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Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Address correspondence to: Julian Koenig, PhD, Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 10, Building 53, Room 1.009, 50931 Köln, Cologne, Germany.
Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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.
Noninvasive transcutaneous vagus nerve stimulation (tVNS) enables electrical stimulation of the vagus nerve while mitigating the risks associated with invasive vagus nerve stimulation (VNS).
International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (version 2020).
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.
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.
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.
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.
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
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
—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.
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).
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.
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.
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,
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,
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.
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.
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.
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,
International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (version 2020).
A literature review on the neurophysiological underpinnings and cognitive effects of transcutaneous vagus nerve stimulation: challenges and future directions.
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
—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.
International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (version 2020).
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 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.
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.
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.
Treatment of tinnitus with electrical stimulation on acupoint in the distribution area of ear vagus nerve combining with sound masking: randomized controlled trial.
Efficacy and brain mechanism of transcutaneous auricular vagus nerve stimulation for adolescents with mild to moderate depression: study protocol for a randomized controlled trial.
Efficacy and brain mechanism of transcutaneous auricular vagus nerve stimulation for adolescents with mild to moderate depression: study protocol for a randomized controlled trial.
Treatment of tinnitus with electrical stimulation on acupoint in the distribution area of ear vagus nerve combining with sound masking: randomized controlled trial.
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.
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.
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
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
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
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
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.
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
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
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
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.
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
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.
Efficacy and brain mechanism of transcutaneous auricular vagus nerve stimulation for adolescents with mild to moderate depression: study protocol for a randomized controlled trial.
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
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
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.
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.
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.
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.
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.
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,
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.
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.
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.
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.”
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).
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.
References
Guerriero G.
Wartenberg C.
Bernhardsson S.
et al.
Efficacy of transcutaneous vagus nerve stimulation as treatment for depression: a systematic review.
International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (version 2020).
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.
A literature review on the neurophysiological underpinnings and cognitive effects of transcutaneous vagus nerve stimulation: challenges and future directions.
Efficacy and brain mechanism of transcutaneous auricular vagus nerve stimulation for adolescents with mild to moderate depression: study protocol for a randomized controlled trial.
Treatment of tinnitus with electrical stimulation on acupoint in the distribution area of ear vagus nerve combining with sound masking: randomized controlled trial.
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.
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.
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).
Source(s) of financial support: The study was supported by funds from the Germany Federal Ministry of Education and Research (BMBF) under grant number 13GW0492D (PI: Julian Koenig).
Conflict of Interest: Armin Bolz is an investor of tVNS Technologies GmbH, Erlangen. Lars-Oliver Bolz is a shareholder and CEO of tVNS Technologies GmbH, Erlangen. Tobias Jeglorz is employed by SASSE Elektronik GmbH, Erlangen. The remaining authors reported no conflict of interest.
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