High-intensity transcranial alternating current stimulation (HI-tACS) improved emotion regulation and reduced depressive symptoms in adolescents with major depressive disorder (MDD) and nonsuicidal self-injury (NSSI).

In the double-blind, sham-controlled study, researchers described the findings as proof-of-concept evidence that the neuromodulation approach may target core cognitive and emotional mechanisms underlying NSSI. 

"This intervention offers a new clinical option for adolescent NSSI," wrote the investigators, led by Tiejun Kang, PhD, Department of Psychosomatic Medicine, School of Medicine, Tongji University, Shanghai.

The findings were published online June 9 in JAMA Network Open.

Limited Treatment Options

Defined as deliberate, repetitive self-inflicted bodily harm, NSSI temporarily relieves overwhelming emotional distress. This behavior stems from core deficits in emotion regulation and attentional bias toward self-injurious cues.

NSSIis particularly prevalent among adolescents and is more common in females. In teens with MDD, comorbid NSSI markedly increases the risk of hospitalization, emergency visits, and future suicide.

Research shows first-line pharmacological treatments have limited efficacy, and while psychotherapies may be effective, they are often inaccessible. This, said the authors, highlights an urgent need for feasible, effective treatments for NSSI in this patient population. 

The proof-of-concept study was designed to determine whether HI-tACS could improve emotion regulation and reduce self-harm-related attentional bias in adolescents with MDD and NSSI. The trial enrolled 60 adolescents aged 12-18 years who had experienced at least three NSSI episodes in the previous month and had no current suicidal intent. 

Participants were randomly assigned to active treatment or sham stimulation and underwent 30 40-minute sessions over 3 weeks. The active-treatment group received HI-tACS at 77.5 Hz and 15 mA, while the control group received sham stimulation delivered through identical devices.

All maintained a stable MDD pharmacotherapy regimen throughout the trial. This included selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), with adjunctive antipsychotics as needed.

Less Depression, Better Impulse Control

The primary outcome was change in the total score on the Difficulties in Emotion Regulation Scale (DERS), a widely used measure of emotion regulation difficulties in adolescents. Scores range from 36 to 180, with higher scores indicating greater difficulty with emotion regulation.

Assessments were conducted at baseline, postintervention, and at 1-month follow-up. At baseline, the mean DERS total score was 122.8 in the active group and 118.7 in the sham group.

About 90.0% of the active group, and 93.3% of the sham group, completed the treatment.

The analyses were adjusted for age, sex, duration of NSSI, baseline HAMD-17 score, antidepressant dose converted to fluoxetine equivalents, and relevant baseline outcome measures.

Results showed the active group had significantly lower mean DERS scores compared to the sham group postintervention (108.15; 95% confidence interval [CI] 106.30 to 109.99 vs 117.99; 95% CI 116.27 to 119.72; P < .001) and at follow-up (109.19; 95% CI 107.34 to 111.03 vs 117.73; 95% CI 115.94 to 119.53; P < .001).

Improvements were primarily driven by two core DERS subscale measures. These were difficulty engaging in goal-directed behavior and problems with impulse control. The active group scored significantly lower on these measures postintervention and at follow-up (P < .001 for both).

Secondary outcomes included between-group differences in attentional bias, assessed using a dot-probe task that measures how attention is allocated to neutral vs emotionally salient cues. Attentional bias toward NSSI-related cues decreased significantly more in the active-treatment group than in the sham group after treatment.

Depressive symptoms, as measured by the HAMD-17, decreased significantly in both groups, but improvement was greater among participants who received active treatment. The estimated mean between-group difference was -2.78 points (95% CI, -4.12 to -1.44; P < .001) at post-treatment and -3.30 points (95% CI, -4.65 to -1.95; P < .001) at follow-up. 

A 'Positive Feedback Loop'?

The investigators hypothesize that HI-tACS "synchronizes dysregulated gamma activity via neural entrainment, enhancing prefrontal efficiency in emotion regulation and impulse inhibition."

They believe the findings support a bidirectional feedback model, in which improved attentional control reduces the salience of NSSI-related cues and lessens reliance on maladaptive emotion regulation strategies, while better emotion regulation frees cognitive resources needed to disengage attention from those cues. 

The investigators believe that improvements in attentional control and emotion regulation may reinforce one another in a "positive feedback loop," although longitudinal studies are needed to clarify the direction of these effects. 

At least one adverse event (AE) was reported by 29.6% of participants in the active-treatment group and 10.7% of those in the sham group. Headache was the most common event, with other reported AEs including sleepiness, tenderness at the stimulation site, and dizziness. All adverse events were mild, resolved without intervention, and did not lead to treatment discontinuation.

"Given the mild, transient adverse events and substantial clinical benefit for this high-risk, treatment-limited population, the risk-benefit profile is favorable," the investigators noted. 

Study limitations included the fact that it lacked direct neuroimaging evidence for neural oscillation modulation and was conducted at a single center. Another limitation was the study's relatively short, 1-month follow-up period, which precluded assessment of long-term efficacy, durability of treatment effects, and outcomes such as NSSI recurrence.

The study received support from the National Postdoctoral Program for Innovative Talents, the National Natural Science Foundation of China, and the National Key Research and Development Program of China. The investigators report no relevant disclosures.