LasaiON is an Evidence-informed, Multimodal Self-regulation Program Designed to Reduce Emotional Distress and Strengthen Stress-regulation Skills by Combining Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) With Breathing Supported by Heart-rate Variability Biofeedback (HRV-B; emWave).

NCT07498881 | Not Yet Recruiting

• 1 other identifier: M10/2026/055. March 2, 2026
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to evaluate whether the LasaiON program, which combines transcutaneous auricular vagus nerve stimulation (taVNS) with breathing supported by heart rate variability biofeedback (HRV-B; emWave), reduces emotional distress and improves stress-regulation processes in adults. The study will also assess the safety, tolerability, and feasibility of the intervention. The main questions it aims to answer are:

• undergo baseline assessments on Day 1 before the intervention;
• complete 5 consecutive daily 60-minute sessions according to group allocation;
• undergo post-intervention assessments on Day 5 after the final session;
• complete psychometric, physiological, and verbal-cognitive assessments, including STAI, HAM-D, WHO-5, EEG, skin conductance, startle response, heart rate variability measures derived using Kubios HRV Premium, and daily five-word reports with valence ratings analyzed using IRaMuTeQ;
• have adherence and tolerability recorded at each session using a checklist.

Conditions

Adult

Keywords

slow, paced breathing; transauricualr vagus nerve stimulation

Outcome Measures

Primary Outcomes (14)

• State anxiety score

  Change in state anxiety assessed with the State Anxiety subscale of the State-Trait Anxiety Inventory (STAI-State). Scores range from 20 to 80, with higher scores indicating greater anxiety.

  From baseline (day 1) to post-intervention (day 5)

• Depressive symptom score

  Change in depressive symptoms assessed with the 17-item Hamilton Depression Rating Scale (HAM-D). Scores range from 0 to 52, with higher scores indicating greater depressive symptom severity.

  From baseline (day 1) to post-intervention (day5)

• WHO-5 well-being score

  Change in emotional well-being assessed with the World Health Organization-Five Well-Being Index (WHO-5). Raw scores range from 0 to 25, with higher scores indicating better emotional well-being.

  From baseline (day 1) to post-intervention (day 5)

• Change in RMSSD

  Change in heart rate variability assessed by the root mean square of successive differences (RMSSD) using Kubios HRV software. RMSSD reflects beat-to-beat variability in heart rate and is reported in milliseconds (ms). Higher values indicate greater vagally mediated heart rate variability, whereas lower values indicate lower vagally mediated heart rate variability.

  from baseline (day 1) to post-intervention (day 5)

• Change in skin conductance level

  Change in physiological arousal assessed by skin conductance level, measured in microsiemens (µS). Higher values indicate greater sympathetic arousal.

  From baseline (day 1) to post-intervention (day 5)

• Change in startle response amplitude

  Change in physiological reactivity assessed by the peak amplitude of the acoustic startle eyeblink response, recorded from the orbicularis oculi muscle using electromyography (EMG). Startle amplitude will be defined as the peak EMG response occurring within 20 to 150 milliseconds after startle probe onset relative to the mean 50-millisecond pre-probe baseline. Amplitude will be reported in microvolts (µV), with higher values indicating greater physiological reactivity.

  From baseline (day 1) to post-intervention (day 5)

• Change in frontal midline theta band power at Fz

  Change in frontal midline theta band power at Fz, recorded using the 8-channel Unicorn Hybrid Black electroencephalography (EEG) system. EEG data will be acquired at 250 Hz per channel and analyzed as absolute spectral power in the theta frequency band (4-8 Hz). Theta band power will be reported in microvolts squared per hertz (µV²/Hz). Higher values indicate greater frontal midline theta band power.

  from baseline (day 1) to post-intervention (day 5)

• Change in frequency of intrusive-thought-related lexical occurrences

  Change in intrusive thoughts assessed by counting prespecified intrusive-thought-related lexical occurrences in written self-reports using IRaMuTeQ text analysis software. Frequency will be reported as the number of intrusive-thought-related lexical occurrences per written self-report. A value of 0 indicates no intrusive-thought-related lexical occurrences, and higher values indicate greater intrusive-thought-related lexical content.

  from baseline (day 1) to post-intervention (day 5)

• Change in SDNN

  Change in heart rate variability assessed by the standard deviation of normal-to-normal RR intervals (SDNN) using Kubios HRV software. SDNN reflects overall heart rate variability, including both short-term and longer-term components, and is reported in milliseconds (ms). Higher values indicate greater overall heart rate variability, whereas lower values indicate lower overall heart rate variability.

  From baseline (day 1) to post-intervention (day 5)

• Change in high-frequency power

  Change in heart rate variability assessed by high-frequency (HF) power using Kubios HRV software. HF power reflects high-frequency heart rate variability and will be reported as absolute power in milliseconds squared (ms²). Higher values generally indicate greater vagally mediated, parasympathetic modulation of heart rate variability.

  From baseline (day 1) to post-intervention (day 5)

• Change in low-frequency power

  Change in heart rate variability assessed by low-frequency (LF) power using Kubios HRV software. LF power reflects low-frequency heart rate variability and will be reported as absolute power in milliseconds squared (ms²). Higher values indicate greater low-frequency heart rate variability.

  From baseline (day 1) to post-intervention (day 5)

• Change in LF/HF ratio

  Change in heart rate variability assessed by the ratio of low-frequency to high-frequency power (LF/HF) using Kubios HRV software. The LF/HF ratio will be reported as a unitless ratio. Higher values indicate a higher ratio of low-frequency to high-frequency power.

  From baseline (day 1) to post-intervention (day 5)

• Change in PNS index

  Change in autonomic function, assessed using the parasympathetic nervous system (PNS) index obtained from Kubios HRV software. In Kubios, a value of 0 reflects autonomic activity comparable to the normative population mean; positive values indicate higher parasympathetic activity, whereas negative values indicate lower parasympathetic activity.

  From baseline (day 1) to post-intervention (day 5)

• Change in SNS index

  Change in autonomic function assessed by the sympathetic nervous system (SNS) index using Kubios HRV software. In Kubios, a value of 0 indicates values comparable to the normal population average; positive values indicate above-average sympathetic activity, and negative values indicate below-average sympathetic activity.

  From baseline (day 1) to post-intervention (day 5

Other Outcomes (3)

• Number of participants with adverse events

  At each session during the 5-day intervention period

• Procedure-related discomfort score

  At each session during the 5-day intervention period

• Number of participants who complete all intervention sessions

  During the 5-day intervention period

Study Arms (4)

Sham taVNS + HRV-Biofeedback Training

EXPERIMENTAL

Participants assigned to this arm will receive sham taVNS together with active HRV-biofeedback training over 5 consecutive intervention days, with one supervised 60-minute session per day. In each session, participants will sit comfortably in front of a computer. A sham taVNS device will be positioned at the tragus but will not deliver active electrical stimulation, while heart rate variability biofeedback will be provided through an ear sensor connected to the emWave platform. Sessions will include a brief pre-session checklist, fitting of psychophysiological recording equipment (EEG, HRV, EDA/EMG), a short quiet baseline, approximately 10 minutes of slow paced breathing (\~6 breaths/min) supported by Coherence Coach, followed by post-session tolerability/comfort ratings. This arm is designed to isolate the effect of active HRV-biofeedback training in the absence of active taVNS.

Combination Product: LasaiON

Active taVNS + Control Training

EXPERIMENTAL

Participants assigned to this arm will receive active transcutaneous auricular vagus nerve stimulation (taVNS) combined with control training across five consecutive intervention days, with one supervised 60-minute session per day. During each session, participants will be seated comfortably in front of a computer. Active taVNS will be delivered at the tragus, while the training component will consist of a control condition without the Coherence Coach application, rather than active HRV biofeedback. Sessions will include a brief pre-session checklist, fitting of psychophysiological recording equipment (EEG, HRV, and EDA/EMG), a short resting baseline, and post-session ratings of tolerability and comfort. This arm is intended to isolate the effect of active taVNS in the absence of active HRV biofeedback training.

Combination Product: LasaiON

Active taVNS + HRV-Biofeedback Training

EXPERIMENTAL

Participants assigned to this arm will receive the full active LasaiON intervention over 5 consecutive intervention days, with one supervised 60-minute session per day. In each session, participants will sit comfortably in front of a computer while receiving active transcutaneous auricular vagus nerve stimulation (taVNS) at the tragus together with active heart rate variability biofeedback (HRV-biofeedback) breathing training supported by the emWave platform. Sessions will include a brief pre-session checklist, fitting of psychophysiological recording equipment (EEG, HRV, EDA/EMG), a short quiet baseline, delivery of both active intervention components, and post-session tolerability/comfort ratings. This arm is designed to evaluate the combined effect of active taVNS and active HRV-biofeedback training and to determine whether their combination produces greater benefits than either component alone or than the fully control condition.

Combination Product: LasaiON

sham taVNS+control training

SHAM COMPARATOR

This control condition is delivered over 5 consecutive days, with one supervised 60-minute session per day, and is designed to match the active intervention in schedule, setting, and researcher contact without providing the active therapeutic components. Participants attend the sessions in the same standardized format, but the sham taVNS device placed at the tragus does not deliver active electrical stimulation, and the training condition does not include active HRV-biofeedback or the paced-breathing training intended to consolidate a respiratory rhythm of approximately 6 breaths per minute. This condition is intended to control for expectancy, procedural context, and time spent in session while withholding both active taVNS and active HRV-biofeedback training.

Combination Product: LasaiON

Interventions

LasaiON COMBINATION_PRODUCT

Participants will complete one 60-minute session per day. After verification of pre-session requirements, the researcher will place the EEG cap and the HRV, EDA, and EMG sensors and obtain baseline measures. Depending on allocation, participants will receive either active taVNS through stimulation electrodes placed on the auricular target area or sham taVNS using the same device setup without active therapeutic stimulation. From minutes 5-35, participants will remain seated while physiological activity is continuously recorded and they view segmented material from Our Oceans. From minutes 35-50, those allocated to active HRV-biofeedback will use the Coherence Coach platform to learn and practice slow breathing at 6 breaths/min, whereas control participants will observe their physiological activity on screen without guided breathing training. Each night at home, intrusive thoughts will be recorded through a brief Google Forms self-report and later analyzed with IRaMuTeQ.

Active taVNS + Control Training; Active taVNS + HRV-Biofeedback Training; Sham taVNS + HRV-Biofeedback Training; sham taVNS+control training

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Ability to provide written informed consent
• Physically healthy, with no relevant uncontrolled medical condition
• Availability to complete the 5-day study protocol (1 session/day), including baseline and post-intervention assessments
• Intact external ear and suitability for electrode placement on the tragus and acquisition of study recordings (EEG, EDA, HRV)

You may not qualify if:

• History of cardiovascular disease, diabetes, or hypertension
• Severe bradycardia
• Active implanted electronic device (e.g., pacemaker, cochlear implant, neurostimulator)
• History of vagus nerve transection surgery (cervical vagotomy)
• Pregnancy
• Current or past clinically significant psychiatric disorder
• Current or past clinically significant neurological disorder
• Use of CNS-active medication
• Substance misuse, including nicotine or alcohol
• Dermatitis, infection, or lesions of the ear that could interfere with electrode application
• Ongoing treatment with medications that modulate autonomic nervous system activity or may alter psychophysiological measures (e.g., HRV, EDA, EEG)

Sponsors & Collaborators

• University of the Basque Country (UPV/EHU): lead
• Parasym Ltd.: collaborator

Study Sites (1)

Euskal Herriko Unibertsitatea

San Sebastián, Gipuzkoa, 20018, Spain

Location

Related Publications (20)

• Zhang, Y., Lin, P., Wang, R., Zhou, J., Xu, X., Jiang, W., Pu, X., & Ge, S. (2024). Insula-medial prefrontal cortex functional connectivity modulated by transcutaneous auricular vagus nerve stimulation: An fMRI study. IEEE Journal of Biomedical and Health Informatics, 28(10), 5962-5970. https://doi.org/10.1109/JBHI.2024.3423019

  BACKGROUND

• Valérie Dormal, Nicolas Vermeulen, & Sandrine Mejias. (2021). Is heart rate variability biofeedback useful in children and adolescents? A systematic review. Journal of Child Psychology and Psychiatry, 62(12), 1379-1390. https://doi.org/10.1111/jcpp.13463

  BACKGROUND

• Tian, Q.-Q., Cheng, C., Yin, Z.-X., Yuan, Y.-Y., Wang, C., Zeng, X., Sun, J.-B., Yang, Q., Yang, X.-J., & Qin, W. (2024). Combined transcutaneous auricular vagus stimulation (taVNS) with 0.1 Hz slow breathing enhances insomnia treatment efficacy: A pilot study. Brain Stimulation, 17(1), 4-6. https://doi.org/10.1016/j.brs.2023.11.015

  BACKGROUND

• Napadow, V., Edwards, R. R., Cahalan, C. M., Mensing, G., Greenbaum, S., Valovska, A., Li, A., Kim, J., Maeda, Y., Park, K., & Wasan, A. D. (2012). Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular vagal afferent nerve stimulation. Pain Medicine, 13(6), 777-789. https://doi.org/10.1111/j.1526-4637.2012.01385.x

  BACKGROUND

• McAllister-Williams, R. H., Sousa, S., Kumar, A., Greco, T., Bunker, M. T., Aaronson, S. T., Conway, C. R., & Rush, A. J. (2020). The effects of vagus nerve stimulation on the course and outcomes of patients with bipolar disorder in a treatment-resistant depressive episode: A 5-year prospective registry. International Journal of Bipolar Disorders, 8(1), Article 13. https://doi.org/10.1186/s40345-020-0178-4

  BACKGROUND

• Kim, A. Y., Marduy, A., de Melo, P. S., et al. (2022). Safety of transcutaneous auricular vagus nerve stimulation (taVNS): A systematic review and meta-analysis. Scientific Reports, 12, 22055. https://doi.org/10.1038/s41598-022-25864-1

  BACKGROUND

• Hiran Thabrew, Philip Ruppeldt, & John J. Sollers III. (2018). Systematic review of biofeedback interventions for addressing anxiety and depression in children and adolescents with long-term physical conditions. Applied Psychophysiology and Biofeedback, 43(3), 179-192. https://doi.org/10.1007/s10484-018-9399-z

  BACKGROUND

• Goessl, V. C., Curtiss, J. E., & Hofmann, S. G. (2017). The effect of heart rate variability biofeedback training on stress and anxiety: A meta-analysis. Psychological Medicine, 47(15), 2578-2586. doi:10.1017/S0033291717001003

  BACKGROUND

• Garcia, R. G., et al. (2021). Respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) modulates brain response to stress in major depression. Journal of Psychiatric Research. https://doi.org/10.1016/j.jpsychires.2021.07.048

  BACKGROUND

• Garcia, R. G., Cohen, J. E., Stanford, A. D., Gabriel, A., Stowell, J., Aizley, H., Barbieri, R., Gitlin, D., Napadow, V., & Goldstein, J. M. (2021). Respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) modulates brain response to stress in major depression. Journal of Psychiatric Research, 142, 188-197. doi:10.1016/j.jpsychires.2021.07.048.

  BACKGROUND

• Fang, J., Rong, P., Hong, Y., Fan, Y., Liu, J., Wang, H., Zhang, G., Chen, X., Shi, S., Wang, L., Liu, R., Hwang, J., Li, Z., Tao, J., Wang, Y., Zhu, B., & Kong, J. (2016). Transcutaneous vagus nerve stimulation modulates default mode network in major depressive disorder. Biological Psychiatry, 79(4), 266-273. https://doi.org/10.1016/j.biopsych.2015.03.025

  BACKGROUND

• Eyşan Hanzade Umaç, & Remziye Semerci. (2023). Effect of biofeedback-based interventions on the psychological outcomes of pediatric populations: A systematic review and meta-analysis. Applied Psychophysiology and Biofeedback, 48, 299-310. https://doi.org/10.1007/s10484-023-09583-5

  BACKGROUND

• Dormal, V., Vermeulen, N., & Mejias, S. (2021). Is heart rate variability biofeedback useful in children and adolescents? A systematic review. Journal of Child Psychology and Psychiatry, 62(12), 1379-1390. doi:10.1111/jcpp.13463.

  BACKGROUND

• Darabi, M. D., Silber, S. P., Slotkin, R., & Peechatka, A. L. (2025). Biofeedback-based digital games and well-being in childhood: A systematic review. Research on Child and Adolescent Psychopathology, 53(12), 2115-2130. https://doi.org/10.1007/s10802-025-01387-x (pubmed.ncbi.nlm.nih.gov)

  BACKGROUND

• Cui, Y., Sun, J., Zhang, B., Guo, T., Zhang, S., Li, Z., Chen, Y., Su, M., Wu, D., Wu, J., Wang, Q., Yuan, Y., Wang, J., Tian, Q., He, F., Wu, L., Li, X., Gong, Y., … Qin, W. (2025). Efficacy and safety of transcutaneous auricular vagus nerve stimulation for patients with treatment-resistant schizophrenia with predominantly negative symptoms: A randomized clinical trial. Molecular Psychiatry, 30, 5437-5447. doi:10.1038/s41380-025-03132-8.

  BACKGROUND

• Austelle, C. W., Cox, S. S., Connolly, D. J., Vogel, B. B., Peng, X., Wills, K., Sutton, F., Tucker, K. B., Ashley, E., Manett, A., Cortese, B., Short, E. B., & Badran, B. W. (2025). Accelerated transcutaneous auricular vagus nerve stimulation for inpatient depression and anxiety: The iWAVE open label pilot trial. Neuromodulation, 28(4), 672-681. doi:10.1016/j.neurom.2025.02.003.

  BACKGROUND

• Aranberri Ruiz, A. (2024). Transcutaneous Auricular Vagus Nerve Stimulation to Improve Emotional State. Biomedicines, 12(2), 407. https://doi.org/10.3390/biomedicines12020407

  BACKGROUND

• Aranberri Ruiz, A., Nevado, B., Migueles Seco, M., & Aritzeta, A. (2024). Heart rate variability biofeedback intervention programme to improve attention in primary schools. Applied Psychophysiology and Biofeedback, 49(4), 651-664. https://doi.org/10.1007/s10484 024 09659 w

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• Aranberri Ruiz, A., Aritzeta, A., Olarza, A., Soroa, G., & Mindeguia, R. (2022). Emotional self regulation in primary education: A heart rate variability biofeedback intervention programme. International Journal of Environmental Research and Public Health, 19(9), 5475. https://doi.org/10.3390/ijerph19095475

  BACKGROUND

• Aranberri Ruiz, A. (2023). Emotional Experience and its Biological Underpinnings: Improving Emotional Well-Being Through Vagal Tone. Papeles Del Psicólogo, 44(2), 95-101. https://doi.org/10.23923/pap.psicol.3016

  BACKGROUND

Central Study Contacts

Ainara Aranberri Ruiz, Ph.D.

CONTACT

943018311; ainara.aranberri@ehu.eus

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PhD. Ainara Aranberri, Lead Investigator

Model Details: This study uses a 2 × 2 factorial randomized controlled design to evaluate the independent and combined effects of stimulation and training. The two intervention factors are stimulation condition (active transcutaneous auricular vagus nerve stimulation \[taVNS\] vs. sham taVNS) and training condition (active heart rate variability biofeedback \[HRV-biofeedback\] vs. control training). Participants will be randomly assigned in equal proportions (1:1:1:1) to one of four parallel groups: sham taVNS + control training, sham taVNS + HRV-biofeedback, active taVNS + control training, or active taVNS + HRV-biofeedback. This model allows estimation of the main effects of each factor and their interaction. Assessments will be performed at baseline (Day 1, pre-intervention) and post-intervention (Day 5, after the final session).

Study Record Dates

• First Submitted: March 3, 2026
• First Posted: March 27, 2026
• Study Start: March 30, 2026
• Primary Completion (Estimated): September 3, 2026
• Study Completion (Estimated): March 30, 2028
• Last Updated: March 27, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

ES (1)