Major depressive disorder (MDD) is characterized by persistent low mood, loss of interest, and cognitive and physical symptoms (1). Converging evidence has revealed abnormalities in several brain regions linked to emotional and cognitive processing in MDD, including the dorsolateral prefrontal cortex (DLPFC) (2). Specifically, hypo-activity in the left DLPFC is consistently found in MDD and correlates with symptom severity (3, 4). As the DLPFC is critical for executive functions, left DLPFC hypo-activation likely contributes to the cognitive deficits frequently observed in MDD (5).

Emerging evidence also indicates hyperactivity in the right DLPFC in MDD, which has been associated with negative mood and cognitive impairments (6) (6–9). This suggests bi-hemispheric alterations in DLPFC function in MDD, with hypo-frontality in the left DLPFC and hyper-frontality in the right DLPFC. Neuromodulatory techniques like repetitive transcranial magnetic stimulation (rTMS) allow direct modulation of cortical activity in targeted regions. High-frequency (HF) rTMS applied to the left DLPFC has shown antidepressant efficacy, potentially by correcting left hypo-activity (10, 11). Low-frequency rTMS over the right DLPFC has been proposed to potentially reduce hyperactivity in this region and alleviate associated negative cognitive and affective symptoms in major depressive disorder, such as impaired executive functioning, rumination, and persistent negative mood (8, 12, 13). Bilateral protocols incorporating left HF-rTMS and right low-frequency rTMS may have additive benefits in MDD by normalizing the bi-hemispheric imbalance (13). However, most studies have focused on unilateral left stimulation, with limited direct comparisons of bilateral and unilateral rTMS, especially on cognition. Elucidating differences between unilateral and bilateral neuromodulation can provide insights into optimizing protocols (14).

Here, we investigated and compared the effects of unilateral HF-rTMS over left DLPFC versus bilateral rTMS (left high-frequency DLPFC and right low-frequency DLPFC stimulation) on depression severity, visual-spatial memory, response inhibition, and cognitive flexibility in MDD. We hypothesized bilateral rTMS would enhance cognition along with similar antidepressant efficacy as unilateral protocol.

The primary hypothesis was that bilateral repetitive transcranial magnetic stimulation (rTMS), combining high-frequency (HF) stimulation over the left dorsolateral prefrontal cortex (DLPFC) and low-frequency (LF) stimulation over the right DLPFC, would enhance cognitive functioning in major depressive disorder (MDD) patients. Specifically, it was hypothesized that bilateral rTMS would improve visual-spatial memory performance, response inhibition accuracy, and cognitive flexibility. Additionally, it was postulated that bilateral rTMS would demonstrate comparable antidepressant efficacy to unilateral HF-rTMS over the left DLPFC alone.

The original participant sample included 60 individuals who underwent pre-testing. However, 13 subjects dropped out for reasons including post-test non-completion or unwillingness to continue. The final analyzed sample comprised 47 in three groups including unilateral stimulation (n=15; mean age 36.12 ± 9.45 years), bilateral stimulation (n=15; mean age 35.58 ± 10.22 years), and sham stimulation control (n=17; mean age 34.50 ± 9.50 years).

The groups did not significantly differ in age (p >.05). Baseline ANOVA tests found no significant between-group differences in depression severity (BDI-II), visual-spatial memory (CBT), response inhibition (GNGT), or cognitive flexibility (WCST) performance. The comparative effects of unilateral and bilateral DLPFC rTMS on depression severity, visual-spatial memory, response inhibition, and cognitive flexibility in Major Depressive Disorder are presented in Figure 2 .

In the present study, we compared the effects of left unilateral versus bilateral rTMS over the DLPFC on depression severity, response inhibition, and cognitive flexibility in MDD patients.

As the DLPFC is critical for executive functions, left DLPFC hypoactivation likely contributes to the cognitive deficits frequently observed in this disorder (21).

Neuromodulatory techniques like repetitive transcranial magnetic stimulation (rTMS) allow direct modulation of cortical excitability and hold promise in ameliorating MDD symptoms (22). This method uses a magnetic field to stimulate nerve cells in targeted brain areas. High-frequency (HF) rTMS enhances cortical excitability and metabolic activity in the stimulated regions (23).

Given the role of left DLPFC hypofunction in MDD, HF-rTMS applied to this region has been extensively studied for its antidepressant effects. A large body of evidence now demonstrates that HF-rTMS over the left DLPFC has significant antidepressant efficacy in MDD, likely by correcting the baseline dysfunction of this area (24, 25). Alongside mood improvements, HF-rTMS could also potentially enhance cognition by modulating left DLPFC activity (17).

While most studies have focused on left DLPFC stimulation, emerging insights into the bilateral nature of prefrontal cortex changes in MDD have prompted interest in bilateral modulation (26). A few studies applying bilateral rTMS over left and right DLPFC have shown positive mood effects in treatment-resistant MDD (26, 27).

However, very few studies have directly compared the antidepressant and cognitive impact of bilateral vs unilateral HF-rTMS protocols. Elucidating the differences can help determine the optimal stimulation approach to address the mood and cognitive deficits in MDD. In the present study, we compared the effects of left unilateral versus bilateral rTMS over the DLPFC on depression severity, response inhibition, and cognitive flexibility in MDD patients. We hypothesized bilateral stimulation would improve executive functioning along with similar antidepressant efficacy as unilateral protocol.

Our study found that both unilateral and bilateral rTMS led to significant reductions in depression levels based on BDI-II scores, with no significant differences between the protocols. This indicates comparable antidepressant effects for uni- and bilateral stimulation, consistent with some prior studies (28, 29). The mood improvements likely arise from modulating left DLPFC activity, a key region implicated in MDD pathophysiology (30).

For visual-spatial memory, while bilateral rTMS did not increase Corsi span, unilateral stimulation elicited significant gains from pre- to post-treatment. Although there are other findings regarding the effect of stimulating the right DLPFC on visuospatial functions, this likely arises from the role of the left DLPFC in manipulating visuospatial representations (31, 32). The unilateral protocol directly targeted this region compared to the bilateral approach. Furthermore, additional posterior brain areas like the parietal cortex contribute to visual-spatial memory (33).

For response inhibition, accuracy on the Go/No-Go task improved following both unilateral and bilateral rTMS. The DLPFC is involved in inhibitory control (34), so the increased left DLPFC activation from unilateral stimulation likely improved this executive function. The bilateral protocol applied high-frequency stimulation to the left DLPFC and low-frequency stimulation to the right DLPFC. This approach is based on the hypothesis that such a protocol could potentially normalize hemispheric imbalances in prefrontal cortex activity that may contribute to cognitive dysfunction in depression (35).

In their framework, Schutter & van Honk propose that high-frequency rTMS over the left DLPFC could enhance activity in this hypoactive region, while low-frequency rTMS over the right DLPFC could reduce hyperactivity. They suggest this bi-hemispheric modulation might help restore prefrontal balance and improve symptoms.

Several studies have suggested that while high-frequency rTMS over the left DLPFC can enhance cognitive functioning, low-frequency (1 Hz) rTMS over the right DLPFC may impair certain cognitive domains (17, 36). The rationale behind our bilateral protocol was to potentially normalize prefrontal asymmetry by upregulating the hypoactive left DLPFC and downregulating the hyperactive right DLPFC in MDD. However, inhibiting right DLPFC activity with low-frequency rTMS could have counteracted some of the cognitive benefits provided by high-frequency left DLPFC stimulation.

Indeed, while both unilateral and bilateral rTMS improved response inhibition accuracy on the Go/No-Go task compared to sham, only the unilateral protocol enhanced visuospatial memory performance on the Corsi Block-Tapping Test. This suggests that the addition of right DLPFC inhibition may have negated visuospatial memory improvements in the bilateral group. The lack of significant effects on cognitive flexibility, as measured by the Wisconsin Card Sorting Test, could also be related to the inhibitory right DLPFC stimulation component.

Previous work has implicated the right DLPFC in various cognitive processes, including working memory, attention, and cognitive control (17, 37). Therefore, suppressing activity in this region with low-frequency rTMS may disrupt these functions. Future studies are needed to clarify the specific cognitive consequences of inhibiting the right DLPFC and delineate the optimal parameters for bilateral rTMS protocols in depression. Approaches that modulate the right DLPFC in a more focal or patterned manner may be preferential.

However, neither protocol significantly impacted cognitive flexibility based on the Wisconsin Card Sorting Test performance. While some studies show rTMS-induced flexibility (38), others report no effects (39), likely because multiple regions beyond just DLPFC contribute to cognitive flexibility (40, 41).

The study had a relatively small sample size and also lacked comprehensive demographic and clinical data, which are caveats to the interpretation and generalizability of our findings. A longer treatment duration with follow-up assessments could better elucidate the therapeutic effects. Given the need to consider individual differences in brain function when hypothesizing the effects of the two protocols, and the inability to simply explain depression as a static phenomenon based solely on the function of select brain regions or their causal relationships, we initially sought to assess and analyze neurophysiological components like brain waves and vital signs before and after the interventions. However, due to the unreliability of the data obtained through these methods because of technical issues with the equipment, we were forced to exclude them.

Our study did not directly measure changes in prefrontal cortex activity or hemispheric balance. Therefore, while our bilateral protocol was designed based on this theoretical framework, we cannot conclude that it normalized our participants’ hemispheric imbalances. Future studies combining rTMS with neuroimaging techniques could provide direct evidence of whether bilateral stimulation alters prefrontal cortex activity patterns in this way.

One of the key limitations of this study is the exclusion of participants who did not complete the secondary assessments from the analysis, despite being actual clinical patients. This per-protocol analysis approach could potentially introduce attrition bias and limit the generalizability of the findings. The intention-to-treat (ITT) principle, which analyzes all randomized participants in their assigned treatment groups regardless of adherence or completion, is generally recommended for clinical trials (42).

By not adhering to the ITT principle, our study may have overestimated the treatment effects or underestimated the potential for adverse events or dropout rates associated with the rTMS protocols (43). Future studies should employ ITT analysis, using appropriate methods for handling missing data, such as multiple imputation or mixed-effects models, to provide a more robust and unbiased assessment of the efficacy and tolerability of unilateral versus bilateral rTMS approaches (43).

Another limitation of this study is the lack of comprehensive reporting and analysis of demographic and clinical variables beyond age. Factors such as sex, education level, employment status, marital status, baseline depression severity, duration of current depressive episode, number of previous episodes, treatment resistance (defined as failure of adequate trials of multiple antidepressant medications), concomitant psychotropic medications, and medical comorbidities could all potentially impact the response to rTMS interventions (15).

Ideally, these variables should have been reported, and their potential influence on the primary and secondary outcomes should have been statistically assessed to ensure that the treatment groups were well-balanced at baseline. If significant differences existed, these variables could have been included as covariates in the analyses. The lack of comprehensive demographic and clinical characterization limits the interpretability and generalizability of our findings.

Future studies should carefully record and report these relevant variables and conduct appropriate statistical analyses to account for potential confounding factors. This would not only enhance the internal validity of the study but also facilitate the identification of potential moderators or predictors of treatment response, which could inform the personalization of rTMS protocols (15)Another limitation of this study is the use of the BDI-II as the primary depression outcome measure, rather than clinician-administered scales like the HDRS or MADRS, which are considered gold standards by regulatory agencies.

Side effects such as headaches, dizziness, and spasms in the facial muscles, albeit very mild and transient, existed in both the dropout participants and the other subjects, but did not have a particular impact on the individuals’ motivation to continue or leave the study, especially since the possibility of these transient side effects had been explained to them before the start of the interventions. The subjects who withdrew from the trial, did not respond to telephone follow-ups and no information is available about them, or those who were available did not state these side effects as the reason for discontinuing the interventions.

It is acknowledged that the observed differences between unilateral and bilateral stimulation may have been influenced by low statistical power. The relatively small sample size (n=15 per active treatment group) could have resulted in insufficient power to detect subtle differences between protocols, particularly for cognitive measures. While significant effects were observed in some domains, such as visual-spatial memory improvements in the unilateral group, it is possible that other real differences remained undetected due to limited statistical power.

Future studies could further explore optimal rTMS protocols and parameters, such as combining rTMS with cognitive training to potentially enhance cognitive benefits (18). Additionally, an integrative, multidimensional approach could provide insights into depression mechanisms based on objective measures across units of analysis, including cognitive/behavioral functions, brain activity, genetics, and neurochemistry [RDoC framework] (44).

The unilateral protocol’s partial superiority over bilateral stimulation on some outcomes may relate to greater left DLPFC excitation and less right DLPFC inhibition from fewer inhibitory pulses. The dose-response relationship between left DLPFC pulses and effects could be examined further. Elucidating the contribution of right DLPFC inhibition in bilateral protocols represents another area for future research. Overall, comparisons of unilateral versus bilateral rTMS can help optimize protocols for managing depression’s neuropsychiatric burden.

While the BDI-II is a valid and reliable measure of depression severity (53), future studies may benefit from including both self-report and clinician-administered scales to provide a more comprehensive assessment of depressive symptoms (54) and to align more closely with regulatory recommendations. This approach would allow for a more robust evaluation of treatment effects, as seen in recent rTMS studies (45).

Another potential limitation of this study lies in the partial complexity of our statistical approach. While we believe our use of ANCOVA and MANCOVA was justified given the nature of our data and research questions, we acknowledge that simpler statistical methods, such as repeated measures ANOVA or analysis of change scores, might have provided more easily interpretable results. The choice between these methods involves trade-offs between statistical power, control of confounds, and ease of interpretation (46–48).

It is suggested that future studies employ larger sample sizes to enhance statistical power and more definitively compare the efficacy of unilateral versus bilateral rTMS protocols. Such an approach would allow for more robust detection of potential differences in both clinical and cognitive outcomes.