Major depressive disorder (MDD) is increasingly conceptualized not merely as a disorder of mood, but as a dysfunction of distributed and plastic prefrontal-limbic circuits that support cognitive and emotional control (McGaugh, 2013). Within this framework, a reproducible feature of the illness is an imbalance in functional engagement between left and right prefrontal systems, reflecting disrupted large-scale network organization rather than isolated regional pathology (Gibson et al., 2022). Evidence from neuroimaging, electrophysiology and structural morphology indicates a pattern often summarized as relative left-prefrontal hypoactivity (and structural compromise) alongside either preserved or relatively increased right-prefrontal responsivity. Importantly, this hemispheric imbalance manifests across modalities (fMRI, EEG, cortical excitability) and is increasingly understood as macroscopic manifestations of underlying network-level dysfunction, particularly involving deficits in top-down control over subcortical affective nodes such as the amygdala and hippocampus (Miller et al., 2015; Liu et al., 2017; Brunoni et al., 2017). Recent network-based models of depression further emphasize dysfunction within prefrontal–limbic circuits, including aberrant connectivity between the dorsolateral prefrontal cortex (DLPFC) and subgenual anterior cingulate cortex (sgACC), as well as disrupted integration across frontoparietal and default mode networks (Bennett, 2011; Taylor and Liberzon, 2007). From this perspective, hemispheric imbalance can be viewed as a manifestation of maladaptive network plasticity, rather than a competing explanatory framework. Framing MDD as a syndrome of disturbed hemispheric plasticity clarifies why therapies that restore network-level plasticity-pharmacological, psychotherapeutic or neuromodulatory-produce clinical benefit: symptom resolution often corresponds to restoration of adaptive, experience-dependent changes in prefrontal circuits rather than correction of a unitary chemical deficit (Berwian et al., 2024).

Non-invasive brain stimulation, and specifically repetitive transcranial magnetic stimulation (rTMS) and theta-burst variants, has been developed to act directly upon these prefrontal control systems. Many established clinical protocols are explicitly grounded in the hemispheric imbalance model, aiming to upregulate hypoactive left prefrontal regions and/or downregulate putatively hyperactive right prefrontal cortex (Prasser et al., 2014). Common clinical paradigms include left-sided high-frequency stimulation to enhance left DLPFC excitability, right-sided low-frequency stimulation to suppress putative right-hemisphere hyperactivity, sequential bilateral “left-high/right-low” combinations, and patterned burst protocols such as intermittent theta-burst stimulation (iTBS) intended to induce rapid long-term potentiation (LTP)-like plasticity (Prasser et al., 2014; Huang et al., 2005; Blumberger et al., 2018; Suppa et al., 2016). Randomized trials and network meta-analyses indicate that multiple active rTMS modalities are superior to sham for acute symptom reduction, and that iTBS can achieve clinical outcomes comparable to conventional high-frequency stimulation while drastically shortening treatment time (Buhle et al., 2013). However, direct comparative evidence across hemispherically distinct stimulation strategies remains limited and partially inconsistent, with some studies reporting comparable short-term efficacy across protocols, while others suggest differential response patterns depending on stimulation laterality, frequency, or patient characteristics (Lang et al., 2011; Blumberger et al., 2018). As a result, the short-term clinical effectiveness of these commonly used protocols−and the sources of their heterogeneous response profiles−remains incompletely resolved. This uncertainty highlights a central knowledge gap in the field: how different hemispherically informed rTMS/iTBS protocols compare in their short-term antidepressant efficacy.

In parallel with efforts to optimize stimulation protocols, increasing attention has been directed toward identifying cognitive mechanisms that might account for variability in clinical response. Cognitive reappraisal-the intentional reinterpretation of affective stimuli to lessen their emotional impact-is a canonical prefrontal-mediated emotion regulation strategy and a compelling candidate mediator of rTMS efficacy in MDD (Kluetsch et al., 2012). Behaviorally, individuals with MDD use reappraisal less frequently and less successfully than non-depressed controls, and poorer reappraisal capacity correlates with symptom severity and impaired functional outcomes (Ge et al., 2022; Li et al., 2023; Neacsiu et al., 2021). Neuroimaging meta-analyses of reappraisal consistently implicate left lateral prefrontal regions (VLPFC and DLPFC) in the implementation and selection of reinterpretation strategies, with effective reappraisal associated with down-regulation of amygdala responses via prefrontal control signals (Blumberger et al., 2022). Importantly, recent neuromodulation studies demonstrate that directly stimulating lateral prefrontal nodes modifies the neural substrates of reappraisal: TMS-fMRI and TMS-EEG experiments show that left-prefrontal stimulation can alter downstream amygdala reactivity and enhance electrophysiological markers associated with cognitive control during reappraisal tasks (Philip et al., 2017; Paneva et al., 2025; Plewnia et al., 2021). However, existing evidence remains fragmented: many studies focus on reappraisal-related neural effects without assessing clinical outcomes, whereas clinical trials rarely examine whether short-term symptom improvement is accompanied by changes in emotion-regulation capacity. Thus, whether modulation of cognitive reappraisal contributes to short-term antidepressant response−and whether such modulation differs across hemispherically informed stimulation protocols−remains an open mechanistic question rather than an established causal pathway.

On this basis, the present comparison is not intended to establish the superiority of bilateral over unilateral stimulation, but to dissociate their short-term clinical effects and cognitive mechanisms, given that both approaches remain widely used in routine practice. We tested the hypothesis that stimulation mode−intermittent theta-burst stimulation (iTBS) targeted to left lateral prefrontal cortex versus a sequential bilateral “left-high/right-low” rTMS regimen−will differentially engage the prefrontal mechanisms that subserve cognitive reappraisal and therefore produce distinct profiles of change in both reappraisal ability and depressive symptoms. Mechanistically, iTBS is designed to induce rapid, focal LTP-like plasticity in the stimulated cortex and its functionally connected network, thereby preferentially potentiating left-hemisphere control signals that implement reinterpretation strategies (Chen et al., 2021; Lu et al., 2023; Murgaš et al., 2023); by contrast, a sequential left-high/right-low protocol may exert therapeutic effects via a mixture of left-hemisphere facilitation and right-hemisphere down-regulation that restores interhemispheric balance but with a different spatial and temporal signature of plasticity (Prasser et al., 2014). We therefore prespecified the change in depression severity as the primary outcome, with clinical (cognitive reappraisal score) secondary endpoints to test whether protocol-specific modulation of left-prefrontal control predicts symptomatic improvement. If iTBS produces greater and faster gains in reappraisal capacity than sequential bilateral stimulation, and if those gains mediate symptom reduction, the result would furnish a concrete, mechanistic rationale for selecting stimulation paradigms based on the dominant cognitive-affective deficit of the patient−a step toward phenotype-matched, mechanism-driven neuromodulation for MDD (Hühne et al., 2023).

In this randomized controlled trial, we compared the efficacy of sequential bilateral rTMS and iTBS in patients with MDD. Our findings demonstrate that iTBS elicited more pronounced improvements across multiple domains, including depressive symptom severity, cognitive reappraisal ability, expressive suppression, and anxiety, compared with sequential bilateral rTMS over the 2-weeks intervention period. Importantly, changes in cognitive reappraisal were significantly associated with reductions in depressive symptoms in the iTBS group; however, these associations are correlational and do not imply causal mediation. Nonetheless, both interventions produced clinically meaningful improvements, highlighting that sequential bilateral rTMS also confers therapeutic benefit, albeit with a potentially different temporal pattern of clinical response.

Baseline demographic and clinical characteristics, including age, sex, depression severity, anxiety, sleep quality, social support, anhedonia, suicidal ideation, and emotion regulation scores, were comparable between groups, minimizing potential confounding. These baseline associations underscore the importance of targeting both affective and cognitive-emotional regulation processes when evaluating treatment response.

In the present study, iTBS demonstrated superior efficacy in alleviating depressive symptoms compared with sequential bilateral rTMS. This finding is consistent with prior trials showing that standard iTBS targeting the L-DLPFC produces antidepressant effects comparable to, or exceeding, those of conventional high-frequency rTMS, while offering greater treatment efficiency (Blumberger et al., 2018). Moreover, studies employing accelerated iTBS protocols have demonstrated that increased session density can lead to rapid and robust symptom improvement, highlighting the potential of iTBS to induce early therapeutic effects (Cole et al., 2020). In contrast, classical bilateral rTMS protocols−typically combining high-frequency stimulation of the L-DLPFC with low-frequency stimulation of the R-DLPFC−have demonstrated antidepressant efficacy comparable to unilateral stimulation (Fitzgerald et al., 2006), but have not consistently shown superiority in terms of clinical outcomes or speed of response, and typically require longer session durations per day (Chen et al., 2014). Notably, Prasser et al. (2014) reported a trend toward greater symptom improvement with bilateral theta-burst stimulation compared with bilateral rTMS at follow-up, suggesting that bilateral TBS-based approaches may represent a promising alternative to conventional bilateral rTMS protocols. Notably, although overall symptom reduction was greater in the iTBS group, the relatively greater improvement in anhedonia observed in the sequential bilateral stimulation group may reflect differential engagement of reward-related neural circuits. Anhedonia has been closely linked to dysfunction within frontostriatal networks, and bilateral prefrontal modulation may exert a more balanced influence on these circuits than unilateral stimulation alone. This interpretation is consistent with prior evidence that prefrontal stimulation can indirectly modulate striatal and limbic activity via network-level mechanisms (Russo and Nestler, 2013; Fox et al., 2012). Taken together, these findings, in conjunction with the present results, support the notion that iTBS-based interventions−particularly those targeting the L-DLPFC−may offer a more efficient and clinically advantageous neuromodulation strategy for MDD, while underscoring the need for future trials directly comparing dose-matched and protocol-matched bilateral and unilateral TBS paradigms.

The observed differences in emotional and cognitive outcomes between the two modalities provide insight into protocol-specific mechanisms of action. iTBS may rapidly prime the left prefrontal cortex to support the acquisition and implementation of adaptive reappraisal strategies, translating to faster and more robust clinical improvement (Cristancho et al., 2020; Liston et al., 2014; Hayatbini et al., 2021). Sequential bilateral rTMS, while slower in onset, may promote global network reorganization and interhemispheric balance, offering a complementary route to symptom amelioration. Taken together, these findings highlight that the choice of stimulation protocol can be informed by the dominant cognitive-affective deficits of individual patients, aligning with the paradigm of mechanism-driven, phenotype-matched neuromodulation for MDD (Fitzgerald et al., 2016).

The present findings have several important clinical implications. Although the twice-daily intervention protocol may pose logistical challenges in routine clinical practice, such an approach is likely feasible in structured rehabilitation settings or short-term, supervised intervention programs, particularly among individuals at early disease stages. From a cost perspective, the non-invasive nature of the intervention may reduce medical risk and monitoring burden compared with pharmacological strategies; however, cumulative time and personnel requirements may increase overall costs, underscoring the need for future cost-effectiveness evaluations and optimized delivery models. Patient adherence may be facilitated by the favorable safety profile and potential perceived cognitive benefits, yet treatment burden remains a relevant consideration for long-term implementation. Importantly, our results suggest that patient selection strategies informed by specific cognitive or regulatory deficits−such as impaired reappraisal-related processes−may enhance both clinical efficacy and resource efficiency. This aligns with emerging precision-oriented approaches in cognitive intervention and may improve the translational potential of the present findings.

Several limitations should be acknowledged. First, the absence of a sham control condition precludes disentangling stimulation-specific effects from nonspecific placebo or expectancy effects; therefore, treatment effects should be interpreted with caution. Second, the intervention period was limited to 2 weeks, preventing assessment of the long-term durability of treatment effects. Third, although changes in cognitive reappraisal were associated with symptom improvement, causal mediation cannot be conclusively inferred from the current design, and relevant covariates (e.g., baseline HAMD score, baseline reappraisal score, medication status, age, and sex) may have influenced these associations. Fourth, the iTBS and sequential bilateral rTMS protocols differed in total stimulation dose, daily session frequency, and stimulation pattern, which limits isolation of dose-response effects and may partly account for between-group differences. Finally, the modest sample size, incomplete blinding, single-center design (including restriction to Han ethnicity and a relatively young sample), and short follow-up constrain statistical power and generalizability. Future sham-controlled, dose-matched studies with larger samples, longer follow-up, and mediation or mixed-effects modeling are warranted.

In conclusion, our results indicate that iTBS targeting the left DLPFC produces more pronounced improvements in depressive symptoms and cognitive reappraisal compared with sequential bilateral rTMS over the 2-weeks intervention period, whereas both modalities confer meaningful clinical benefits. Observed changes in cognitive reappraisal were associated with reductions in depressive symptoms, suggesting that improvements in emotion regulation capacity may accompany clinical symptom relief. Future studies incorporating neurophysiological or neuroimaging measures are warranted to directly investigate the neural substrates underlying these clinical and cognitive changes and to inform individualized neuromodulation strategies in MDD.