Metabolic-Brain Functional Coupling Mechanism Underlying iTBS Treatment for Adolescent Depression
Background: Adolescents with depression pose a significant public health challenge, yet individual variability in treatment response to accelerated intermittent theta-burst stimulation (iTBS) for depression remains substantial. This study aims to integrate metabolomics with multimodal neuroimaging techniques to identify objective biomarkers of response to iTBS treatment and investigate the relationship between brain and metabolism. Methods: Patients received an accelerated iTBS protocol targeting the left dorsolateral prefrontal cortex. Assessments included plasma metabolomic profiling, resting-state and naturalistic functional magnetic resonance imaging, and clinical scale evaluations conducted at baseline and post-treatment. Results: The study enrolled 85 adolescents with depression and 48 healthy controls. 53 adolescent patients with depression completed the full course of iTBS treatment and provided blood samples for biomarker detection and analysis. Seventeen differential metabolites were identified that distinguished patients from controls and changed significantly after iTBS treatment. The area under the curve (AUC) for the metabolites 3-hydroxymethylglutaric acid, malonic acid, N-acetylphenylalanine, norepinephrine and tryptophanamide exceeds 0.8. The metabolites isovalerylcarnitine, taurochenodeoxycholic acid, taurodeoxycholic acid, and valerylcarnitine were significantly correlated with the reduction in scores on the Hamilton Depression Rating scale (HAMD). Furthermore, alterations in the metabolites 3-Indolepropionic acid, N-acetylphenylalanine, 3-Methylhistidine, Norepinephrine, Ortho-hydroxyphenylacetic acid, 3-Hydroxymethylglutaric acid and Indole-3-carboxaldehyde were associated with functional changes in key prefrontal regions, specifically, the Amplitude of Low-Frequency Fluctuations (ALFF) and Regional Homogeneity (ReHo) in the left superior frontal gyrus, and ReHo in the left middle frontal gyrus. Conclusions: This study uncovers preliminary evidence of a distinct metabolic signature in adolescent depression that normalizes following iTBS treatment and correlates with both prefrontal functional recovery and clinical improvement. The identified metabolites serve as potential candidate biomarkers and shed light on the brain-metabolism relationship. These findings offer preliminary candidate biomarkers for future investigations into interindividual variability in iTBS treatment response and offer a tentative framework for developing personalized neuromodulation strategies for adolescent depression. Clinical Trial Registration: The study has been registered on https://www.chictr.org.cn/ (registration number: ChiCTR2500106503 and ChiCTR2500113926; registration link: https://www.chictr.org.cn/showproj.html?proj=279390 and https://www.chictr.org.cn/showproj.html?proj=279455).