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STUDY PROTOCOL
Asia Pac J Clin Trials Nerv Syst Dis 2017,  2:91

Transcutaneous auricular vagus nerve stimulation for food craving: study protocol for a phase II randomized, sham-controlled clinical trial


1 Department of Psychiatry, School of Medicine, Federal University of São Paulo; Reference Center for Alcohol, Tobacco and Other Drugs (CRATOD), São Paulo State Secretariat of Health, São Paulo, SP, Brazil
2 Department of Psychiatry, School of Medicine, Federal University of São Paulo; Reference Center for Alcohol, Tobacco and Other Drugs (CRATOD), São Paulo State Secretariat of Health, São Paulo; Santa Casa School of Medical Sciences, São Paulo, Brazil

Date of Web Publication2-Aug-2017

Correspondence Address:
Alisson Paulino Trevizol
Department of Psychiatry, School of Medicine, Federal University of São Paulo; Reference Center for Alcohol, Tobacco and Other Drugs (CRATOD), São Paulo State Secretariat of Health, São Paulo; Santa Casa School of Medical Sciences, São Paulo
Brazil
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Source of Support: The study was funded by the Reference Center for Alcohol, Tobacco and Other Drugs (CRATOD), São Paulo State Secretariat of Health, São Paulo, SP, Brazil., Conflict of Interest: None


DOI: 10.4103/2542-3932.211590

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  Abstract 

Background and objectives: Obesity is one of the most important diseases around the world and it is an increasing issue for public health. Food craving is a usually noticeable symptom that is described as a “strong desire or urge to eat”. The vagus nerve and its relations to the neurocircuitry of the reward system play essential roles in the regulation of food intake. Transcutaneous stimulation of the auricular branch of the vagus nerve (taVNS) was previously described for its neuromodulatory effects in neuropsychiatric disorder. This study aims to investigate the effects of transcutaneous auricular vagus nerve stimulation on food craving in patients with obesity.
Design: A two-arm, triple-blinded, randomized, sham-controlled phase II trial.
Methods: This will be conducted at The Center for Neuromodulation Studies, Federal University of São Paulo, Brazil. Fifty-four subjects with food craving will be assigned to either: 1) a 10-session treatment protocol of real taVNS, or 2) a 10-session treatment protocol of sham taVNS. Participants will be evaluated for outcome measures before and after intervention, with a follow-up visit of 30 days after the end of treatment.
Outcome measures: The primary outcome measure will be changes in food craving evaluated by Food Craving Questionnaire-State and Trait. The secondary outcomes will be improvement of anthropometric measures (body mass index and hip/waist ratio), metabolic profile (blood pressure, cholesterol and triglycerides levels and fasting glucose), dietary habits (dietary diary and Food Craving Inventory) and depressive symptoms (Inventory for Depressive Symptoms), and quantitative electroencephalography and heart rate variability.
Discussion: To the best of our knowledge, there are no studies on the effects of taVNS on alleviating craving symptoms. Given the epidemiological situation and economic and social burdens, the possibility of modulating the reward system neurocircuitry through the vagus nerve using an easy-to-operate, low-cost, safe and potential at-home use method represents a breakthrough in the treatment of obesity.
Ethics and dissemination: The study will be approved by the ethics committee from the Federal University of São Paulo, Brazil. Patient recruitment will initiate in October 2017; analysis of primary outcome measures will be completed in October 2018 and the study will be finished in October 2019. Dissemination plans include presentations at scientific conferences and scientific publications.
Trial registration: ClinicalTrials.gov identifier: NCT03217929; registered on July 11th, 2017.

Keywords: clinical trial; obesity; food craving; food and eating disorders; Binge-Eating disorder; vagus nerve; transcutaneous vagus nerve stimulation; non-invasive brain stimulation


How to cite this article:
Grigolon RB, Cordeiro Q, Trevizol AP. Transcutaneous auricular vagus nerve stimulation for food craving: study protocol for a phase II randomized, sham-controlled clinical trial. Asia Pac J Clin Trials Nerv Syst Dis 2017;2:91-8

How to cite this URL:
Grigolon RB, Cordeiro Q, Trevizol AP. Transcutaneous auricular vagus nerve stimulation for food craving: study protocol for a phase II randomized, sham-controlled clinical trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2017 [cited 2017 Sep 26];2:91-8. Available from: http://www.actnjournal.com/text.asp?2017/2/3/91/211590


  Introduction Top


Obesity is a worldwide public health with a continuous increase and a great concern across the globe. In the United State, the prevalence of obesity among adults aged over 20 is approximately 36% (Ogden et al., 2015), with an estimated cost of $147 to $210 billion/year with preventable strategies for obesity and overweight (Cawley and Meyerhoefer, 2012) (obese adults spend 42% more on direct health care costs than adults who have a healthy weight) and approximately $4.3 billion annually (Cawley and Meyerhoefer, 2012) with absenteeism, and $506 per obese worker per year due to presenteeism (Cawley and Meyerhoefer, 2012). In addition, obesity is associated with an increased risk of premature death (Di Angelantonio et al., 2016). The risks of coronary heart disease, stroke, respiratory disease, and cancer are all increased in the obese population, with a premature death (before age 70) proportion three times higher in overweight and obese patients than in healthy subjects (Di Angelantonio et al., 2016).

Common treatments include pharmacotherapy, lifestyle modification, and bariatric surgery. However, these available interventions present some limitations: 20–40% of those who undergo bariatric surgery fail to lose sufficient weight (Christou et al., 2006; Livhits et al., 2012) or regain significant weight after treatment (DiGiorgi et al., 2010; Adams et al., 2012), and can experience a number of complications during and after surgery or medical and psychiatric comorbidities (Bolen et al., 2012). Among other patients, medications or restrict diet have little effect and cannot be prescribed in the long run.

Brain reward system in food craving

Food craving in obesity, related to changes in dopaminergic neurocircuitry, may increase the susceptibility to opportunistic overeating. In addition, tolerance occurs similarly to abuse of other substance, with food intake being less rewarding, less goal directed and more habitual (Guo et al., 2014). Considerable evidence suggests that overeating contributes to down-regulation of the dopamine-based reward circuitry (Stice et al., 2011). It is hypothesized that habitual intake of high-fat diets causes decreased synthesis of oleoylethanolamine (a lipid that regulates food intake and body weight), a gastrointestinal lipid messenger, reducing dopamine signaling capacity (Tellez et al., 2013).

Food craving has been recently added to the diagnostic criteria for addiction disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and is defined as a “strong desire or urge to use”. This symptom can be triggered by cue-exposure of the substance (motivational “wanting”) and its hedonic effects (“reward craving”) or by withdrawal symptoms (“relief craving”) – hedonic “liking”. The essence of food or drug addiction is an excessive value of psychological “wanting”, especially triggered by cues, without necessarily overvaluing “liking” (Berridge and Robinson, 2016).



The reward system consists of a complex interaction between neurotransmitters (primarily dopaminergic and opioidergic) resulting in a brain reward cascade of “feelings of satisfaction and pleasure”. It interacts with powerful brain chemicals and neurotransmitters (e.g., serotonin and the opioids) that control mood and craving. When the reward system is dysfunctional, two mechanisms are likely to occur: (1) motivational “wanting” and (2) hedonic “linking”. The motivational “wanting” mechanism consists of a neural system that includes mesolimbic dopamine neurons. Individuals who demonstrate elevated craving for palatable foods, such as high-fat, high-sugar and/or processed foods, may experience a strong wanting for food reward (Berridge, 2009). In addition, the reward surfeit model demonstrates that individuals with greater reward region responsiveness to food intake are at an elevated risk for overeating (Stice et al., 2008). In this case, the occurrence of “an intense desire to consume a specific food that is difficult to resist” is called food craving (White et al., 2002), and it seems to trigger the same pathways related drug craving (Kelley and Berridge, 2002; Pelchat, 2002; Pelchat et al., 2004; Tang et al., 2012).

The vagus nerve and its relations to the brain reward system

The vagus nerve and its relations to the neurocircuitry of the reward system play essential roles in the regulation of food intake. Due to multiple regulatory functions of the vagus nerve, devices focused on modulating the vagus nerve activity have been studied for multiple disorders. The vagus nerve stimulation (VNS) consists in implanting an electrode to the vagus nerve in the cervical area to modulate the frequency of its excitability. It was initially approved for the treatment of refractory epilepsy. Abubakr and Wambacq (2008) demonstrated significant improvements in 31 patients with a 6-month follow-up of stimulation, reducing seizure frequency. In addition, 16 (51%) patients experienced sustained response to VNS therapy 4 years later. Four patients demonstrated significant weight loss. Burneo et al. (2002) performed a study with implanted cervical VNS therapy in 27 patients with epilepsy. They observed that 17 (62%) individuals presented with weight loss. VNS therapy has some gastrointestinal side effects that may decrease appetite and eating behaviors (hunger and satiety) that could result in weight loss. Bodenlos et al. (2007) investigated the effects that acute left cervical VNS might have on food cravings in adults with major depression disorders. The results were associated with a significant change in craving ratings for sweet foods, mostly in depression patients receiving VNS than in depression patients not receiving VNS and in healthy controls. Beyond that, Vijgen et al. (2013) hypothesized that weight loss induced by VNS may be the result of increased energy expenditure through brown adipose tissue stimulation. Subjects with active brown adipose tissue presented significantly higher energy expenditure compared to subjects without it. VNS therapy may increase brown adipose tissue activity and this could be a new treatment for obesity (Vijgen et al., 2013).

Recently, an intra-abdominal device for weight loss was approved by the Food and Drugs Administration (FDA) for obesity treatment. The purpose of the device is to block signals along the nerves connected the brain, altering eating behaviors (reducing hunger and promoting earlier satiety). Studies demonstrated a 14.2% weight loss and a decrease of 30% in caloric intake in 6 months, with patients reporting earlier satiety and reduced hunger (Camilleri et al., 2008). Although studies have shown great results in weight loss among obese individuals, there is still a need for further investigations related to this device (Sarr et al., 2012; Ikramuddin et al., 2014).

Recently, researchers have demonstrated the possibility of transcutaneously stimulating the auricular branch of the vagus nerve (taVNS), with initial evidence for major depressive disorder (Trevizol et al., 2015a, b, 2016). In the field of endocrinology, Huang et al. (2014) found that taVNS therapy led to a significant reduction in 2-hour glucose tolerance in patients with impaired glucose tolerance than sham taVNS. The systolic blood pressure over 12-week observation period was significantly decreased in patients receiving taVNS than in patients who received no treatment. Frangos and Komisaruk (2017) investigated the effect of such techniques using functional magnetic resonance image (fMRI) on primary vagal projections, including nucleus of the solitary tract (primary central relay of vagal afferents), parabrachial area, primary sensory cortex, insula, regions of the basal ganglia, frontal cortex, hippocampus, visual cortex, and spinal trigeminal nucleus and found that taVNS plays an important role in the regulation of the reward system circuitry. To the best of our knowledge, there are no reports on the effects of taVNS on reducing craving symptoms.

Given the epidemiological situation and economic and social burdens, the possibility of modulating the reward system neurocircuitry through the vagus nerve with an easy-to-operate, low-cost, safe and potential at-home use method represents a breakthrough in the treatment of obesity. Based on the neurobiology of food craving and on the initial data on taVNS demonstrating the safety and efficacy in open-label and randomized sham-controlled trials, we proposed the first randomized, sham-controlled, triple-blind trial involving taVNS therapy for food craving in obesity. Results from this study will add information to the use of taVNS for food carving, which contributes to further studies on its possible use for eating disorders and obesity. We hypothesize that taVNS will ameliorate not only food craving symptoms, but also comorbid anxiety.


  Methods/Design Top


Overview

This is a two-arm, triple-blinded, randomized sham-controlled trial. Fifty-four subjects with food craving will be assigned to either: 1) a 10-session treatment protocol of real taVNS, or 2) a 10-session treatment protocol of sham taVNS. Participants will be evaluated for outcome measures before and after intervention, with a follow-up visit of 30 days after the end of treatment [Figure 1].
Figure 1: Study protocol flowchart.
BMI: Body mass index; FCQ-T: Food Craving Questionnaire-Trait; FCQ-S: Food Craving Questionnaire-State; FCI: Food Craving Inventory; taVNA: transcutaneous auricular vagus nerve stimulation.


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Study population

The study will be conducted at the Center for Neuromodulation Studies, Federal University of São Paulo. Inclusion criteria: (1) Body mass index (BMI) > 29 kg/m2; (2) age between 18 and 55 years old; (3) Food Craving Questionnaire-State and Trait (FCQ-S and FCQ-T) score > 108; (4) agreement to participate and sign the informed consent term before any procedure is conducted. Exclusion criteria: (1) history of head injury or epilepsy; (2) use of metallic implants and pacemaker; (3) current or previous (within 6 months) use of psychotropic or anorexigenic medications, recreational drugs, and/or participation in weight loss programs; (4) pregnancy or breastfeeding; (7) indication of hospitalization; (8) substance dependence; (9) psychiatric disorder, except for anxiety disorders; (10) personality disorders; (11) suicidal ideation; (12) non-controlled clinical comorbidities.

Participants will be withdrawn from the study if they: (1) become pregnant; (2) experience any adverse event which the study investigator specifies as an indicator that is no longer safe for the individual to participate; (3) change the pharmacological protocol; (4) develop psychotic, manic symptoms or depressive; (5) failure to complete three consecutive taVNS sessions; (6) initiating a weight loss program; (7) use of recreational drugs or anorexigenic drugs.

Sample size

For sample size calculation, we used an alpha error of 0.05 for main hypothesis testing, an expected effect size of 0.4, as reported in our previous studies with taVNS (Trevizol et al., 2016), and a power of 80%. Sample size was calculated for 22 patients in each group. An attrition rate of 20% was used for the final sample size of 54 patients.

Recruitment

Patients will be recruited in three major obesity centers and a primary care clinics in São Paulo – Brazil.

Randomization and allocation concealment

A blocked randomization with variable sizes of blocks with permute in each block will be conducted with a 1:1 allocation using the website www.randomization.org. Participants will be randomly assigned to one of the two treatments: group 1 for active taVNS and group 2 for sham taVNS. Patient allocation will be blinded to all participants and study staff, including the statistician, in exception to the professionals providing the taVNS treatment and one researcher not related to this study, responsible for the randomization and allocation concealment. Thus, patients, investigator who performs assessments and the statistician will be blinded. The allocation sequence will be concealed in sequentially numbered, sealed and stapled dark opaque envelopes and locked in a key protected cabinet file.

Baseline assessment

Subjects will be evaluated regarding: sex, age, educational status, religion, social status, working status and monthly income, clinical comorbidities, use of previous and current medications, BMI, hip/waist ratio, weight, blood pressure, skinfold measures of body fat, cholesterol and triglycerides levels and fasting glucose.

Intervention

Stimulation will be performed using the Neurodyn II (Ibramed, São Paulo, SP, Brazil) equipment approved by the national regulatory agency (ANVISA). The following parameters will be used: 120 Hz of frequency, 250 μs of pulse duration and 12 mA of intensity for a continuous stimulation for 30 minutes. This intensity corresponds to a non-painful mild paresthesia without muscle contraction previously described and evaluated (Trevizol et al., 2016). The 25 cm2 electrodes will be positioned over the retroauricular area as previously described (Trevizol et al., 2015a, b, 2016). Regarding sham protocol, the device will be turned off after 60 seconds of stimulation without the knowledge of the patient. After this initial period, the referred paresthesia seems to diminish due to nerve accommodation. A total of 10 sessions (one session per day for 10 days) will be performed. Every session will be followed by an interview with a trained psychiatrist to evaluate possible adverse effects and guarantee safety issues regarding the study itself.

Outcome measures

Primary outcome measure

The primary outcome measure is the difference between the Brazilian version of the FCQ-S and FCQ-T scores (Queiroz de Medeiros et al., 2016; Ulian et al., 2017). The comparison between sham and real taVNS groups will be performed using scores from three occasions: (1) baseline (T1); (2) the end of the stimulation protocol (T2); and (3) 30 days after the last day of stimulation (T3). Participant timeline is shown in [Table 1].
Table 1: Visiting schedule

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Secondary outcome measures

Patients will be evaluated using the following scales for symptom assessment: (1) Dietary diary; (2) Food Craving Inventory (FCI) (Queiroz de Medeiros et al., 2017); (3) Inventory for Depressive Symptoms (Self-Report version); (4) anthropometric measures; (5) metabolic profile; (6) quantitative electroencephalography; and (7) heart rate variability. These secondary outcomes will be assessed according to [Table 1].

Quantitative electroencephalography (qEEG)

In order to establish possible biomarkers, we will perform a comparison between sham and real taVNS groups in three occasions (T1, T2 and T3). EEG acquisition will be performed during daytime, sitting, relaxed, with eyes opened and eyes closed, for 10 minutes each. We will adopt a monopolar montage, with the ears as references, positioned in 21 regions according to the 10-20 system (Fp1, Fpz, Fp2, F7, F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, T6, P3, Pz, P4, O1, Oz, O2). qEEG acquisition will be performed using the MITSAR-EEG 202 with 24 + 8 channels (Mitsar Co., Saint Petersburg - Russia). Resting-state EEG and qEEG evaluation will be performed using the WinEEG 2.103.70 and LORETA-KEY and sLORETA software (Mitsar Co., Saint Petersburg, Russia).

Heart rate variability (HRV)

HRV is a safe parameter capable of identifying the sympathetic and parasympathetic systems functions, enabling cardiovascular risk assessment. We will perform electrocardiographic (EKG) acquisition with the subject in sitting position, after 5 minutes of relaxed sitting. Acquisition will be performed for 10 minutes, using the polychannel EKG from the MITSAR equipment (Mitsar Co., Saint Petersburg, Russia), simultaneously to qEEG acquisition. HRV evaluation will be performed using the WinHRV 1.34.15 software (Mitsar Co., Saint Petersburg, Russia) for time and frequency domain evaluation.

Side effects

This is a technique that poses a non-significant risk to subjects with safety addressed and tested by multiple researchers (Trevizol et al., 2015a, b, 2016). The most common side effects according to a recent consensus are: headache, dizziness, nausea, itchy sensation and irritation under the area of the electrodes (Trevizol et al., 2015a, b, 2016). Studies showed that several sessions of taVNS are safe to be used in depression patients with epilepsy and impaired blood glucose (Ramsay et al., 1994; Uthman et al., 2004; Abubakr and Wambacq, 2008). Thus, a growing body of researches from different laboratories have shown that taVNS is a safe, noninvasive and painless technique for modulating neural excitability (Trevizol et al., 2015a, b, 2016).

Data and safety monitoring plan

Adverse events will be collected from the start of taVNS sessions to the end of study completion. All adverse events regardless of attribution to intervention will be collected and recorded, using standard adverse event forms. A diagnosis rather than signs, symptoms, and/or other clinical information will be recorded when possible. Participants will be asked in an open-ended way about the presence of any adverse events. Intensity will be graded as mild, moderate or severe for each adverse event. The likelihood that the event is related to the specific intervention for taVNS (or sham) will be noted. Events will be medically evaluated as appropriate, including testing and referral. All applicable local regulatory requirements related to the reporting of serious adverse events to regulatory authorities and the institutional review board (IRB) will be followed during this study. Serious adverse events will be promptly reported to the IRB. The issue of placing the study on hold will be raised by the investigators with our local IRB if any serious adverse events occur. Importantly, a data safety monitoring board will be set up for the study, comprised of two neurologists with expertise in noninvasive brain stimulation.

Risks and coping strategy

Risks to subjects

(a) Human subject involvement and characteristics: A total of 54 patients will be enrolled in this study. Patients will be recruited from three major obesity centers and basic unity of health in the city of São Paulo, Brazil. Overall, we expect a large population with anxiety symptoms to be eligible for this study.

(b) Sources of materials: Commercially available taVNS equipment. taVNS will be applied using two auto-adhesive electrodes of 5 cm2 each. To deliver the current, we will use a battery-operated device that can deliver the alternating current and can automatically be adjusted to deliver a fixed value of intensity.

(c) Potential risks: taVNS is a safe technique that poses a non-significant risk to participants. The safety of this technique has been addressed and tested by multiple researchers (e.g., Trevizol et al., 2015a, b, 2016) who have concluded that taVNS, as applied in a manner similar to our proposed protocol, induces only temporary mood, cognitive/motor effects, and no negative side effects are observed. No undesirable or long-lasting effects have been reported, nor have any subjects reportedly abandoned a study due to discomfort.

The most common side effects are: headache, dizziness, nausea, and diurnal sleepiness (Huang et al., 2014; Rong et al., 2016; Trevizol et al., 2016).

Initial studies from different laboratories show that taVNS is a safe, noninvasive and painless technique for modulating neural excitability, with only transient adverse effects. The protocol described here uses stimulation levels that fall well within the safety limits established by basic research investigating neural tissue damage using similar technologies, as well as studies using human participants (Huang et al., 2014; Rong et al., 2016; Trevizol et al., 2016).

All experiments will be supervised by a licensed medical doctor.

EEG assessment: EEG is a non-invasive test with no known adverse physiologic effects. Medical risk to subjects during the paradigm is not anticipated. There is a low risk of minor superficial skin irritation. However, it is infrequent, easily treated and fully reversible.

Questionnaires and behavioral studies: There are no potential risks posed to participants in the behavioral tasks or questionnaires. Though participants may become fatigued during testing, they will be informed that they are allowed to take a break at any point.

Adequacy of protection against risk

Recruitment and informed consent: Patients will be recruited from three major obesity centers and basic unity of health in the city of São Paulo, Brazil. Eligible patients will be included in this study. All recruitment methods will conform to local IRB and HIPAA requirements. Enrollment occurs when the subject signs a consent form. We will make sure that patient's legal representative understands the study entirely before enrolling and we will make sure that he/she understands that there is absolutely no obligation to be part of the study.

Prospective enrollees will be provided with a copy of the consent form.

taVNS: taVNS is safe and the most common adverse effect is dizziness at the beginning and end of the session. To minimize the occurrence of these adverse events, we will use ramp up and down at the beginning and end of the session.

All taVNS sessions will be conducted at the Reference Center of Alcohol, Tobacco and Other Drugs (CRATOD) of the Health Secretary of São Paulo, Brazil. All the laboratory personnel are trained in basic life support and in the recognition and treatment of convulsions, syncope and other medical emergencies. A physician will be available during the application of taVNS. A fully equipped and regularly checked crash cart is available for potential emergencies. In addition, CRATOD has a fully equipped emergency room. This emergency equipment also includes oxygen supply, intravenous line supplies, and emergency medications. Therefore, any unexpected complication will be provided with rapid medical coverage.

To protect the confidentiality of participant information, data files are assigned unique numbers and no names of the subjects are part of the data files. The information connecting names to numbers is kept in a separate secure location.

Potential benefits of the proposed research to subjects and others

The present study will enable a better understanding of the uses of neuromodulation using the auricular branch of the vagus nerve for food craving in obese subjects and will shed some light on the possible treatment for obesity and its comorbidities.

Importance of the knowledge to be gained

The knowledge gained from this study will enable us to better understand the possible uses of taVNS for craving symptoms in obesity, and help design further trials for obesity and compulsions.

Ethical issues

The study will be approved by the ethics committee from the Federal University of São Paulo, Brazil. An oral informed consent will be taken from each patient in the presence of a third party. The study is performed in accordance with the Declaration of Helsinki. The study protocol follows the Consolidated Standards of Reporting Trials (CONSORT) statement on randomized trials of non-pharmacological treatment and Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting.

Statistical analysis

Statistical analyses will be performed using the STATA 13.1 SE software (StataCorp LLC, College Station, TX, USA). All analyses will be performed using the intention-to-treat principle, in which all patients will be included in the analyses using last observation carried forward. Analyses will be considered significant for a P < 0.05. For primary outcome evaluation, we will use a general linear model with a continuous dependent variable and two independent categorical variables. The main hypothesis will be considered valid if interaction time and group are not significant. Secondary analyses will be performed in the same way.

We will evaluate how socio-demographic and clinical characteristics influence the effect of taVNS by correlation tests. Food craving, qEEG power band ranges, qEEG asymmetry and HRV will be analyzed as continuous outcomes.


  Discussion Top


To the best of our knowledge, there are no studies on the effects of taVNS on alleviating craving symptoms. Given the epidemiological situation and economic and social burdens, the possibility of modulating the reward system neurocircuitry through the vagus nerve using an easy-to-operate, low-cost, safe and potential at-home use method represents a breakthrough in the treatment of obesity.


  Study Status Top


Patient recruitment will initiate in October 2017; analysis of primary outcome measures will be completed in October 2018 and the study will be finished in October 2019.[36]

 
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Author contributions
All authors participated in the design of the clinical trial, manuscript elaboration and approved the final version of this manuscript for publication.
Conflicts of interest
None declared.
Research ethics
The study will be approved by the ethics committee from the Federal University of São Paulo, Brazil. An oral informed consent will be taken from each patient in the presence of a third party. The study will be performed in accordance with the Declaration of Helsinki.
Declaration of patient consent
The authors certify that they will obtain all appropriate patient consent forms. In the form, the patients will give their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Data sharing statement
No data is reported in the article.
Plagiarism check
Checked twice by iThenticate.
Peer review
Externally peer reviewed.


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