Vagus Nerve Stimulation Working Module Proposal COST Action: BM1309 COST EMF-MED proposed by Univ.-Ass. DI Stefan Kampusch, Vienna University of Technology Univ. Prof. DI Dr.techn. Eugenijus Kaniusas, Vienna University of Technology Dr.med. Jozsef Constantin Széles, Medical University Vienna
Working Module Description 1 Working Module Description Due to the functional organization of the vagus nerve and its projections to various body/brain regions, a number of physiological processes are affected by modulating the vagus nerve. However, common neuromodulation methods are often characterized by empirical settings of stimulation parameters due to a lack of knowledge on particular mechanisms of action. This may lead to overstimulation or understimulation and thus missed therapeutic effects. Difficulties arise in dividing responders and non-responders whereas a low likelihood of symptom remission results. Continuous and objective monitoring of therapy progress and of stimulation effects is mostly missing or impossible, which does not allow for proper readjustment of stimulation with respect to individual patients needs, pathological processes and physiological (adaptation) processes. The aim of this Working Module within the scope of COST EMF-MED is the exploration, development and optimization of novel methods for personalized electrical stimulation of the vagus nerve in chronic diseases. Targeted diseases include cardiovascular and systemic affections congestive heart failure, atrial fibrillation, peripheral arterial dysfunction, diabetes mellitus, diabetes and/or ischemic induced chronic ulcers, or inflammation and central nervous system disorders movement disorders, epilepsy, mental disorders, or chronic pain. The addressed research may include the following topics (non-exclusively): Modeling o established and novel neuromodulation techniques o modeling of stimulation and its effects o tissue-electrode interface Therapeutic Applications o established and novel stimulation methods o mechanisms of action in various diseases o objective tracking of therapeutic effects o effects on autonomous nervous system (sympathovagal modulation) o effects on central nervous system (modulation of afferent sensory input) Safety Issues o tissue-electrode interface o exposure assessment (e.g., wireless communication and power supply) Optimization o novel stimulation methods o stimulation paradigms for specific patients/diseases/symptoms o electrodes for selective stimulation and/or sensing o multiparametric biosignal assessment and processing o control algorithms for individualized feedback-controlled stimulation o combination of vagal neuromodulation with other therapeutic approaches (e.g., medication, DBS) - 2 -
State-of-the-Art 2 State-of-the-Art The vagus nerve (Xth cranial nerve) as integral part of the so called parasympathetic nervous system represents a unique interface to intervene with autonomous and central nervous system activity by artificial neuromodulation techniques. Cervical branches of the vagus nerve mediate the afferent and efferent (motoric and parasympathetic) innervation of pharynx, larynx, heart, lungs, and visceral organs [1]. Additionally, auricular branches of the vagus nerve mediate the afferent innervation of the auricle [2], [3]. Common neuromodulatory methods include the electrical stimulation of the vagus cervical trunk in terms of cervical vagus nerve stimulation (cvns) [4]. Typically, devices are implanted in the subcutaneous tissue of the upper chest and connected with the left or right cervical vagus nerve via a bipolar stimulation lead [5]-[7]. Ribbon electrodes fixed on silicon helices or multi-contact cuff electrodes are used. The stimulation amplitude is adjusted by a physician with respect to desired effects and side-effects. Common realizations allow triggering of stimulation by the patients use of a handheld magnet. Treatment is delivered continuously with a given duty cycle. cvns gained importance as treatment option for therapy refractory epilepsy and, more recently, for major depression and congestive heart failure [5]-[8]. In addition, research on cvns indicates possible effects on various other disorders including pain syndromes, anxiety, fibromyalgia, essential tremor or Alzheimer s disease [9]. A further recently established method is stimulation of the auricular branch of the vagus nerve, which aims to modulate (preferentially) thick afferent Aβ-fibers [10]-[12]. Stimulation pulses are applied transcutaneously (surface electrodes, tvns) or percutaneously (needle electrodes, pvns), using one or more bipolar stimulation electrodes at the concha, antihelix, or tragus region of the auricle [2], [11]. Stimulation amplitude is adjusted by the physician/patient to produce a tingling sensation at the stimulation region. So far, devices are designed for intermittent treatment only (e.g., 3 applications a day for in total 4 to 5 hours, or 3 days a week with a duty cycle of 3 h/3 h). Studies evidence similar beneficial therapeutic effects of auricular stimulation, as compared to cvns. Current areas of treatment include epilepsy, mood disorders, chronic pain, and selected cardiovascular diseases [13]-[16]. Furthermore, scientific data indicates possible modulation of atrial fibrillation, insomnia, diabetes induced ulcers, inflammation, or dystonia by modulating vagal activity [17]-[21]. Brain activation studies during vagus nerve stimulation give rise to a huge variety of possible interactions with central nervous system structures involved in chronic diseases. Recent investigations indicate alternated brain activity in regions involved in, e.g., autonomic regulation, pain processing, alertness, mood, or motor control [22]-[24]. In addition, improved autonomic control and increased parasympathetic power in response to VNS was already observed [25]-[27]. Common fields of research to advance vagus nerve stimulation include (non-exclusively): Attempts for selective stimulation of afferent/efferent nerve fibers, specific electrode design and measurement of nerve activity for biofeedback (multi-contact electrode arrays) [11], [28]-[31] - 3 -
State-of-the-Art Attempts to track projections of various stimulation signals/patterns to brain regions in various diseases [22]-[24], [32] Attempts to find objective and reliable markers for therapeutic effects on the level of physiological date [11], [20], [25] Attempts to establish feedback controlled stimulation [7], [26], [33], [34] - 4 -
Motivation 3 Motivation Gaps and Challenges The following motivational points can be identified as trigger for this Working Module: Challenge 1: Empirical stimulation patterns There are little systematic investigations on the impact of stimulation parameters with respect to different patients/diseases/symptoms [9], [32]. Empirical, uncontrolled stimulation patterns and constant output characteristics over long periods of therapy make the stimulation insensitive to prevailing pathology, stress level, and actual physiological state of the patient. Stimulation efficiency may be reduced with respect to high inter-patient variability and the bodies attempts to adapt to constant stimulation characteristics. This may lead to understimulation or overstimulation and finally missed therapeutic effects, whereas full symptom remission gets unlikely because of inappropriate stimulation parameters. Challenge 2: Unspecific stimulation Electrical stimulation aims at selective modulation of the sensory input to brain structures involved in the genesis of diseases, of the autonomous sympathovagal regulation, and/or of specific effector organs. Stimulation of targeted nerve fibers as well as characterization of best targets is still in its infancy. The attained selectivity of stimulation is often limited by the electrode design and the used stimulation patterns. For instance, unspecific stimulation of the vagus cervical trunk may lead to side effects, like hoarseness, cough, pain, or dyspnea, during therapy for e.g., epilepsy and depression [6]. Those side effects are elicited by undesired efferent stimulation. Control of specific physiological parameters or control systems (e.g., blood pressure regulation) by selective stimulation is hardly possible today. Challenge 3: Leaking objective assessment of stimulation efficiency on the level of physiological data Easy accessible biomarkers have to be established which reflect both stimulation impact and disease progress/modification. This will allow for a disease specific objective monitoring of therapeutic efficiency in clinics with the aim of therapy optimization. Repetitive clinical or even continuous biomarker assessments will allow for new insights into underlying disease mechanisms and (timely) stimulation impacts on both the central and autonomous nervous system. An unobtrusive physiological monitoring is preferred, as it holds the possibility for continuous progress assessment or identification of (non-) responders, and offers data for biofeedback-controlled stimulation [26]. Challenge 4: Uncontrolled stimulation State-of-the-art neuromodulation applications mostly do not utilize feedback-controlled approaches so far. However, straightforward stimulation does not account neither for changes in physiological parameters, disease state and inter-patient variability, nor for intrinsic body rhythms. Furthermore, physiological adaptation processes (plasticity) are hardly tractable today. Therefore, an optimization of stimulation is hardly possible. - 5 -
Motivation Challenge 5: Partner contributions - 6 -
Objectives 4 Objectives This Working Module aims at the exploration, development and optimization of established and novel methods for personalized neuromodulation techniques which can effectively intervene with vagus nerve activity. Attempts should lead to effective and comfortable treatment modalities as well as to a reliable and feasible assessment of therapeutic efficiency of vagus nerve stimulation in chronic diseases. The following objectives can be identified with respect to the aforementioned challenges: Objective 1: Personalized adaptive stimulation patterns (refer to challenge 1) Effects of established and novel stimulation schemes are studied. This includes variation of stimulation site, waveform shape, amplitude, pulse width, frequency, duty cycle, or a favourable combination with other therapies. Investigations in different patient populations and diseases allow for insights into underlying mechanisms and improve therapeutic efficiency concerning established and new application areas. Objective 2: Specific stimulation (refer to challenge 2) Sophisticated electrode designs and stimulation paradigms (current steering, etc.) are needed to attain varying stimulation intensity in different nerve structures (to avoid refractory behaviour of stimulated nerves or to address adaptation processes appropriately) and to stimulate selectively (adaptively) central nervous system structures, parasympathetic and/or sympathetic nerve branches, or specific effector organs. This reduces undesired side effects of stimulation and enables a variety of new application fields. Furthermore, studies on effects of specific stimulation will enable insights into underlying bodily mechanisms. Objective 3: Objective markers for stimulation efficiency (refer to challenge 3) Optimization of neuromodulation techniques requires a sound understanding of stimulation induced changes in physiological parameters, processes, and disease state. An easy assessment is aimed at, which would allow for intermittent or continuous, clinical or home monitoring. Specific biomarkers have to be explored, which reflect best the therapeutic impact. Novel multiparametric sensor technologies can be used for flexible and robust assessment of the patient state. An identification of (non-)responders will be favored. This data would provide the fundament for biofeedback-controlled stimulation. Objective 4: Biofeedback-controlled stimulation (refer to challenge 4) Flexible and adaptable closed-loop stimulation systems offer the possibility to optimize stimulation patterns and therapy with respect to individual patients, specific diseases, and the (adaptive) dynamics of the nervous system. Highly flexible stimulation parameters account for the actual needs of different patients and human adaptive effects. Synchronization of stimulation patterns with intrinsic body rhythms will also be considered. New approaches in biofeedback controlled stimulation provide better understanding of the complex relationships between stimulation patterns, recorded biosignals, and therapeutic effects. Appropriate control algorithms will facilitate a fast identification of (non-)responders. - 7 -
Objectives Objective 5: Partner contributions - 8 -
Proposed Research Activities 5 Proposed Research Activities Within the scope of the proposed working module for COST EMF-MED, several research activities will be performed. Activity 1: Personalized adaptive stimulation (refer to objective 1 & 2) A small number of fixed novel stimulation schemes with adaptive stimulation amplitude (to produce a tingling sensation at the stimulation region) will be applied in diabetics and peripheral arterial disease patients suffering from pain and chronic wounds as well as in healthy controls. A pilot study including patients with cervical dystonia should proof pvns effects. This study should evaluate long term effects of stimulation utilizing a fixed number of previously defined stimulation paradigms. Stimulation will be performed in distinct areas of the auricle, all showing vagal innervation, to explore differences in specific therapies. Novel stimulation schemes will be established with respect to novel electrode designs. Activity 2: Objective assessment of stimulation efficiency (refer to objective 3) Short term effects during short interventional sessions will be monitored. Multiparametric assessment of physiological parameters (such as ECG, blood pressure, pulse waveform, etc.) and of subjective measures (VAS, pain free walking distance, etc.) will give insights into varying stimulation effects with respect to disease, symptom, and stimulation paradigm. Out of this multiparametric set of data, most appropriate physiological parameters should be identified for future assessment of stimulation efficiency and therapeutic outcome. Activity 3: Biofeedback-controlled stimulation (refer to objective 4) The acquired data of the aforementioned investigations will be utilized to test biofeedbackcontrolled adapted stimulation. Therapeutic effects will be compared to uncontrolled stimulation. Activity 4: Partner contributions Room for your appreciated contributions - 9 -
References References [1] F.H. Martini, M.J. Timmons, R.B. Tallitsch. Human Anatomy. Pearson, 2009. [2] E.T. Peuker, T.J. Filler. The nerve supply of the human auricle. Clinical Anatomy, vol. 15, pp. 35-37, 2002. [3] S.A. Safi, W. Neuhuber. Anatomical study of the auricular branch of the vagus nerve (ABNV) in man. 57 th Annual Meeting of the German Society for Neuropathology and Neuroanatomy, German Medical Science GMS Publishing House, 2012. [4] S.C. Schachter, C.B. Saper. Vagus Nerve Stimulation. Epilepsia, vol. 39(7), pp. 677 686, 1998. [5] D.A. Groves, V.J. Brown. Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects. Neuroscience and Biobehavioral Reviews, vol. 29, pp. 493-500, 2009. [6] A.P. Amar, M.L. Levy, et al. Vagus nerve stimulation. Proceedings of the IEEE, vol. 96(7), pp. 1142-1151, 2008. [7] P.J. Schwartz, G.M. DeFerrari, et al. Long term vagal stimulation in patients with advanced heart failure: first experience in man. European Journal of Heart Failure, vol. 10(9), pp. 884 91, 2008. [8] C.B. Nemeroff, H.S. Mayberg, S.E. Krahl. VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms. Neuropsychopharmacology, vol. 31(7), pp. 1345-55, 2006. [9] R. Terry, L. Fellow. Vagus Nerve Stimulation: A Proven Therapy for Treatment of Epilepsy Strives to Improve Efficacy and Expand Applications. 31 st Annual International Conference of the IEEE EMBS, Minneapolis, pp. 4631 4634, 2009. [10] J.C. Széles, M.R. Hoda, P. Polterauer. Application of electrostimulation acupuncture (P- Stim) in clinical practice. Schmerznachrichten from Austrian Pain Association, vol. 1, 2001. [11] S. Kampusch, E. Kaniusas, J.C. Széles. New approaches in multi-punctual percutaneous stimulation of the auricular vagus nerve. Proceedings of the 6 th International IEEE EMBS Conference on Neural Engineering, pp. 263-266, 2013. [12] J. Ellrich. Transcutaneous vagus nerve stimulation. European Neurological Review, vol. 6(4), pp. 254-256, 2012. [13] H. Stefan, G. Kreiselmeyer, et al. Transcutaneous vagus nerve stimulation (t-vns) in pharmacoresistant epilepsies: a proof of concept trial. Epilepsia, vol. 53(7), pp. 115-118, 2012. [14] P.J. Rong, J.L. Fang, et al. Transcutaneous vagus nerve stimulation for the treatment of depression: a study protocol for a double blinded randomized clinical trial. BMC Complementary and Alternative Medicine, vol. 12, 2012. - 10 -
References [15] S.M. Sator-Katzenschlager, G. Scharbert, et al.: The short and long term benefit in chronic low back pain through adjuvant electrical versus manual auricular acupuncture. Anesthesia & Analgesia, vol. 98, pp. 1359-1364, 2004. [16] T. Payrits, A. Ernst, et al. Vagal Stimulation A new possibility for conservative treatment of peripheral arterial occlusion disease. Zentralblatt für Chirurgie, vol. 136, pp. 431-435, 2011. [17] J.C. Széles, S. Kampusch, E. Kaniusas. Peripheral blood perfusion controlled by auricular vagus nerve stimulation. Proceedings of 17 th International Conference on Biomedical Engineering, pp. 73-77, 2013. [18] J.C. Széles, G. Varoneckas, E. Kaniusas. Auricular electrical stimulation (P-STIM) for insomnia treatment using remote control. Med-e-Tel, Luxembourg, 2010. [19] S. Kampusch, E. Kaniusas, J.C. Széles. Expected effects of auricular vagus nerve stimulation in dystonia. Biomedizinische Technik, vol. 58(1), 2013. [20] A. Haensel, P.J. Mills, et al. The relationship between heart rate variability and inflammatory markers in cardiovascular diseases. Psychoneuroendocrinology, vol. 33(10), pp. 1305 12, 2008. [21] L. Yu, B.J. Scherlag, et al. Low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve: a noninvasive approach to treat the initial phase of atrial fibrillation. Heart Rhythm, vol. 10(3), pp. 428 435. 2013. [22] K. Vonck, V. De Herdt, et al. Thalamic and limbic involvement in the mechanism of action of vagus nerve stimulation, a SPECT study. Seizure : The Journal of the British Epilepsy Association, vol. 17(8), pp. 699 706, 2008. [23] T. Kraus, K. Hösl, et al. BOLD fmri deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation. Journal of Neural Transmission, vol. 114, pp. 1485-1493, 2007. [24] S. Dietrich, J. Smith, et al. A novel transcutaneous vagus nerve stimulation leads to brainstem and cerebral activations measured by functional MRI. Biomedizinische Technik, vol. 53(3), pp. 104-111, 2008. [25] E. Kaniusas, L. Gbaoui, et al. Validation of auricular electrostimulation by heart rate variability and blood perfusion: possibilities and restrictions. Proceedings of Microelectronics Conference 2008, pp. 180-184, 2008. [26] E. Kaniusas, J.C. Széles, et al. Adaptive auricular electrical stimulation controlled by vital biosignals. Proceedings of the 2 nd International Conference on Biomedical Electronics and Devices, pp. 304-309, 2009. [27] R. La Marca, M. Nedeljkovic, et al. Effects of auricular electrical stimulation on vagal activity in healthy men: evidence from a three-armed randomized trial. Clinical Science, vol. 118, pp. 537-46, 2010. - 11 -
References [28] E. Kaniusas, G. Varoneckas, et al. Optic visualization of auricular nerves and blood vessels: optimisation and validation. IEEE Transactions on Instrumentation and Measurement, vol. 60(10), pp. 3253 3258, 2011. [29] T.A. Anholt, S. Ayal, J.A. Goldberg. Recruitment and blocking properties of the CardioFit stimulation lead. Journal of Neural Engineering, vol. 8, 2011. [30] D.T.T. Plachta, M. Gierthmuehlen et al. Blood pressure control with selective vagal nerve stimulation and minimal side effects. Journal of Neural Engineering, vol. 11, 2014. [31] J. Rozman, S. Ribaric. Selective recording of electroneurograms from the left vagus nerve of a dog during stimulation of cardiovascular or respiratory systems. The Chinese Journal of Physiology, vol. 50(5), pp. 240 250, 2007. [32] Q. Mu, D.E. Bohning, et al. Acute vagus nerve stimulation using different pulse widths produces varying brain effects. Biological Psychiatry, vol. 55, pp. 816-825, 2004. [33] M. Tosato, K. Yoshida et al. Closed-loop control of the heart rate by electrical stimulation of the vagus nerve. Medical & Biological Engineering & Computing, vol. 44, pp. 161-169, 2006. [34] V. Napadow, R.R. Edwards, et al. Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular vagal afferent nerve stimulation. Pain Medicine, vol. 13(6), pp. 777-789, 2012. - 12 -
Full Contact Details Full Contact Details Proposers / Austria team Our group is concerned with novel attempts concerning electrical stimulation of percutaneous afferent vagus nerve endings in the human auricle (pvns). Univ.-Ass. Dipl.-Ing. Stefan Kampusch Tel.: +43 (0)1 58801 351 101 E-Mail: stefan.kampusch@tuwien.ac.at Vienna University of Technology Institute of Electrodynamics, Microwave, and Circuit Engineering Research Group Biomedical Sensing Gußhausstraße 27-29/ E354, A-1040 Vienna Ao.Univ.Prof. Dipl.-Ing. Dr.techn. Eugenijus Kaniusas Tel.: +43 (0)1 58 80 1-351 22 E-Mail: kaniusas@tuwien.ac.at Vienna University of Technology Institute of Electrodynamics, Microwave, and Circuit Engineering Head of Research Group Biomedical Sensing Chairman of Study Commission Biomedical Engineering Gußhausstraße 27-29/ E354, A-1040 Vienna Dr.med. Jozsef Constantin Széles Tel.: +43 (0)676 87832013 E-Mail: jozsef.szeles@meduniwien.ac.at Medical University of Vienna University Clinic for Surgery, Department of Transplantation Vienna General Hospital Head of the Special Outpatient Clinic P-Stim Therapy Währinger Gürtel 18-20, A-1090 Vienna Partners - 13 -