ADHD PreSMART: ADHD PreSMA Response inhibition Therapy

PROJECT SUMMARY Attention Deficit Hyperactivity Disorder (ADHD), the most common childhood behavioral diagnosis, is a heterogeneous disorder linked to poor adult outcomes. The challenge of ADHD treatment and the limitations of current approaches are exemplified in the results of the most comprehensive, NIH-funded study (Multimodal Treatment of ADHD) in which, at 8-year follow up, individuals in all four treatment arms showed the same high rates of psychiatric hospitalizations, traffic citations, illicit drug use, and arrests. These results call for a need to explore innovative therapeutic option such as circuit-based noninvasive neuromodulation. Here we propose to use accelerated (i.e., >1 session/day) intermittent theta-burst transcranial magnetic stimulation (iTBS) to target the pre-supplementary motor area (pre-SMA), a brain region affected in ADHD and involved in the abnormal response inhibition observed in this disorder. The proposed target engagement will focus on neurophysiologic and behavioral measures. The rationale of the proposal is based on preliminary data showing that transcranial magnetic stimulation (TMS) and electroencephalography (EEG) inhibitory network biomarkers can be modulated by pre-SMA iTBS. We hypothesize that pre-SMA iTBS can modulate inhibitory network biomarkers (R61 phase) and behavioral response inhibition (R33) in ADHD. In the R61 phase, we will deliver sham- controlled accelerated pre-SMA iTBS (2 iTBS sessions per day) to 40 ADHD adolescents (12-17 years old) to detect whether TMS-quantified (cortical silent period, short-interval intracortical inhibition; Aim 1) and EEG- based (alpha and beta-band power; Aim 2) inhibitory biomarkers can be modulated. For Aim 3 (R33 phase), we propose to recruit 50 ADHD adolescents and deliver 5 consecutive days of sham vs active accelerated pre- SMA iTBS (total 10 iTBS sessions) and quantify iTBS effects on stop-signal reaction time. Completion of this project will provide the basis for designing a large sample clinical trial for the treatment of ADHD. Furthermore, this study will provide crucial tolerability and safety data for accelerated iTBS in the pediatric population and promote repetitive TMS research in other pediatric neuropsychiatric disorders.