Numerous studies have emphasized the aberrant nature of the DLPFC and its FC with large-scale brain networks in MDD. However, prior research has predominantly focused on MRI methodologies, with EEG and ERP receiving limited attention. Notably, EEG changes shortly after initiating antidepressant medication, whereas baseline resting-state EEG may offer a more trait-like biomarker for predicting treatment response and subtyping depression, early treatment related EEG changes reflect state-dependent alterations in brain activity and connectivity patterns. These state-dependent biomarkers may be more sensitive to the specific neural changes induced by the drug, potentially making them better predictors of treatment response compared to trait-like baseline measures.
The present cohort study aimed to better elucidate the neural mechanisms underlying MDD by leveraging the ability of high-density EEG to directly measure neural activity and to assess the early dynamic changes in brain function associated with treatment response. This approach allows for the identification of state-dependent biomarkers that may be more closely linked to the specific neural changes induced by antidepressant medication, in contrast to the more trait-like baseline measures examined in prior research.
Compared to HCs, patients with MDD exhibited significantly diminished current density in the right DLPFC during the N2 and P3 time windows under the oddball stimulus. Importantly, heightened right DLPFC current density during the N1, P2 and N2 time windows predicted lower HAMD-21 scores across 1 week of treatment. Furthermore, remitters showed a significantly greater increase in the right DLPFC current density during the N1, P2, N2 and P3 time windows compared to non-remitters. These findings indicate that DLPFC activity patterns are closely linked to depressive symptoms, and increased current density in certain time windows is associated with better treatment outcomes for MDD patients. The N1 and P2 components represent early sensory processes elicited by stimuli, reflecting the reflecting the detection, initial perceptual characterization, and inhibition of the stimuli [27–30]. In contrast, the N2 and P3 components constitute mid- to late-stage negative components evoked by oddball stimuli, reflecting automatic attentional mechanisms and cognitive control [31]. The observed changes in these ERP components provide insights into the cognitive and neural processes that are impaired in MDD and those that are involved in the recovery or remission of depressive symptoms.
Prior studies on repetitive transcranial magnetic stimulation (rTMS) or electrical stimulation to activate the DLPFC has shown promise for ameliorating clinical symptoms in patients with MDD, further indicating that increasing DLPFC activity may help alleviate depressive symptoms [32, 33]. However, the discovery of increased DLPFC activity in remitters during the visual oddball paradigm in the present study contradicts findings from a previous task-based fMRI study, which reported decreased DLPFC activity in remitters during the Go/NoGo paradigm [14]. This discrepancy may reflect divergent cognitive and neurobiological processes across different task paradigms. Notably, ERPs can capture distinct stages of cognitive processing, such as early attentional orienting and later cognitive control, whereas fMRI primarily reflects average activity levels across the entire task duration, making it difficult to differentiate activity patterns at different cognitive stages [34, 35]. Additionally, the differences in the temporal measurement time windows of ERPs and fMRI during task performance may also contribute to the observed discrepancies.
Further investigating the influence of DLPFC activity on the DMN and SN, we discovered that higher theta-band FC between the left DLPFC and the right IC, as well as lower alpha-band FC between the right DLPFC and right IC, predicted lower HAMD-21 scores after one week of treatment. This finding suggests that enhanced communication between the DLPFC, which is associated with cognitive control processes, and the right IC, a key node in the SN responsible for processing salient stimuli and regulating attention, may facilitate more rapid alleviation of depressive symptoms during the initial stages of treatment. This result is partly in line with prior fMRI studies which have documented decreased FC between the ECN and SN in patients with MDD [10]. Additionally, a body of fMRI literature has consistently indicated that MDD primarily manifests as dysfunctions within the prefrontal-limbic circuitry [9, 36, 37]. Notably, the SN has been shown to exhibit increased connectivity with the DMN but reduced connectivity with the ECN individuals with MDD [10]. This pattern may reflect an over-allocation of attention towards internal negative information coupled with a neglect of external stimuli, as well as reduced recruitment of ECN resources for cognitive control processes [10].
Finally, the present study observed that higher FC in the theta-band and beta-band between the left DLPFC and both the left PCC and right PCC predicted higher HAMD-21 scores over 1 week of treatment. Furthermore, an early decrease in the beta-band FC between the left DLPFC and both the left PCC and right PCC predicted a greater probability of achieving remission at week 12. These findings align with previous fMRI studies indicating increased FC between the ECN and DMN in MDD [10, 38, 39]. Reduced DLPFC activity may impair cognitive control and emotion regulation abilities in MDD patients, the increased FC between the DLPFC and DMN regions in the beta-band may be a compensatory mechanism adopted by the brain to cope with the reduced DLPFC function, aiming to maintain the regulation of DMN activity [40, 41]. However, further research is needed to validate this hypothesized mechanism.
Strengths and limitations
This study offers several key strengths compared to prior research in this area. Firstly, this prospective longitudinal study encompassed both MDD patients and HCs, and collected psychological assessment, EEG and ERP data at baseline and week 1 post-treatment, enabling continuous observation of dynamic alternations in brain network and depressive symptoms, as well as evolving associations between brain networks alterations and symptoms progression. Secondly, by examining changes in brain activity states and FC before and after treatment, this study reduces the impact of individual variances and the inherent diversity of MDD symptomatology. Thirdly, the concurrent examination of DLPFC activity and DLPFC seed-based FC provided further insights into the pathophysiological mechanisms of MDD. Fourthly, unlike previous research predominantly relying on MRI, this study utilized EEG, offering several advantages, including higher temporal resolution, lower cost, greater portability, and insensitivity to motion artifacts. Additionally, the source seed-based FC analysis of the EEG data enhanced interpretability compared to direct calculations between scalp channels, facilitating a more comprehensive understanding of brain areas interactions. Lastly, and importantly, this study revealed that the EEG changes observed soon after initiating antidepressant medication reflect state-dependent modifications in brain function and connectivity. By investigating early treatment response and long-term remission, this study provides crucial insights that have the potential to optimize treatment selection and outcomes for MDD patients, thereby reducing morbidity and economic burden by facilitating timely transitions to more effective interventions when initial antidepressants are predicted to have limited benefit.
However, future research should address several limitations. Firstly, the single-center recruitment and relatively small sample size necessitate further validation. Secondly, limited analyzable EEG and ERP data at week 12 due to participant refusal and poor quality highlight the need for more comprehensive treatment assessment over time. The long-term effectiveness of antidepressants warrants further investigation, including 6- and 12-month follow-ups. Moreover, the exclusive use of SNRI medications limits generalizability. Additionally, while EEG offers high temporal resolution, cost-effectiveness, and portability compared to MRI, its spatial resolution remains limited. Finally, individual differences in symptoms and treatment response should be carefully considered and controlled for in future research.