Abstract
<title>Abstract</title> <p>Background Attention-deficit/hyperactivity disorder (ADHD) diagnosis currently relies on subjective behavioral reports; therefore, objective biomarkers of prefrontal dysfunction are urgently needed. This study aimed to characterize prefrontal hemodynamic responses in ADHD across varying cognitive loads and to quantify the effect of clinical interventions on functional normalization using functional near-infrared spectroscopy (fNIRS). Methods A systematic search of PubMed, Embase, CENTRAL, Web of Science, and PsycINFO was conducted from database inception to April 2026. Observational and interventional fNIRS studies measuring task-evoked prefrontal oxygenated hemoglobin (HbO) in individuals with ADHD were included. Two independent reviewers extracted data in accordance with PRISMA and MOOSE guidelines. Effect sizes, including cross-sectional standardized mean differences (SMDs) and longitudinal standardized mean changes (SMCs), were pooled using a random-effects model with restricted maximum likelihood (REML) estimation and Knapp-Hartung adjustment. Results Twenty-four studies (966 participants) were included. Cross-sectional analyses (15 comparisons; 399 ADHD, 386 controls) showed significant prefrontal hypoactivation in ADHD (SMD, − 0.71; 95% CI, − 0.98 to − 0.44; P < .001), significantly moderated by cognitive load (P = .03), with the largest deficit during high-load tasks (SMD, − 1.09; 95% CI, − 1.88 to − 0.30). Interventional analyses (10 studies; 204 participants) revealed a significant increase in prefrontal activation post-treatment (SMC, 0.53; 95% CI, 0.27 to 0.78). After trim-and-fill adjustment for publication bias, the effect remained significant (adjusted SMC, 0.35; 95% CI, 0.05 to 0.65). Conclusions Load-dependent prefrontal hypoactivation is a significant functional hallmark of ADHD that partially normalizes after clinical intervention. fNIRS shows promise as an adjunctive tool for characterizing ADHD pathophysiology and monitoring treatment response, though high heterogeneity in nonpharmacological interventions warrants further investigation.</p>