Effects of taVNS Combined With tACS on Adolescents With Non-Suicidal Self-Injury

Condition(s) studied

Investigational drug(s) / intervention(s)

25Hz、300us transcutaneous auricular vagus nerve stimulation and10hz transcranial alternating current stimulation: The active taVNS stimulation was applied to the cymba conchae, an area exclusively innervated by the auricular branch of the vagus nerve. Active taVNS stimulation protocol was set as follows: pulse width of 300 μs, frequency of 25 Hz, and current intensity adjusted based on each participant's individual threshold, set at 80% of the sensory threshold. The stimulation duration was 15 minutes. Active 10hz transcranial alternating current stimulation: 10 Hz tACS delivered through a 4×1-ring high-definition electrode montage centered on left DLPFC (F3), 2 mA peak-to-peak, 100 % intensity, gradually ramped up over 30 s, maintained for 20 min, then ramped down over 30 s; two sessions per day with at least 4 h between sessions, repeated for 7 consecutive days (14 total sessions).

sham 25Hz、300us transcutaneous auricular vagus nerve stimulation and 10hz transcranial alternating current stimulation: The sham taVNS stimulation was placed on the earlobe. The two procedures were indistinguishable in terms of appearance, ensuring effective blinding. The stimulation duration was 15 minutes. Active 10HZ transcranial alternating current stimulation: 10 Hz tACS delivered through a 4×1-ring high-definition electrode montage centered on left DLPFC (F3), 2 mA peak-to-peak, 100 % intensity, gradually ramped up over 30 s, maintained for 20 min, then ramped down over 30 s; two sessions per day with at least 4 h between sessions, repeated for 7 consecutive days (14 total sessions).

active 25Hz、300us transcutaneous auricular vagus nerve stimulation and sham10hz transcranial alternating current stimulation: The active taVNS stimulation was applied to the cymba conchae, an area exclusively innervated by the auricular branch of the vagus nerve. active taVNS stimulation protocol was set as follows: pulse width of 300 μs, frequency of 25 Hz, and current intensity adjusted based on each participant's individual threshold, set at 80% of the sensory threshold. The stimulation duration was 15 minutes. Sham 10HZ transcranial alternating current stimulation: identical 4×1-ring high-definition electrode montage centered on left DLPFC (F3), 2 mA peak-to-peak current ramped up over 30 s and immediately ramped down to 0 mA, followed by 19.5 min of no stimulation to match the 20-min session duration of active tACS; delivered twice daily (≥4 h apart) for 7 consecutive days (14 total sessions).

Study summary

NSSI behavior is highly prevalent among adolescents, and its mechanisms are closely associated with attentional bias toward self-injury-related information and impulsivity, both of which may be related to reduced dlPFC activation levels. Introducing taVNS as a priming stimulus to pre-regulate brain state and optimize subsequent tACS treatment response provides a novel approach to addressing inconsistent intervention effects. Simultaneously, this facilitates a shift in the brain from passive stimulus reception to active state regulation, offering important theoretical foundations for developing more precise and efficient cross-modal neuromodulation therapies.This study aims to systematically validate the efficacy of a combined protocol using taVNS as a priming modality followed by tACS over the left dlPFC through a randomized controlled trial (RCT). The investigators hypothesize that:

① Compared to tACS intervention alone, this combined approach will not only demonstrate non-inferiority in overall therapeutic efficacy but, more importantly, significantly reduce inter-individual variability in treatment response to tACS. This would mitigate the issue of high clinical response heterogeneity and enhance the stability and predictability of treatment outcomes.

② Early behavioral biomarkers of intervention response are anticipated: Immediate improvements in attentional bias following a single combined intervention session will significantly predict reductions in the frequency and intensity of Non-Suicidal Self-Injury (NSSI) after a full course (14 sessions) of treatment. This suggests that early positive changes in cognitive function could serve as valid indicators predicting long-term clinical efficacy, offering a critical time window for implementing individualized treatment adjustments.

③ The study will elucidate the effects of the taVNS-primed combined tACS treatment on neuroimaging mechanisms in adolescents with NSSI.

Eligibility

Primary outcome measure(s)

• Adolescent Non-suicidal Self-injury Assessment Questionnaire (ANSAQ) reduction in the frequency of self-injury — Assessments were conducted at baseline (pre-treatment), as well as on day 1, at week 1, and at month 1 post-treatment.
  The ANSAQ is a brief, self-report tool specifically designed for adolescents aged 12-18 to quantify non-suicidal self-injury (NSSI) over the past year. It is used both to screen for clinically relevant self-harm and to track changes in self-injury frequency after an intervention. Higher frequencies indicate more severe NSSI behavior.
• Brief Barratt Impulsiveness Scale (BBIS) — Assessments were conducted at baseline (pre-treatment) and on day 1 post-treatment.
  The BBIS is an 8-item, self-report subset of the well-known Barratt Impulsiveness Scale. Each item (e.g., "I act on the spur of the moment") is answered on a 4-point scale: 1 = rarely/never, 2 = occasionally, 3 = often, 4 = almost always/always. Total scores range 8-32; higher scores indicate greater impulsivity. Total score: 32. Higher scores indicate greater impulsivity.
• Eye movement index-fixation counts — Assessments were conducted at baseline (pre-treatment) and on day 1 post-treatment.
  A free-viewing paradigm consisting of 60 images was employed, with eye movements recorded using an SMI-RED eye-tracking system. Each trial comprised a four-image array: three neutral stimuli and one NSSI-related stimulus, presented for 4000 ms. A dot-probe paradigm consisting of 204 trials was employed, with eye movements recorded using an SMI-RED eye-tracking system. Each trial comprised a pair of images: one neutral stimulus and one NSSI-related stimulus, presented for either 200 ms or 500 ms.The region of interest (ROI) was defined as the area containing the NSSI-related cue. 'Dwell time' was operationalized as the total duration (in milliseconds) that the eyes remained fixated within the ROI during image presentation. Values were averaged across all NSSI-related cue images at baseline (Day 0) and post-intervention (Day 8). A clinically relevant improvement in inhibitory control was defined as a ≥20% reduction in total dwell time on NSSI-related cues relative to baseline.
• Stop Signal Task（SST） — Assessments were conducted at baseline (pre-treatment) and on day 1 post-treatment.
  The experiment consisted of 192 trials (64 × 3), preceded by a 20-trial practice phase. Each trial began with a 1.5-second fixation cross, followed by a left- or right-pointing arrow (maximum duration: 2 seconds), to which participants responded as quickly and accurately as possible. In approximately 25% of trials, an auditory stop signal was presented after a variable delay, requiring participants to inhibit their response. The stop-signal delay (SSD) was dynamically adjusted using a staircase procedure (initial delay: 250 ms; ±50 ms based on performance) to index inhibitory control. The inter-trial interval was fixed at 30 seconds.
• Delay Discounting Task (DDT) — Assessments were conducted at baseline (pre-treatment) and on day 1 post-treatment.
  The study employed a Delay Discounting Task (DDT) to assess individuals' preference for immediate versus delayed rewards. The task included 80 trials, generated by fully crossing four delayed reward amounts (¥25, ¥50, ¥100, ¥500), five delay durations (7, 14, 30, 90, and 180 days), and four discount rates (70%, 85%, 90%, and 95%). Each trial began with a 1.5-second fixation cross, followed by a simultaneous presentation of two options: a smaller immediate reward and a larger delayed reward, with their positions randomized across trials. Participants selected their preferred option using the left or right arrow keys, and no feedback was provided.、

Trial sites (1)

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