (S), while it is also possible for the treatment to automatically terminate at the end of the predetermined duration. In a preferred embodiment of the invention, it may be enabled to deliver the current for a certain time during the treatment, then wait for a certain time without delivering any current, and deliver the current again at the end of said time. Preferably, it is also possible to set the time for which the electric current is to be delivered to the electrodes (E), the time to be allowed to elapse without delivering any current after the previous delivery of the current, and the duration after which the current is to be delivered again. In other words, the on/off periods may be set in said system and method.

In a preferred embodiment of the invention, the vagus nerve is stimulated via the ear area. In a preferred embodiment of the invention, the vagus nerve passing through both ears is stimulated. In other words, electrodes (E) are attached to both ears and the electric current is applied simultaneously and/or separately to both ears. In a preferred embodiment of the invention, the electric current is transmitted to each ear via at least two points of the ear. In this embodiment, the vagus nerve stimulation is enabled by applying electric current to the concha and tragus sections of the ear.

In a preferred embodiment of the invention, the current may be applied simultaneously to both ears and/or to only one of the ears and the current may be optionally applied to each ear alternately and separately.