REWARD – rTMS Effects in Adolescent Depression and Behavioral Addictions

<b></b> <i>Background:</i> Impairments in reward processing and inhibitory control are key neurocognitive dysfunctions implicated in various mental disorders during adolescence, including major depressive disorder (MDD) and behavioral addictions (BAs). They are associated with greater symptom severity and poorer treatment outcomes. Among adults, repetitive transcranial magnetic stimulation (rTMS) targeting the left dorsolateral prefrontal cortex (DLPFC) has shown promise as a neuromodulation approach targeting these neural circuits. However, evidence regarding the neurophysiological effects of rTMS in adolescents with these conditions remains scarce. This study investigates the acute, short-term, and medium-term effects of high-frequency rTMS on neurophysiological markers and clinical symptoms in adolescents with MDD and BAs. <i>Methods:</i> This protocol describes a double-blind, randomized, sham-controlled trial enrolling adolescents 12-17 years diagnosed with MDD or BAs. We randomized the participants to receive either active rTMS (15 Hz, 120 % resting motor threshold, 1,600 pulses per session in 40 trains of 4 s) or sham stimulation. We studied the immediate rTMS effects after and during a singular rTMS session in both diagnostic groups as well as the effects of 12 rTMS sessions for the MDD group. We assessed self-report via the Children's Depression Rating Scale-Revised (CDRS-R) and craving scales adapted for BA. The neurophysiological outcomes include EEG-derived event-related potentials (Reward Positivity, N45, P300, P60, N100, LPP) to examine reward processing, cortical excitability/inhibition, and cue reactivity. The statistical analyses applied mixed-effects models with a planned sample size of 32 participants per group. <i>Discussion:</i> This study provides novel insights into the neurophysiological mechanisms underlying rTMS effects on the DLPFC in adolescent MDD and BAs. Demonstrating modulation of reward- and inhibition-related EEG markers alongside clinical improvement could strengthen the evidence for rTMS as a safe and effective intervention, while informing future personalized treatment strategies for these vulnerable populations.