Cognition-Modulated EEG Signatures and Clinical Features in Major Depressive Disorder: A Machine Learning-Based Exploratory Study.

Background: Major depressive disorder (MDD) includes heterogeneous clinical dimensions, including depressive symptom severity, treatment refractoriness, and suicidality, which are commonly assessed using subjective rating scales and retrospective clinical histories. Dysfunction of frontal and anterior cingulate cortex (ACC) networks has been implicated in MDD, suggesting that electroencephalography (EEG)-based approaches combined with machine learning (ML) may help with objective characterization of clinical heterogeneity. Methods: Resting-state and cognition-modulated EEG data were analyzed from 209 patients with MDD. A rostral ACC-engaging cognitive task (RECT) was used to probe frontal-ACC circuitry. Linear and non-linear EEG features extracted from frontal electrodes across multiple frequency bands were integrated with several ML classifiers to perform exploratory classification of suicidality, depressive symptom severity, and treatment refractoriness. Class imbalance in suicidality was addressed using synthetic oversampling applied to the training data only. Results: ML models, particularly Random Forest (RF), outperformed support vector machines across all outcomes. RF achieved classification accuracies of around 83% (area under curve (AUC) = 0.83) for depression severity and 87% (AUC = 0.87) for treatment refractoriness. Suicidality categorization performance improved following data balancing. Feature importance studies found consistent patterns across outcomes, with useful predictors primarily obtained from frontal electrodes and nonlinear EEG complexity measures. Conclusions: The combination of cognition-engaging frontal modulation and ensemble-based ML applied to EEG data suggests the feasibility of an exploratory, unified EEG-based approach for identifying important characteristics of MDD. These findings highlight the importance of frontal network dysfunction across the severity spectrum of MDD and the need for further validation in larger and longitudinal cohorts.