Bilateral theta burst stimulation modulates dorsolateral prefrontal cortex functional connectivity for emotion regulation in young adults: A randomized controlled trial

Perceived stress is a complex psychobiological process with a high prevalence of 34.5% in young adults [1Ramón-Arbués E. Gea-Caballero V. Granada-López J.M. Juárez-Vela R. Pellicer-García B. Antón-Solanas I. The prevalence of depression, anxiety and stress and their associated factors in College students.Int J Environ Res Publ Health. 2020; 17: 7001https://10.3390/ijerph17197001Crossref PubMed Scopus (200) Google Scholar]. Prolonged exposure to high-level perceived stress can lead to abnormal brain activations, particularly in the prefrontal cortex and amygdala, ultimately resulting in impaired emotional regulation [2Zhong M. Wang X. Xiao J. Yi J. Zhu X. Liao J. Wang W. Yao S. Amygdala hyperactivation and prefrontal hypoactivation in subjects with cognitive vulnerability to depression.Biol Psychol. 2011; 88: 233-242https://10.1016/j.biopsycho.2011.08.007Crossref PubMed Scopus (125) Google Scholar,3Scult M.A. Knodt A.R. Swartz J.R. Brigidi B.D. Hariri A.R. Thinking and feeling: individual differences in habitual emotion regulation and stress-related mood are associated with prefrontal executive control.Clin Psychol Sci. 2017; 5: 150-157https://10.1177/2167702616654688Crossref PubMed Scopus (32) Google Scholar]. Regarding stress-related psychiatric disorders, a recent guideline has recommended the use of repetitive transcranial magnetic stimulation (rTMS) on dorsolateral prefrontal cortex (DLPFC) to alleviate negative emotional symptoms [4Lefaucheur J.P. Aleman A. Baeken C. Benninger D.H. Brunelin J. Di Lazzaro V. Filipović S.R. Grefkes C. Hasan A. Hummel F.C. et al.Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014-2018).Clin Neurophysiol. 2020; 131: 474-528https://10.1016/j.clinph.2019.11.002Crossref PubMed Scopus (1003) Google Scholar]. Specifically, the bilateral theta-burst stimulation (TBS) model of rTMS has been demonstrated to reduce functional connectivity between DLPFC and insula/operculum in ongoing depressed patients, indicating a reversal of DLPFC function [5Struckmann W. Bodén R. Gingnell M. Fällmar D. Persson J. Modulation of dorsolateral prefrontal cortex functional connectivity after intermittent theta-burst stimulation in depression: combining findings from fNIRS and fMRI.Neuroimage Clin. 2022; 34103028https://10.1016/j.nicl.2022.103028Crossref PubMed Scopus (15) Google Scholar]. Our previous study has also reported the positive effects of TBS on the high-level perceived stress in young adults and identified its modulatory effects on brain subnetwork topology [6He Y. Li Z. Cao L. Han M. Tu J. Deng H. Huang Z. Geng X. Wu J. Effects of dorsolateral prefrontal cortex stimulation on network topological attributes in young individuals with high-level perceived stress: a randomized controlled trial.Psychiatr Res. 2023; 326115297https://10.1016/j.psychres.2023.115297Crossref Scopus (1) Google Scholar]. However, further investigation is needed to determine whether TBS modulates DLPFC functioning to promote the recovery of negative emotional symptoms. Herein, we investigated the effects of bilateral TBS on DLPFC functional connectivity and its association with the relief of stress-related symptoms. Resting-state fMRI was utilized to measure DLPFC functional connectivity by employing seeds to calculate Pearson's correlation coefficients with other regions. Following the eligibility screening, fifty eligible young adults with high-level perceived stress were recruited and randomly assigned to receive either active or sham TBS stimulation. The simulations were conducted using the Magstim Rapid 2 stimulator. The intermittent TBS model and continuous TBS model were applied on left and right DLPFC, comprising a total of twelve sessions, three times per week over four weeks. The specific details regarding inclusion/exclusion criteria, randomization procedures, and intervention were provided in the supplementary material. The Depression Anxiety Stress Scale (DASS) 21-item version was used to measure depression, anxiety, and stress states. MRI data were obtained using the Siemens Prisma 3.0 Tesla system with Gradient-echo EPI sequence and MPRAGE T1-weighted sequences. The left and right DLPFC seeds were defined based on Montreal Neurological Institute coordinates (MNI, left: x −27, y 43, z 31; right: x 30, y 37, z 36), with a radius of 6mm according to the Brainnetome atlas (http://atlas.brainnetome.org/). Changes in DLPFC functional connectivity maps were calculated and compared between groups using SPM12 with the threshold: voxel-wise P < 0.005 uncorrected, cluster-wise P < 0.05 FDR corrected. Due to excessive head-motion in MRI images, two participants were excluded. Hence, forty-eight participants (24 in each group) were included for analysis. The comparison of demographic and baseline assessment comparison indicated no significant group difference in age, sex, years of education, and baseline DASS scores (P > 0.05) (Table S1). General linear model analysis showed statistically great improvement of DASS total scores after active TBS (β = −5.80, 95%CI: [−10.49, −1.12], P = 0.016), after adjusting age, gender, and years of education (Fig. 1 panel A(a) and Table S2). Our results revealed significant within-group differences in DASS total scores (Z = −3.91, P < 0.001), anxiety scores (Z = −2.66, P = 0.008), and stress scores (Z = −3.04, P = 0.002) after active TBS (Fig. 1 panel B(e,g,h)). Similarly, sham stimulation led to a smaller but significant decrement in stress scores (t = −2.37, P = 0.026) (Fig. 1 panel B(h)); with no evident effects found in total scores, depression, and anxiety scores after sham stimulation (Fig. 1 Panel B(e-g)). Our results showed decreased functional connectivity between left DLPFC and left supplementary motor area (SMA) (MNI coordinates: 9, −12, 48, voxel number = 423) and between right DLPFC and right superior frontal medial gyrus (SFGmed) (MNI coordinates: 3, 60, 9, voxel number = 443) after active bilateral TBS stimulation compared to sham stimulation. Partial correlation analysis revealed significant associations between DLPFC_SMA functional connectivity and stress (r = 0.395, P = 0.043) and anxiety (r = 0.523, P = 0.018) scores after controlling age, sex, years of education, and total intracranial volume (Fig. 1 Panel B and Table S3). Our results revealed statistical improvements in anxiety scores in the active group and stress scores in both groups, while the active TBS exhibited a superior effectiveness of stress relief than sham stimulation. In line with previous studies, our findings demonstrate statistical improvements within both groups, but the active bilateral TBS showed a superior effect on stress relief than the sham condition. This phenomenon was believed to be a therapeutic response to TBS and further suggested a potential placebo effect of sham TBS [7Valkonen-Korhonen M. Leinola H. Könönen M. Niskanen E. Purhonen M. Pakarinen M. Ruusunen A. Lehto S.M. Mervaala E. Honkalampi K. et al.Bifrontal active and sham rTMS in treatment-resistant unipolar major depression.Nord J Psychiatr. 2018; 72: 586-592https://10.1080/08039488.2018.1500640Crossref PubMed Scopus (9) Google Scholar]. This finding provides support for the benefits of active TBS on DLPFC for ameliorating stress in young adults. It is suggested that negative emotional symptoms primarily arise from impaired emotion regulation. Emotion regulation involves automatic and effortful cognitive processes that influence the experience and trajectory of emotions. This regulation process relies on cognitive control and is modulated by the cognitive control network, wherein the DLPFC works in the mental manipulation of affective information [8Etkin A. Buchel C. Gross J.J. The neural bases of emotion regulation.Nat Rev Neurosci. 2015; 16: 693-700https://10.1038/nrn4044Crossref PubMed Scopus (746) Google Scholar]. Notably, hyperactivation of DLPFC functions has been observed in stress-related disorders [9Dhami P. Atluri S. Lee J.C. Knyahnytska Y. Croarkin P.E. Blumberger D.M. Daskalakis Z.J. Farzan F. Prefrontal cortical reactivity and connectivity markers distinguish Youth depression from healthy Youth.Cerebr Cortex. 2020; 30: 3884-3894https://10.1093/cercor/bhaa004Crossref PubMed Google Scholar]. This excessive increase in DLPFC functional activities might potentially result in a diminished top-down prefrontal cognitive control input from the prefrontal region, consequently contributing to emotional regulation dysfunctions [10Han H.J. Jung W.H. Yun J.Y. Park J.W. Cho K.K. Hur J.W. Shin N.Y. Lee T.Y. Kwon J.S. Disruption of effective connectivity from the dorsolateral prefrontal cortex to the orbitofrontal cortex by negative emotional distraction in obsessive-compulsive disorder.Psychol Med. 2016; 46: 921-932https://10.1017/S0033291715002391Crossref PubMed Scopus (23) Google Scholar]. Our findings revealed significant reduction in DLPFC functional connectivity with SMA and SFGmed. Whereas we did not observe notable finding in subcortical regions. This suggests that the functional normalization of prefrontal cognitive control areas may serve as the foundation for emotion regulation. We speculate that these decrements may indicate the reduction of exaggerated compensation of prefrontal functions after TBS. It also emphasized the significant role of DLPFC projection to SMA in perceiving emotional information and regulating negative emotional behavior. This study has several limitations, including a relatively small sample size and a lack of follow-up assessment to explore the long-term effects of TBS. Additionally, the study only tested the effects of a twelve-session stimulation, and whether fewer sessions could be effective remains unclear. Therefore, it would be valuable for future studies to consider exploring the potential dose effect of TBS. In summary, our findings provide evidence of bilateral TBS on ameliorating stress and anxiety and remodeling DLPFC plasticity for young adults. This work also suggests the importance of DLPFC projection to SMA in the regulation of negative emotions. These findings can potentially inform future research and interventions aimed at addressing stress and anxiety in this population. This work was supported by the Youth Program of National Natural Science Foundation of China (No.8180418 and No.31701002), Young Scientific and Technological Innovative Talents Training Project of Fujian University of Traditional Chinese Medicine (No. XQC2023004), 2022 Research Project of Chinese Association of Rehabilitation Medicine (KFKT-2022–013), and National Innovation and Entrepreneurship Training Program for Chinese College Student (No. 202110393001S).

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