PREFRONTAL HEMISPHERIC ASYMMETRY AND RTMS RESPONSE IN DEPRESSION: EVIDENCE FROM A NATURALISTIC COHORT

Interindividual variability in antidepressant response to repetitive transcranial magnetic stimulation (rTMS) suggests that intrinsic features of brain organization shape treatment efficacy. Hemispheric asymmetry of the dorsolateral prefrontal cortex (DLPFC) is a core property of cortical architecture implicated in affective regulation, yet its relevance for rTMS outcomes remains unclear. We investigated whether structural DLPFC asymmetry predicts clinical response in a naturalistic cohort of patients with major depressive disorder. Forty-seven patients received neuronavigated, robot-assisted bilateral DLPFC rTMS, comprising left intermittent theta-burst stimulation and right continuous theta-burst stimulation. Structural magnetic resonance imaging was used to derive normalized left and right DLPFC gray matter volumes, and a hemispheric asymmetry index was calculated as (left minus right) divided by (left plus right). Depressive symptoms were assessed using the Beck Depression Inventory before and after treatment. Clinical improvement was quantified as absolute and percentage symptom change, with response defined as a reduction of at least fifty percent. Associations between structural measures and outcome were examined using parametric and nonparametric correlations, group comparisons, and multivariable regression models controlling for age, sex, and total intracranial volume. Receiver operating characteristic analyses were conducted with false discovery rate correction. Greater symptom improvement was consistently associated with more negative DLPFC asymmetry values, indicating reduced leftward hemispheric asymmetry. This association was robust across analytical approaches and remained significant after correction for multiple comparisons. In contrast, absolute left, right, or total DLPFC gray matter volumes were not independently related to treatment response. Overall, interhemispheric prefrontal balance appears critical for individualized rTMS antidepressant efficacy.