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Transcutaneous Auricular Vagus Nerve Stimulation in Pediatric Patients: A Systematic Review of Clinical Treatment Protocols and Stimulation Parameters

Open AccessPublished:August 19, 2022DOI:https://doi.org/10.1016/j.neurom.2022.07.007

      Abstract

      Background

      Noninvasive transcutaneous vagus nerve stimulation (tVNS) has promising therapeutic potential in a wide range of applications across somatic and psychiatric conditions. Compared with invasive vagus nerve stimulation, good safety and tolerability profiles also support the use of tVNS in pediatric patients. Potential neurodevelopment-specific needs, however, raise concerns regarding the age-appropriate adjustment of treatment protocols and applied stimulation parameters.

      Objective

      In this study, we aimed to review registered trials and published studies to synthesize existing tVNS treatment protocols and stimulation parameters applied in pediatric patients.

      Materials and Methods

      A systematic search of electronic data bases (PubMed, Scopus, MEDLINE, Cochrane Library, and PsycINFO) and ClinicalTrials was conducted. Information on patient and study-level characteristics (eg, clinical condition, sample size), the tVNS device (eg, brand name, manufacturer), stimulation settings (eg, pulse width, stimulation intensity), and stimulation protocol (eg, duration, dosage of stimulation) was extracted.

      Results

      We identified a total of 15 publications (four study protocols) and 15 registered trials applying tVNS in pediatric patients (<18 years of age). Most of these studies did not exclusively address pediatric patients. None of the studies elaborated on neurodevelopmental aspects or justified the applied protocol or stimulation parameters for use in pediatric patients.

      Conclusions

      No dedicated pediatric tVNS devices exist. Neither stimulation parameters nor stimulation protocols for tVNS are properly justified in pediatric patients. Evidence on age-dependent stimulation effects of tVNS under a neurodevelopment framework is warranted. We discuss the potential implications of these findings with clinical relevance, address some of the challenges of tVNS research in pediatric populations, and point out key aspects in future device development and research in addition to clinical studies on pediatric populations.

      Keywords

      Introduction

      Noninvasive transcutaneous vagus nerve stimulation (tVNS) enables electrical stimulation of the vagus nerve while mitigating the risks associated with invasive vagus nerve stimulation (VNS).
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      Efficacy of transcutaneous vagus nerve stimulation as treatment for depression: a systematic review.
      tVNS is applied in a wide range of clinical fields with increasing evidence of its efficacy
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      International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (version 2020).
      ; it also demonstrates good safety and tolerability.
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      • Leung H.
      • et al.
      Safety and tolerability of transcutaneous vagus nerve stimulation in humans; a systematic review.
      Given its favorable risk-benefit profile, tVNS has potential for application in pediatric patients. However, for several reasons, it remains unclear whether treatment protocols and stimulation parameters require adjustment for use in this patient group. Concerning the underlying neurobiological mechanisms targeted by tVNS, children and adolescents are characterized by developmental specifics that need to be considered when contemplating tVNS as a treatment option in pediatric patients. Furthermore, pediatric populations pose considerable practical challenges to the application of stimulation, compliance monitoring, and the proper assessment of adverse events.
      Early childhood is a critical time for brain development, marked by massive growth spurts (the human brain reaches approximately 90% of adult size by the age of six years), whereas a significant amount of remodeling in later childhood and throughout adolescence and young adulthood takes place before the brain can fully function as an adult brain.
      • Casey B.J.
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      The adolescent brain.
      Adolescence in particular is a period of dramatic neural reorganization owing to increased neural plasticity, whereas the maturation of various neural circuits also depends, to a large degree, on one's experiences on both physical and psychosocial levels.
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      • Braams B.R.
      Experience during adolescence shapes brain development: from synapses and networks to normal and pathological behavior.
      In general, brain sites that involve primary functions, such as motor and sensory systems, are assumed to mature earlier than higher-order association areas that integrate these primary functions.
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      Dynamic mapping of human cortical development during childhood through early adulthood.
      ,
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      Mapping changes in the human cortex throughout the span of life.
      Pruning processes further allow for fine-tuning and strengthening of connections between prefrontal and subcortical regions.
      • Casey B.J.
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      • Hare T.A.
      The adolescent brain.
      Besides regional changes, pathways of connectivity continue to develop across childhood into adulthood in nonlinear fashion. Specifically, neural networks underlying social, emotional, and cognitive function exhibit heightened experience-dependent plasticity during sensitive periods that occur in different circuits and regions at specific periods of development.
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      • Andersen S.
      • Braams B.R.
      Experience during adolescence shapes brain development: from synapses and networks to normal and pathological behavior.
      Besides, adolescent sensitive periods are characterized by large interindividual differences.
      • Fuhrmann D.
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      Adolescence as a sensitive period of brain development.
      The afferent vagal system targeted by tVNS has widespread influence across major neural networks, and the mechanisms driving the beneficial effects of electrical stimulation of the vagus nerve as found across health conditions are assumed to overlap extensively
      • Komisaruk B.R.
      • Frangos E.
      Vagus nerve afferent stimulation: projection into the brain, reflexive physiological, perceptual, and behavioral responses, and clinical relevance.
      —yet, and critically, the specific mechanisms behind the therapeutic effects of tVNS are still not known.
      • Yap J.Y.Y.
      • Keatch C.
      • Lambert E.
      • Woods W.
      • Stoddart P.R.
      • Kameneva T.
      Critical review of transcutaneous vagus nerve stimulation: challenges for translation to clinical practice.
      Generally, and very briefly, the vagus nerve conveys information from diverse organ systems in the human body to the nucleus tractus solitarii (NTS) in the brainstem, where input is relayed directly and indirectly to diverse components of the brain. The synaptic projections from the NTS differentially modulate neuronal activity within key regions involved in affect/emotion regulation, pain modulation, or memory and attention processes
      • Komisaruk B.R.
      • Frangos E.
      Vagus nerve afferent stimulation: projection into the brain, reflexive physiological, perceptual, and behavioral responses, and clinical relevance.
      —as outlined earlier, most of these regions are subject to substantial neurodevelopmental growth and remodeling across childhood and adolescence into adulthood.
      The development and application of specific medical devices are required to meet the development-specific needs of children and adolescents.
      Yet development-specific needs, particularly those of adolescents, have long received very limited attention in the history of medical device development.
      • Gelijns A.C.
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      • Vitale M.
      • Vipul M.
      • Moskowitz A.
      The dynamics of pediatric device innovation: putting evidence in context.
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      Experience with pediatric medical device development.
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      • Ho M.
      • Umezu M.
      Comparison of supportive regulatory measures for pediatric medical device development in Japan and the United States.
      Considering children, in turn, medical device development has been described to simply “gravitate […] towards the repurposing of adult’s applications, on the basis of the incorrect assumption that devices can simply be made smaller in line with a child’s size, with little consideration for changes in anatomy and physiology through growth and development” (p. 17).
      • Dimitri P.
      • Pignataro V.
      • Lupo M.
      • et al.
      Medical device development for children and young people—reviewing the challenges and opportunities.
      Critically, the development of tVNS devices, even though commercially available devices show no restrictions of application to exclusively adult populations, currently does not intend specific stimulation systems for children and young people.
      • Bolz A.
      • Bolz L.O.
      Technical aspects and future approaches in transcutaneous vagus nerve stimulation (tVNS).
      This also might seem reminiscent of a past situation in which, alongside clinical practice experience in children and adolescents, the administration of psychotropic drugs in pediatric patients was usually guided by evidence extrapolated from adults, leading to substantial off-label use.
      • Egberts K.M.
      • Mehler-Wex C.
      • Gerlach M.
      Therapeutic drug monitoring in child and adolescent psychiatry.
      In part, this was due to a relative lack of high-quality pharmacokinetic, efficacy, and safety data, partly because drug regulatory authorities did not request evidence for this patient group until not much longer than a decade ago—which put pediatric patients at an increased risk of suboptimal treatment outcomes (eg, inefficacy of treatments, high rates of adverse effects). Respective studies now have demonstrated that, for example, children and adolescents experience higher rates of nausea and activation than adults when prescribed antidepressants,
      • Safer D.J.
      • Zito J.M.
      Treatment-emergent adverse events from selective serotonin reuptake inhibitors by age group: children versus adolescents.
      antipsychotics are associated with higher rates of sedation, weight gain, prolactin elevation, and withdrawal dyskinesia in children than in adults, mood stabilizers have been associated with greater weight gain in children,
      • Correll C.U.
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      Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, randomized, placebo-controlled trials.
      and children receiving lamotrigine experience serious dermatologic adverse effects at higher rates than adults.
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      • Choonara I.
      • Sammons H.M.
      Safety of lamotrigine in paediatrics: a systematic review.
      In sum, the consideration of development-specific needs seems equally critical when good adherence and clinical benefit are to be achieved through a treatment applying medical devices.
      • Lang A.R.
      • Martin J.L.
      • Sharples S.
      • Crowe J.A.
      Medical device design for adolescent adherence and developmental goals: a case study of a cystic fibrosis physiotherapy device.
      • Lang A.R.
      Medical Device Design for Adolescents.
      • Duffy V.G.
      A qualitative assessment of medical device design by healthy adolescents.
      • Lang A.R.
      • Martin J.L.
      • Sharples S.
      • Crowe J.A.
      The effect of design on the usability and real world effectiveness of medical devices: a case study with adolescent users.
      The development and application of medical devices should address changes in growth and psychosocial maturation, physiology, and pathophysiology and avoid inappropriate repurposing of adult technologies.
      • Dimitri P.
      • Pignataro V.
      • Lupo M.
      • et al.
      Medical device development for children and young people—reviewing the challenges and opportunities.
      Regarding the development and application of treatment systems for auricular tVNS in pediatric patients, critical aspects include, among others, ear-anatomical changes in development (ie, electrode fit and engineering), increased needs for independence, especially during puberty (compliance and compliance monitoring), and the assessment of physical symptoms and mental distress, which might be hampered by an inability to communicate such symptoms in specific pediatric subpopulations (ie, affecting the assessment of adverse effects and adverse events). Addressing these aspects should not only be considered in the development of tVNS devices and systems but also should present a key priority in research studies producing relevant data on the clinical application of tVNS in pediatric populations—if really contributing to achieving good clinical benefit presents a primary aim in these studies.
      Several comprehensive reviews of tVNS already exist, addressing, among others, current reporting standards and practice,
      • Farmer A.D.
      • Strzelczyk A.
      • Finisguerra A.
      • et al.
      International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (version 2020).
      safety and tolerability,
      • Redgrave J.
      • Day D.
      • Leung H.
      • et al.
      Safety and tolerability of transcutaneous vagus nerve stimulation in humans; a systematic review.
      the underlying anatomical rationale,
      • Butt M.F.
      • Albusoda A.
      • Farmer A.D.
      • Aziz Q.
      The anatomical basis for transcutaneous auricular vagus nerve stimulation.
      technical aspects and engineering,
      • Bolz A.
      • Bolz L.O.
      Technical aspects and future approaches in transcutaneous vagus nerve stimulation (tVNS).
      ,
      • Kaniusas E.
      • Kampusch S.
      • Tittgemeyer M.
      • et al.
      Current directions in the auricular vagus nerve stimulation II — an engineering perspective.
      physiological aspects,
      • Kaniusas E.
      • Kampusch S.
      • Tittgemeyer M.
      • et al.
      Current directions in the auricular vagus nerve stimulation I — a physiological perspective.
      neurophysiological underpinnings,
      • Colzato L.
      • Beste C.
      A literature review on the neurophysiological underpinnings and cognitive effects of transcutaneous vagus nerve stimulation: challenges and future directions.
      and clinical considerations
      • Yap J.Y.Y.
      • Keatch C.
      • Lambert E.
      • Woods W.
      • Stoddart P.R.
      • Kameneva T.
      Critical review of transcutaneous vagus nerve stimulation: challenges for translation to clinical practice.
      ,
      • Bremner J.D.
      • Gurel N.Z.
      • Wittbrodt M.T.
      • et al.
      Application of noninvasive vagal nerve stimulation to stress-related psychiatric disorders.
      ,
      • Cimpianu C.L.
      • Strube W.
      • Falkai P.
      • Palm U.
      • Hasan A.
      Vagus nerve stimulation in psychiatry: a systematic review of the available evidence.
      of tVNS. Yet none of these reviews specifically addresses aspects to be considered in the research and application of tVNS in pediatric patients. In this study, we aimed to systematically review existing tVNS treatment protocols and stimulation parameters used in pediatric patients, independent of the underlying condition. The primary aim of this review was to synthesize existing approaches concerning the dosage, frequency, and duration of stimulation and to review standards in the use of selected stimulation parameters in children and young people. After the review of existing practice, we aim to provide recommendations to foster future ambitions in the field of pediatric tVNS.
      Of note, current forms of tVNS can include both transcutaneous auricular VNS (applied to the external surface of the ear, in the areas innervated by the auricular branch of the vagus) and transcutaneous cervical VNS (applied to the surface of the neck over the cervical vagus nerve). In this study, we focus on auricular tVNS because it was shown that cervical tVNS can make selective transcutaneous stimulation of vagus nerve fibers difficult, with existing devices most likely indiscriminately stimulating afferent and efferent fibers alike
      • Yap J.Y.Y.
      • Keatch C.
      • Lambert E.
      • Woods W.
      • Stoddart P.R.
      • Kameneva T.
      Critical review of transcutaneous vagus nerve stimulation: challenges for translation to clinical practice.
      ,
      • Yuan H.
      • Silberstein S.D.
      Vagus nerve and vagus nerve stimulation, a comprehensive review: part II.
      —impeding our objective to synthesize stimulation protocols of tVNS in children and youths that produce consistent and reproducible results. In principle, auricular tVNS is achieved by means of an ear electrode connected to the actual stimulation device.
      • Farmer A.D.
      • Strzelczyk A.
      • Finisguerra A.
      • et al.
      International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (version 2020).
      The ear electrode, typically consisting of two surface electrodes, is placed at the target site, innervated by the auricular branch of the vagus.
      • de Gurtubay I.G.
      • Bermejo P.
      • Lopez M.
      • Larraya I.
      • Librero J.
      Evaluation of different vagus nerve stimulation anatomical targets in the ear by vagus evoked potential responses.
      In the clinical setting, patients are instructed to apply stimulation for a defined duration (minutes to hours) per day during a defined treatment period (weeks or months). Commercially available devices are handheld and allow stimulation during daily routine. Furthermore, these devices typically allow the adjustment of certain stimulation parameters (predominantly the stimulation intensity) according to individual needs by the user or as defined in treatment protocols based or not based on a clinical rationale. Custom-made devices (ie, modified devices for transcutaneous electrical nerve stimulation [TENS]) may come with restrictions concerning these degrees of freedom, explaining expected variance in stimulation parameters and treatment protocols.

      Material and Methods

      Published studies on auricular tVNS in children and adolescents were searched in electronic data bases (PubMed, Scopus, MEDLINE, Cochrane Library, and PsycINFO). The following search strategy was applied: “transcutaneous vagus nerve stimulation” OR “taVNS” OR “tVNS” OR “t-VNS,” AND “child∗” OR “youth” OR “adolescen∗.” No additional search engine filters or restrictions were used. Empirical studies published in peer-reviewed journals in English, French, Spanish, or German language up to July 28, 2021 were considered for inclusion in the review. Duplicates were removed, followed by an initial screening of titles and abstracts to identify articles of relevance. All studies reporting on interventional studies using auricular tVNS in pediatric patients (<18 years of age) were included. Studies addressing a broader age range were considered if underage patients were part of the reported sample. Reference lists of all included articles were screened for additional papers published on the topic (snowballing). The following information was extracted from all eligible studies: clinical condition; sample size; sample composition in terms of sex; sample mean age and SD; tVNS device use (ie, brand name, manufacturer); electrode type for auricular stimulation; stimulation site; pulse width; stimulation intensity (in mA); stimulation frequency (in Hz); and dosage of stimulation. In cases where insufficient data were reported, authors were contacted, and data were requested. To complement the search in electronic data bases, ongoing clinical trials on tVNS in pediatric patients were searched on ClinicalTrials.gov.

      Results

      Search Results

      The systematic search and study selection procedure is depicted below (Fig. 1). The systematic search identified a total of 169 articles. After removal of duplicates, 79 articles (46.8%) remained for further screening. Finally, 13 published articles (7.7%) fulfilled the inclusion criteria. Two articles were further identified by snowballing of the reference lists of included studies (Table 1). A total of 15 registered trials were identified (Table 2). Data were requested and provided from one ongoing clinical trial (also included in Table 1).
      Figure thumbnail gr1
      Figure 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 flow diagram depicting the current systematic search and study selection procedure. iVNS, invasive vagus nerve stimulation.
      Table 1Summary of tVNS Treatment Protocols and Stimulation Parameters Reported in Registered Trials in Children and Adolescents.
      StudyClinical conditionStudy designSample size (f)Mean age (range)tVNS deviceType of electrodeStimulation sitePulse widthStimulation intensity (mA)Stimulation frequency (Hz)Stimulation duty cycleStimulation dose
      Aihua et al
      • Aihua L.
      • Lu S.
      • Liping L.
      • Xiuru W.
      • Hua L.
      • Yuping W.
      A controlled trial of transcutaneous vagus nerve stimulation for the treatment of pharmacoresistant epilepsy.
      Pharmaco-resistant epilepsyRCT26 (n.r.)34.5 (16–60)TENS-200, Hua Tuo brandBilateral (plug like)Ramsay-Hunt zone0.2 s2 mA (increasing in steps of 2 mA until discomfort)20 Hzn.r. (likely constant stimulation)20 min, 3 times per day, for 12 mo
      Liu et al
      • Liu A.
      • Rong P.
      • Gong L.
      • et al.
      Efficacy and safety of treatment with transcutaneous vagus nerve stimulation in 17 patients with refractory epilepsy evaluated by electroencephalogram, seizure frequency, and quality of life.
      Refractory epilepsyObservational study17 (7)27 (12–65)TENS-sm, Suzhou Medical Audio Supplies Company Ltd, ChinaClip electrodeCavity of the auricular concha and the outside of the external ear canalBiphasic waveform, 200 s
      Reported as seconds, likely a typographic error and actually reflecting 200 ms.
      4 mA (increasing in steps of 2 mA until individual tolerance level was reached)10 Hzn.r. (likely constant stimulation)20 min, 3 times per day, for 6 mo
      Badran et al
      • Badran B.W.
      • Jenkins D.D.
      • Cook D.
      • et al.
      Transcutaneous auricular vagus nerve stimulation-paired rehabilitation for oromotor feeding problems in newborns: an open-label pilot study.
      Premature/HIE infantsOpen label pilot study14 (n.r.)Preterm infants (<33 wk) and term infants suffering from HIEDigitimer DS7AHCustom ear electrodeTragus500 μs0.1 mA25 Hz2 min on/15 s off30 min per day
      Barbella et al
      • Barbella G.
      • Cocco I.
      • Freri E.
      • et al.
      Transcutaneous vagal nerve stimulation (t-VNS): an adjunctive treatment option for refractory epilepsy.
      Refractory epilepsyProspective, open-label, single-center experimental trial20 (10)38.6 (16–57)n.r.n.r.n.r. (placed according to the 10–20 System)n.r.0.6–0.8 mA20 s on/5 min off4 h in individual sessions (duration of 1 h minimum) per day, for 6 mo
      Fang et al
      • Fang J.
      • Rong P.
      • Hong Y.
      • et al.
      Transcutaneous vagus nerve stimulation modulates default mode network in major depressive disorder.
      MDDSingle blind clinical trial34 (24)40.87 (16–70)n.r.Bilateral clip electrodesAuricular concha1 ms4–6 mA20 Hzn.r.30 min, 2 times per day, for 5 d a week, for 4 wk
      Finetti
      • Finetti C.
      P90. Transcutaneous vagus nerve stimulation (t-VNS) in a child with Dravet syndrome — a case report.
      Dravet syndromeCase report1 (1)11 (n.r.)NEMOS, Cerbomedn.r.n.r.n.r.n.r.n.r.n.r.Daily stimulation time of 4 h
      He et al
      • He W.
      • Jing X.
      • Wang X.
      • et al.
      Transcutaneous auricular vagus nerve stimulation as a complementary therapy for pediatric epilepsy: a pilot trial.
      EpilepsyPilot trial14 (3)7.8 (2–12)TENS-200, Suzhou, ChinaConductive rubber clips (5 mm diameter)Concha cavity and cymba conchaen.r.0.4–1 mA (individual tolerance level)20 Hzn.r.30 min, 3 times a day, for 24 wk
      He et al
      • He W.
      • Wang X.Y.
      • Zhou L.
      • et al.
      Transcutaneous auricular vagus nerve stimulation for pediatric epilepsy: study protocol for a randomized controlled trial.
      EpilepsyRCT (study protocol)42 (n.r.)n.r. (2–14)TENS-200, Suzhou, Jiangsu, ChinaConductive rubber clips (5 mm diameter)Concha cavity and cymba conchaen.r.1 mA20 Hzn.r.30 min, 3 times a day, for 6 mo
      Koenig et al
      • Koenig J.
      • Parzer P.
      • Haigis N.
      • et al.
      Effects of acute transcutaneous vagus nerve stimulation on emotion recognition in adolescent depression.
      MDDPreclinical experimental trial63 (49)n.r. (14–17)VITOS, CerbotechEar electrode “Legacy”Cymba conchae250 μs0.5 mA1 Hz30 s on/30 s off2 stimulation periods of 15 min duration
      Li et al
      • Li T.T.
      • Wang Z.J.
      • Yang S.B.
      • et al.
      Transcutaneous electrical stimulation at auricular acupoints innervated by auricular branch of vagus nerve pairing tone for tinnitus: study protocol for a randomized controlled clinical trial.
      TinnitusRCT (study protocol)120 (n.r.)n.r. (15–65)TENS device; Suzhou Medical Appliance Co Ltd, ChinaCarbon-impregnated silicone connected by metal wireCymba conchae and the triangular fossa<1 ms1–5 mA20 Hzn.r.30 min, every other day, for 8 wk
      Mei et al
      • Mei Z.
      • Yang S.
      • Cai S.
      • et al.
      Treatment of tinnitus with electrical stimulation on acupoint in the distribution area of ear vagus nerve combining with sound masking: randomized controlled trial.
      TinnitusRCT63 (34)41.1 (17–63)TENS-200, Suzhou, ChinaElectrode clipCavum conchae1 ms1 mA20 Hzn.r.20 min, 2 times a day, for 8 wk
      Rong et al
      • Rong P.J.
      • Fang J.L.
      • Wang L.P.
      • et al.
      Transcutaneous vagus nerve stimulation for the treatment of depression: a study protocol for a double blinded randomized clinical trial.
      DepressionDouble-blinded RCT (study protocol)60 (n.r.)n.r. (16–70)TENS device2 carbon- impregnated silicone electrodesConcha<1 ms1 mA (adjustable)20 Hzn.r.30 min, 2 times a day, 5 days a week, for 12 wk
      Rong et al
      • Rong P.
      • Liu A.
      • Zhang J.
      • et al.
      An alternative therapy for drug-resistant epilepsy: transcutaneous auricular vagus nerve stimulation.
      Drug-resistant epilepsyObservational study50 (20)25.2 (n.r.)TENS device; Suzhou Medical Appliance Co Ltd, China2 carbon-impregnated silicone electrodesTriangular fossa of the auricle≤1 ms pulse duration1 mA20–30 Hzn.r. (likely constant stimulation)30 min, 2 times a day, for 24 wk
      Rong et al
      • Rong P.
      • Liu A.
      • Zhang J.
      • et al.
      Transcutaneous vagus nerve stimulation for refractory epilepsy: a randomized controlled trial.
      Refractory epilepsyRCT98 (34)24.44 (n.r.)TENS-sm; Suzhou Medical Appliance Co Ltd, China3 carbon-impregnated silicone electrode tipsTriangular fossa off the auricle≤1 ms pulse duration1 mA20–30 Hzn.r. (likely constant stimulation)30 min, 2 times a day, for 24 wk
      Tauber
      • Tauber M.
      • Valette M.
      Study of emotion and cognition abilities of children with PWS and proposition of an innovative remediation (PRACOM1). Identifier NCT04526379.
      ,
      Registered and ongoing trial.
      Prader-Willi syndromeNonrandomized clinical trial12 (n.r.)n.r. (9–15)Parasym™ tVNS DeviceEar clip electrodeTragus of the left ear200 μs1–36 mA (until a tingling sensation was reported)25 Hzn.r.60 min, 5 d a week, for 6 mo
      Xiao et al
      • Xiao X.
      • Hou X.
      • Zhang Z.
      • et al.
      Efficacy and brain mechanism of transcutaneous auricular vagus nerve stimulation for adolescents with mild to moderate depression: study protocol for a randomized controlled trial.
      DepressionRCT (study protocol)120 (n.r.)n.r. (12–16)n.r.Electrode clipCymba concha (auricular)n.r.Adjustable until discomfort4 Hz for 5 s

      20 Hz for 10 s
      n.r.30 min, 2 times a day (morning and evening), for 8 wk
      HIE, Hypoxic-ischemic encephalopathy; MDD, major depressive disorder; n.r., not reported.
      Reported as seconds, likely a typographic error and actually reflecting 200 ms.
      Registered and ongoing trial.
      Table 2Summary of Pediatric tVNS Trials Currently Registered in ClinicalTrials.
      ContactTrial no.Clinical conditionStudy designEnrollment (N)Ages eligible for studyStatusLast update
      BennerNCT05129020Neonatal opioid withdrawal syndromeRandomized8033 wk–1 yNot yet recruitingFebruary 25, 2022
      ChelimskyNCT04247100Pediatric functional gastrointestinal disordersRandomized1012–18 yTerminatedDecember 21, 2021
      DijanNCT04177511Chronic pelvic pain caused by endometriosisRandomized/open label72≥15 yRecruitingDecember 15, 2021
      HeNCT02004340EpilepsyRandomized1202–18 yRecruitingFebruary 13, 2015
      JenkinsNCT05101707Unilateral upper extremity weaknessNonrandomized/open label56–18 moNot yet recruitingFebruary 25, 2022
      JenkinsNCT04643808Poor oral feedingNonrandomized/crossover40Up to 5 moRecruitingFebruary 25, 2022
      Jenkins
      One previous study protocol by the group (NCT0464380) no longer available at the time of submission.
      NCT04632069Poor oral feedingSingle group/open label10Up to 5 moRecruitingJanuary 24, 2022
      Jenkins and LubeskieNCT04849507Poor oral feedingRandomized/crossover20Up to 5 moNot yet recruitingMarch 11, 2022
      LaurentNCT04169776Idiopathic nephrotic syndromeNonrandomized/open label302–21 yRecruitingAugust 31, 2021
      MaNCT05256173EpilepsyRandomized1007–65 yRecruitingFebruary 25, 2022
      ParkerNCT04396470Prader-Willi syndromeRandomized308–14 yWithdrawnMay 6, 2021
      SahnNCT03863704Pediatric inflammatory bowel diseaseRandomized3010–21 yEnrolling by invitationFebruary 2, 2022
      Tauber and ValetteNCT04526379Prader-Willi syndromeNonrandomized/open label60 (30 with and 30 without Prader-Willi syndrome)9–15 yRecruitingNovember 3, 2020
      Van DiestNCT02113306Fear extinction (experimental study)Randomized5016–50 yUnknownApril 14, 2014
      YangNCT03592446DepressionRandomized crossover6015–70 yNot yet recruitingJuly 19, 2018
      One previous study protocol by the group (NCT0464380) no longer available at the time of submission.

      Reported Study Protocols and Stimulation Parameters in Pediatric Patients

      Stimulation Devices and Electrode Types

      Of the 16 studies (including one ongoing trial) included, three failed to report any information on the tVNS device used.
      • Barbella G.
      • Cocco I.
      • Freri E.
      • et al.
      Transcutaneous vagal nerve stimulation (t-VNS): an adjunctive treatment option for refractory epilepsy.
      • Fang J.
      • Rong P.
      • Hong Y.
      • et al.
      Transcutaneous vagus nerve stimulation modulates default mode network in major depressive disorder.
      • Xiao X.
      • Hou X.
      • Zhang Z.
      • et al.
      Efficacy and brain mechanism of transcutaneous auricular vagus nerve stimulation for adolescents with mild to moderate depression: study protocol for a randomized controlled trial.
      In the remaining studies, most commonly, some devices for TENS were used: four studies
      • Aihua L.
      • Lu S.
      • Liping L.
      • Xiuru W.
      • Hua L.
      • Yuping W.
      A controlled trial of transcutaneous vagus nerve stimulation for the treatment of pharmacoresistant epilepsy.
      • He W.
      • Jing X.
      • Wang X.
      • et al.
      Transcutaneous auricular vagus nerve stimulation as a complementary therapy for pediatric epilepsy: a pilot trial.
      • Mei Z.
      • Yang S.
      • Cai S.
      • et al.
      Treatment of tinnitus with electrical stimulation on acupoint in the distribution area of ear vagus nerve combining with sound masking: randomized controlled trial.
      reported to have used a TENS-200 device (Suzhou Medical Appliance Co Ltd, Jinfeng Town, Zhangjiagang, China); two studies
      • Liu A.
      • Rong P.
      • Gong L.
      • et al.
      Efficacy and safety of treatment with transcutaneous vagus nerve stimulation in 17 patients with refractory epilepsy evaluated by electroencephalogram, seizure frequency, and quality of life.
      ,
      • Rong P.
      • Liu A.
      • Zhang J.
      • et al.
      Transcutaneous vagus nerve stimulation for refractory epilepsy: a randomized controlled trial.
      used a TENS-sm device (Suzhou Medical Appliance Co Ltd, Jinfeng Town, Zhangjiagang, China); and three studies
      • Li T.T.
      • Wang Z.J.
      • Yang S.B.
      • et al.
      Transcutaneous electrical stimulation at auricular acupoints innervated by auricular branch of vagus nerve pairing tone for tinnitus: study protocol for a randomized controlled clinical trial.
      • Rong P.
      • Liu A.
      • Zhang J.
      • et al.
      An alternative therapy for drug-resistant epilepsy: transcutaneous auricular vagus nerve stimulation.
      • Rong P.J.
      • Fang J.L.
      • Wang L.P.
      • et al.
      Transcutaneous vagus nerve stimulation for the treatment of depression: a study protocol for a double blinded randomized clinical trial.
      reported to have used a TENS device, without providing further model specifications. One study
      • Finetti C.
      P90. Transcutaneous vagus nerve stimulation (t-VNS) in a child with Dravet syndrome — a case report.
      used a NEMOS Cerbomed device (tVNS Technologies GmbH, Erlangen, Germany) and one study
      • Koenig J.
      • Parzer P.
      • Haigis N.
      • et al.
      Effects of acute transcutaneous vagus nerve stimulation on emotion recognition in adolescent depression.
      a VITOS Cerbotech device (tVNS Technologies GmbH, Erlangen, Germany). One study
      • Badran B.W.
      • Jenkins D.D.
      • Cook D.
      • et al.
      Transcutaneous auricular vagus nerve stimulation-paired rehabilitation for oromotor feeding problems in newborns: an open-label pilot study.
      reported to have used a Digitimer DS7AH device (Digitimer North America Ltd, Fort Lauderdale, Florida). Of note, some of the device types used have now been discontinued, and access to their technical specifications may be limited. Generally, the electrode type used varied widely between studies (Table 1). Although TENS and Digitimer devices often require custom-made electrodes, the manufacturers of NEMOS Cerbomed and VITOS Cerbotech devices provide an easy-to-use package including specific stimulation electrodes, targeting a prespecified stimulation location (ie, cymba conchae). Two studies
      • Barbella G.
      • Cocco I.
      • Freri E.
      • et al.
      Transcutaneous vagal nerve stimulation (t-VNS): an adjunctive treatment option for refractory epilepsy.
      ,
      • Finetti C.
      P90. Transcutaneous vagus nerve stimulation (t-VNS) in a child with Dravet syndrome — a case report.
      did not provide information on the electrodes used.

      Reported Stimulation Locations

      Generally, large discrepancies were seen between studies regarding reported stimulation locations and respective terminology. This was the case even when the same type of device was used and, presumably, the same location of the auricle was stimulated in some of these studies (Table 1). Two studies
      • Barbella G.
      • Cocco I.
      • Freri E.
      • et al.
      Transcutaneous vagal nerve stimulation (t-VNS): an adjunctive treatment option for refractory epilepsy.
      ,
      • Finetti C.
      P90. Transcutaneous vagus nerve stimulation (t-VNS) in a child with Dravet syndrome — a case report.
      failed to report the stimulation site.

      Studies in Epilepsy

      Rong et al
      • Rong P.
      • Liu A.
      • Zhang J.
      • et al.
      An alternative therapy for drug-resistant epilepsy: transcutaneous auricular vagus nerve stimulation.
      studied patients with drug-resistant epilepsy who received tVNS for 24 weeks in a nonrandomized, uncontrolled observational study. Initially, N = 50 patients were recruited, of whom n = 3 dropped out for adverse events (n = 1 severe dizziness, n = 2 red rashes and swelling). No specifics were reported concerning the adjustment of stimulation parameters in the included pediatric patients. In the same year, the authors published results from a randomized controlled trial (RCT) on tVNS
      • Rong P.
      • Liu A.
      • Zhang J.
      • et al.
      Transcutaneous vagus nerve stimulation for refractory epilepsy: a randomized controlled trial.
      in patients aged between 12 and 65 years with refractory epilepsy. Initially, N = 156 patients were recruited, of whom n = 12 were excluded, for reasons that are not known. Auricular tVNS was compared with a sham non-VNS group receiving stimulation of the outer ear canal. The authors report on transient adverse events (skin itch, 6.2%; red rashes and swelling, 4.1%; dizziness, 1%). However, it is not specified whether these occurred in the tVNS or sham group. (Given the similarity in treatment protocol and stimulation parameters, an overlap in samples between Rong et al
      • Rong P.
      • Liu A.
      • Zhang J.
      • et al.
      Transcutaneous vagus nerve stimulation for refractory epilepsy: a randomized controlled trial.
      and Rong et al
      • Rong P.
      • Liu A.
      • Zhang J.
      • et al.
      An alternative therapy for drug-resistant epilepsy: transcutaneous auricular vagus nerve stimulation.
      cannot be ruled out.) The same group
      • Liu A.
      • Rong P.
      • Gong L.
      • et al.
      Efficacy and safety of treatment with transcutaneous vagus nerve stimulation in 17 patients with refractory epilepsy evaluated by electroencephalogram, seizure frequency, and quality of life.
      published another report on patients between 12 and 65 years of age with refractory epilepsy, receiving six months of tVNS. Initially, N = 24 patients were recruited, of whom n = 3 dropped out for poor compliance and n = 1 for inability to independently apply the stimulation. Two other patients dropped out for reasons unrelated to treatment. Adverse events of the stimulation were reported in one patient of unspecified age, who reported mild dizziness and dropped out of the study. No specifics concerning the adjustment of stimulation parameters in pediatric patients were reported. Another study on epilepsy was published earlier by the respective group of authors.
      • Aihua L.
      • Lu S.
      • Liping L.
      • Xiuru W.
      • Hua L.
      • Yuping W.
      A controlled trial of transcutaneous vagus nerve stimulation for the treatment of pharmacoresistant epilepsy.
      Here, N = 60 patients with pharmaco-resistant epilepsy, aged more than four years, were studied. In the RCT design, patients were allocated to the tVNS group, receiving bilateral tVNS over 12 months of treatment. n = 1 patient of the treatment arm dropped out owing to adverse events (dizziness). In n = 3 cases, reasons for loss to follow-up were not reported. Barbella et al
      • Barbella G.
      • Cocco I.
      • Freri E.
      • et al.
      Transcutaneous vagal nerve stimulation (t-VNS): an adjunctive treatment option for refractory epilepsy.
      also applied tVNS in patients aged 16 years and older with refractory epilepsy in an open label pilot study. Six patients reported a reduction of seizure frequency >30% after six months of daily tVNS during the first trial epoch. Notably, none of the responders was a pediatric patient. Again, no adjustment of the stimulation protocol in pediatric subjects was reported. In a pilot study, He et al
      • He W.
      • Jing X.
      • Wang X.
      • et al.
      Transcutaneous auricular vagus nerve stimulation as a complementary therapy for pediatric epilepsy: a pilot trial.
      specifically addressed pediatric epilepsy in patients aged two to 12 years. n = 13 patients completed the 24-week intervention period. Two patients reported adverse effects (ie, mild ulceration of the skin). A subsequent protocol for an RCT was registered
      • He W.
      • Wang X.Y.
      • Zhou L.
      • et al.
      Transcutaneous auricular vagus nerve stimulation for pediatric epilepsy: study protocol for a randomized controlled trial.
      but apparently not completed (Table 2). In 2015, Finetti
      • Finetti C.
      P90. Transcutaneous vagus nerve stimulation (t-VNS) in a child with Dravet syndrome — a case report.
      published an abstract reporting on a case study of an 11-year-old girl with Dravet syndrome who was treated with tVNS.

      Studies in Depression

      Four studies addressed patients with depression, one of which was an experimental trial in adolescents with depression, not applying long-term tVNS to therapeutically address depressive symptoms.
      • Koenig J.
      • Parzer P.
      • Haigis N.
      • et al.
      Effects of acute transcutaneous vagus nerve stimulation on emotion recognition in adolescent depression.
      The protocol for one RCT including adolescents with depression was published.
      • Rong P.J.
      • Fang J.L.
      • Wang L.P.
      • et al.
      Transcutaneous vagus nerve stimulation for the treatment of depression: a study protocol for a double blinded randomized clinical trial.
      However, although a later publication reported on the study registered under the same identifier (ChiCTR-TRC-11001201), the study was no longer an RCT and did not include pediatric patients as planned
      • Rong P.
      • Liu J.
      • Wang L.
      • et al.
      Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: a nonrandomized controlled pilot study.
      because the inclusion criteria obviously changed (inclusion cirtiera: 18–70 years of age). To our surprise, another publication from the same group,
      • Fang J.
      • Rong P.
      • Hong Y.
      • et al.
      Transcutaneous vagus nerve stimulation modulates default mode network in major depressive disorder.
      presumably reporting on that same sample, apparently included pediatric patients (inclusion criteria: 16–70 years of age). Neither of these studies mentioned the adjustment of stimulation parameters for pediatric patients. Another study protocol for a tVNS trial specifically in adolescent depression was published by Xiao et al.
      • Xiao X.
      • Hou X.
      • Zhang Z.
      • et al.
      Efficacy and brain mechanism of transcutaneous auricular vagus nerve stimulation for adolescents with mild to moderate depression: study protocol for a randomized controlled trial.
      The study has not been preregistered, and the status of recruitment is not known.

      Tinnitus and Other Conditions

      Two studies reported on tVNS in patients with tinnitus, also including adolescents. In a study by Mei et al,
      • Mei Z.
      • Yang S.
      • Cai S.
      • et al.
      Treatment of tinnitus with electrical stimulation on acupoint in the distribution area of ear vagus nerve combining with sound masking: randomized controlled trial.
      again, no adjustments of stimulation parameters or protocol were reported in pediatric patients. Furthermore, no reporting of adverse effects was provided. In 2015, Li et al
      • Li T.T.
      • Wang Z.J.
      • Yang S.B.
      • et al.
      Transcutaneous electrical stimulation at auricular acupoints innervated by auricular branch of vagus nerve pairing tone for tinnitus: study protocol for a randomized controlled clinical trial.
      published a study protocol for an RCT in patients with tinnitus, including pediatric patients. The study was registered in the Chinese Clinical Trials Register. Unfortunately, the registry was not accessible, and we were not able to confirm the status of the trial. Badran et al
      • Badran B.W.
      • Jenkins D.D.
      • Cook D.
      • et al.
      Transcutaneous auricular vagus nerve stimulation-paired rehabilitation for oromotor feeding problems in newborns: an open-label pilot study.
      addressed the effects of tVNS in N = 14 infants with feeding problems. The authors monitored safety aspects closely and report only one adverse event (bradycardia) during the intervention, likely not associated with tVNS. In some instances, excessive fussiness was linked to the intervention, which was transient once stimulation was stopped.

      Discussion

      This systematic review aimed to provide a comprehensive overview of the current state of the art in pediatric tVNS research. We focused on existing treatment protocols and stimulation parameters used for auricular tVNS in the treatment of pediatric patients. tVNS has been applied in pediatric patients with various clinical conditions, mainly including epilepsy, depression, and tinnitus. Registered and ongoing studies investigate the use of tVNS in children and adolescents with other conditions, such as Prader-Willi syndrome, feeding problems, or opioid withdrawal syndrome. Most of the published studies including pediatric patients were not specifically designed for the age group of interest. The inclusion criteria of the respective studies considered a broad range of age groups, irrespective of potential age-related differences in tVNS effects. More recently, studies are specifically designed to address pediatric disorders, as illustrated by studies registered on ClinicalTrials.
      Reviewing the stimulation protocols of published studies (that provided the respective information) illustrates that existing protocols in pediatric patients are characterized by great heterogeneity and are not readily distinguishable from those reported in adults.
      • Farmer A.D.
      • Strzelczyk A.
      • Finisguerra A.
      • et al.
      International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (version 2020).
      Generally, existing studies are characterized by poor reporting standards. For several studies, not even central sample summary statistics, such as either sample mean age or the age range of participants, were provided. Generally, information provided for stimulation devices and electrodes is frequently insufficient, and several studies have failed to report which type of stimulation device and/or which ear electrode had been used. Furthermore, engineering aspects in adjusting adult products for the use in pediatric patients (eg, the size of electrodes) have not been disclosed. Crucially, none of the included studies addressed whether electrodes were adjusted specifically to the ears of pediatric patients (eg, in size, which should deviate from custom-made electrodes intended for use with adult patients). Such lack of reporting hampers scientific progress (eg, by limiting the interpretability, comparability, and reproducibility of study findings).
      Applied daily doses of tVNS differ, ranging from as low as 30 minutes per day to four hours per day. Similarly, applied stimulation intensities vary from 0.1 mA to 6 mA, at varying stimulation frequencies. Of note, the task to define and justify stimulation parameters is not an issue specific to pediatric research but inherent to the tVNS field. In general, the selection of stimulation parameters for clinical application of VNS and tVNS currently relies on subjective sensations (eg, pain or sensory threshold) and benefits reported by patients. In part, this may ground on the fact that the effects of certain stimulation parameters such as frequency and duty cycle are observed postsynaptically in various brain structures and thus cannot be computationally modeled to determine optimal parameters.
      • Helmers S.L.
      • Begnaud J.
      • Cowley A.
      • et al.
      Application of a computational model of vagus nerve stimulation.
      Moreover, the various nerve fibers of the auricular branch of the vagus have not been investigated at a level detailed enough to consider computational modeling.
      • Yap J.Y.Y.
      • Keatch C.
      • Lambert E.
      • Woods W.
      • Stoddart P.R.
      • Kameneva T.
      Critical review of transcutaneous vagus nerve stimulation: challenges for translation to clinical practice.
      Recently suggested electrotechnical and software-based improvements to the state-of-the-art stimulators include the use of individualized tVNS therapy, using evolution algorithms that use device and subject data to optimize stimulation parameters.
      • Bolz A.
      • Bolz L.O.
      Technical aspects and future approaches in transcutaneous vagus nerve stimulation (tVNS).
      One approach to determine stimulation parameters and protocols is the use of biomarkers of tVNS.
      • Burger A.M.
      • D’Agostini M.
      • Verkuil B.
      • Van Diest I.
      Moving beyond belief: a narrative review of potential biomarkers for transcutaneous vagus nerve stimulation.
      Frequently discussed biomarkers of tVNS include heart rate variability (HRV),
      • Wolf V.
      • Kühnel A.
      • Teckentrup V.
      • Koenig J.
      • Kroemer N.B.
      Does transcutaneous auricular vagus nerve stimulation affect vagally mediated heart rate variability? A living and interactive Bayesian meta-analysis.
      event-related (P300) or somatosensory evoked potentials, pupil dilation, or salivary alpha-amylase. Importantly, these potential biomarkers show developmental specifics. HRV, for example, shows tremendous changes early in the course of life, characterized by an increase up to late adolescence and early adulthood, with a following decline during adulthood.
      • Koenig J.
      Neurovisceral regulatory circuits of affective resilience in youth: principal outline of a dynamic model of neurovisceral integration in development.
      Similarly, the P300 cannot be considered a robust trait-like marker but differs as a function of age.
      • van Dinteren R.
      • Arns M.
      • Jongsma M.L.A.
      • Kessels R.P.C.
      P300 development across the lifespan: a systematic review and meta-analysis.
      Diurnal profiles of alpha-amylase have been shown to differ across the adult lifespan,
      • Nater U.M.
      • Hoppmann C.A.
      • Scott S.B.
      Diurnal profiles of salivary cortisol and alpha-amylase change across the adult lifespan: evidence from repeated daily life assessments.
      and studies comparing alpha-amylase secretion in children and adults have shown mixed results—some illustrating differences, and others not.
      • Strahler J.
      • Mueller A.
      • Rosenloecher F.
      • Kirschbaum C.
      • Rohleder N.
      Salivary alpha-amylase stress reactivity across different age groups.
      ,
      • Yang Z.M.
      • Chen L.H.
      • Zhang M.
      • et al.
      Age differences of salivary alpha-amylase levels of basal and acute responses to citric acid stimulation between Chinese children and adults.
      These neurodevelopmental differences need to be considered in the search for a rationale to justify tVNS stimulation parameters in children and adolescents. Furthermore, differences in physiology and anatomy should inform the clinical application of tVNS. Likely, a one-size-fits-all approach is not in the best interest of pediatric patients.
      Moreover, tVNS in pediatric patients bears some practical challenges that should be considered and addressed by empirical research. In the review of existing studies, it is evident that existing stimulators are not specifically built for pediatric patients. Alongside the practical issue mentioned earlier (ie, fitting the ear electrode), future generations of medical devices for tVNS should have the interests of pediatric patients in mind concerning the handling of devices (beyond aesthetic aspects). Furthermore, compliance monitoring seems to be of particular interest in pediatric patients. We were not able to quantify compliance rates with certain protocols in this review. Alongside existing recommendations on minimum reporting standards,
      • Farmer A.D.
      • Strzelczyk A.
      • Finisguerra A.
      • et al.
      International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (version 2020).
      we encourage transparent reporting of compliance rates in future clinical studies applying long-term tVNS in pediatric patients. These issues are of particular concern when applying tVNS in patients with limited capacity for self-application, when tVNS is applied through caregivers, and so on. Attention also should be paid to a detailed assessment and reporting of adverse events in pediatric patients, which in particular concerns those unable to articulate distress given their age or health condition. Potential adverse effects of tVNS in pediatric patients need to receive particular attention and careful monitoring in future studies.
      Another potentially relevant aspect that has not yet gained attention in tVNS research concerns engagement in specific physical, sensory, or mental processes concurrent with stimulation. The possibility of engaging in different kinds of activities (such as playing/listening to music, drawing, completing homework, going for a walk, etc) while applying tVNS provides a great advantage, especially in the treatment of children and adolescents. Evidence from other neuromodulatory techniques, such as repetitive transcranial magnetic stimulation (rTMS), indicates that differences in behavioral engagement/arousal cause a potential source of variability of treatment effects because factors such as attention, arousal, and mood state have been shown to affect modulation of excitability by rTMS.
      • Oberman L.M.
      • Hynd M.
      • Nielson D.M.
      • Towbin K.E.
      • Lisanby S.H.
      • Stringaris A.
      Repetitive transcranial magnetic stimulation for adolescent major depressive disorder: a focus on neurodevelopment.
      It is currently not known whether and how such factors might affect tVNS treatment, and thus, this presents an important avenue for future tVNS research.
      Importantly, the current practice of including patients across a broad age range (ie, pediatric and adult patients) in clinical trials and not reporting on age-related effects of the intervention limits the generalizability of findings and thereby progress in understanding which setting works for whom. Interestingly, one of the reviewed studies that included children, adolescents, and adults only reported adults to respond to the intervention.
      • Barbella G.
      • Cocco I.
      • Freri E.
      • et al.
      Transcutaneous vagal nerve stimulation (t-VNS): an adjunctive treatment option for refractory epilepsy.
      However, the existing evidence is insufficient to 1) come to meaningful recommendations concerning a set of best practice parameters of tVNS in pediatric patients or 2) derive any meaningful insights on appropriate treatment protocols concerning the length and duration of treatment for specific indications in pediatric disorders. Thus, we echo the call for minimum reporting standards in the field.
      • Farmer A.D.
      • Strzelczyk A.
      • Finisguerra A.
      • et al.
      International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (version 2020).
      Moreover, we encourage the adherence to principles in pediatric research considering specific needs of the target population. To iterate, “study protocols and study designs should be evaluated child-specifically and should not be simple modifications of study protocols for adults.”
      • Gill D.
      Ethics Working Group of the Confederation of European Specialists in Paediatrics. Ethical principles and operational guidelines for good clinical practice in paediatric research. Recommendations of the Ethics Working Group of the Confederation of European Specialists in Paediatrics (CESP).

      Conclusions

      This review illustrates an absence of justification of tVNS stimulation protocols and parameters in pediatric patients. Although the entire field of tVNS research has yet to agree on stimulation parameters and empirical ways to address respective differences to determine protocols of greater efficiency and clinical benefit, particular attention should be paid when targeting pediatric patients. tVNS protocol, stimulation site, applied electrode, frequency of stimulation, and dosage may all influence effect sizes in tVNS studies, and optimizing these factors in a neurodevelopmentally informed way could increase the observed treatment effects. Thus, instead of producing data that are neither reproducible nor consistent, the targeted development and clinical evaluation of tVNS for children and adolescents will require collaboration across multiple professional disciplines and must be informed by good scientific practice—because these ingredients are essential to facilitate and drive innovation. In the face of the window of opportunity that is inherently linked with the neurodevelopmental processes occurring across childhood into young adulthood, in combination with the remarkable excitatory, inhibitory, and reflexive properties of the vagus with the widely distributed anatomical and functional projections of its afferent system throughout the brain, tVNS should widely and actively be explored in the treatment of pediatric patients. Custom tVNS devices for use in pediatric patients are warranted, addressing specific needs of the target population by innovative engineering and patient involvement in their development.

      Authorship Statements

      Julian Koenig and Christine Sigrist conceptualized and designed the study, including literature search and study selection, data extraction, and presentation of results, with important intellectual input from Armin Bolz, Tobias Jeglorz, and Lars-Oliver Bolz. Bushra Torki conducted the literature search, identified relevant studies, performed the data extraction, and drafted the presentation of results. Julian Koenig and Christine Sigrist drafted the full manuscript. All authors critically revised the draft for important intellectual input and approved the final manuscript.

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