Toward precision neuromodulation in ADHD: rTMS-evoked excitability as a biomarker and ccPAS as an alternative...

Attention Deficit Hyperactivity Disorder (ADHD) is associated with cognitive and emotional-motivational dysregulation and with right prefrontal cortex (rPFC) dysfunction. While repetitive transcranial magnetic stimulation (rTMS) has shown promise in alleviating ADHD symptoms, treatment outcomes are not consistent or robust. This study was designed to initiate the prospective validation process of a recently suggested electrophysiological biomarker for clinical response to high-frequency rTMS (HF-rTMS) in adults with ADHD. For biomarker non-compatible patients, the study explored the safety and efficacy of a novel treatment protocol using cortico-cortical Paired Associative Stimulation (ccPAS) as an alternative stimulation approach. Fifty-eight TMS-naive adults diagnosed with ADHD underwent biomarker screening to characterize the clinical profile of biomarker-compatible and non-compatible participants. Thereafter, a subgroup of biomarker-compatible participants (n = 15) underwent treatments with HF-rTMS (15 sessions over 3 weeks), while non-compatible participants were randomized to one of two ccPAS protocols with different order of hemispheric stimulation (left-to-right: n = 12; right-to-left: n = 12). Biomarker-compatible participants exhibited significantly lower baseline ADHD symptom severity (d_Cohen = 0.46) and elevated response inhibition (d_Cohen = 0.53) relative to non-compatible participants. Furthermore, symptom severity in the compatible subgroup was associated with alpha-band resting-state asymmetry (r = 0.65). Notably, compared to an existing dataset of participants who were randomly allocated to active (n = 15) and sham (n = 14) treatment, biomarker-allocated HF-rTMS participants exhibited enhanced clinical outcome, both immediately after the treatment and at a one-month follow-up (η²_partial = 0.08-0.12). Conversely, ccPAS treatment yielded modest symptom reduction in the two groups with no significant effect of stimulation order (η²_partial = 0.08), suggesting that treatment outcome was not influenced by the associative mechanism of the ccPAS. These findings provide preliminary support for the potential utility of rTMS-evoked excitability as a biomarker for personalized ADHD treatment and underscore the need for further investigation into ccPAS as a therapeutic alternative.