Effectiveness of non-invasive brain stimulation on depressive symptoms targeting prefrontal cortex in functional magnetic resonance imaging studies: a combined systematic review and meta-analysis

Abstract

The prefrontal cortex (PFC) is a critical non-invasive brain stimulation (NIBS) target for treating depression. However, the alterations of brain activations post-intervention remain inconsistent and the clinical moderators that could improve symptomatic effectiveness are unclear. The study aim was to systematically review the effectiveness of NIBS on depressive symptoms targeting PFC in functional magnetic resonance imaging (fMRI) studies. In our study, we delivered a combined activation likelihood estimation (ALE) meta-analysis and meta-regression. Until November 2020, three databases (PubMed, Web of Science, EMBASE) were searched and 14 studies with a total sample size of 584 were included in the ALE meta-analysis; after NIBS, four clusters in left cerebrum revealed significant activation while two clusters in right cerebrum revealed significant deactivation (P < 0.001, cluster size >150 mm³). Eleven studies were statistically reanalyzed for depressive symptoms pre-post active-NIBS and the pooled effect size was very large [(d = 1.82, 95%CI (1.23, 2.40)]; significant moderators causing substantial heterogeneity (Chi squared = 75.25, P < 0.01; I² = 87%) were detected through subgroup analysis and univariate meta-regression. Multivariate meta-regression was then conducted accordingly and the model suggested good fitness (Q = 42.32, P < 0.01). In all, NIBS targeting PFC balanced three core depressive-related neurocognitive networks (the salience network, the default mode network, and the central executive network); the striatum played a central role and might serve as a candidate treatment biomarker; gender difference, treatment-resistant condition, comorbidity, treatment duration, and localization all contributed to moderating depressive symptoms during NIBS. More high-quality, multi-center randomized controlled trails delivering personalized NIBS are needed for clinical practice in the future.

Keywords

non-invasive brain stimulation / prefrontal cortex / depressive symptom / functional magnetic resonance imaging / activation likelihood estimation meta-analysis / meta-regression

Supplementary Data

Supplementary data is available at Psychoradiology Journal online.

Author contributions

Yao Xiao (Methodology, Software, Visualization, Writing - original draft, Writing - review & editing), Shuai Dong (Formal analysis, Methodology), Chunyu Pan (Methodology), Huiling Guo (Formal analysis, Methodology), Lili Tang (Formal analysis, Methodology), Xizhe Zhang (Validation), and Fei Wang (Conceptualization, Supervision)

Conflict of interests

The authors declare no conflict of interest.

Acknowledgements

The authors were supported by National Science Fund for Distinguished Young Scholars (81725005 to Fei Wang), National Natural Science Foundation Regional Innovation and Development Joint Fund (U20A6005 to Fei Wang), Jiangsu Provincial Key Research and Development Program (BE2021617 to Fei Wang), National Natural Science Foundation of China (62176129 to Xizhe Zhang).

References

[1] Abend R, Sar-El R, Gonen T, et al. (2019) Modulating emotional experience using electrical stimulation of the medial-prefrontal cor-tex: a preliminary tDCS-fMRI study. Neuromodulation 22:884-93. https://doi.org/10.1111/ner.12787.

[2] Avissar M, Powell F, Ilieva I, et al. (2017) Functional connectivity of the left DLPFC to striatum predicts treatment response of depression to TMS. Brain Stimul 10:919-25. https://doi.org/10.1016/j.brs.2017.07.002.

[3] Baeken C, Duprat R, Wu GR, et al. (2017) Subgenual anterior cingulate-medial orbitofrontal functional connectivity in medication-resistant major depression: a neurobiological marker for accelerated intermittent theta burst stimulation treatment? Biol Psychiatry Cogn Neurosci Neuroimaging 2:556-65. https://doi.org/10.1016/j.bpsc.2017.01.001.

[4] Baeken C, Marinazzo D, Wu GR, et al. (2014) Accelerated HF-rTMS in treatment-resistant unipolar depression: insights from subgenual anterior cingulate functional connectivity. World J Biol Psychiatry 15:286-97. https://doi.org/10.3109/15622975.2013.872295.

[5] Bakker N, Shahab S, Giacobbe P, et al. (2015) rTMS of the dorsomedial prefrontal cortex for major depression: safety, tolerability, effectiveness, and outcome predictors for 10 hz versus intermittent theta-burst stimulation. Brain Stimul 8:208-15. https://doi.org/10.1016/j.brs.2014.11.002.

[6] Begemann MJ, Brand BA, Ćurčić-Blake B, et al. (2020) Efficacy of noninvasive brain stimulation on cognitive functioning in brain disorders: a meta-analysis. Psychol Med 50:2465-86. https://doi.org/10.1017/S0033291720003670.

[7] Brunoni AR, Sampaio-Junior B, Moffa AH, et al. (2019) Noninvasive brain stimulation in psychiatric disorders: a primer. Braz J Psychiatry 41:70-81. https://doi.org/10.1590/1516-4446-2017-0018.

[8] Carlén M. (2017) What constitutes the prefrontal cortex? Science 358:478-82. https://doi.org/10.1126/science.aan8868.

[9] Cash RFH, Weigand A, Zalesky A, et al. (2020) Using brain imaging to improve spatial targeting of transcranial magnetic stimulation for depression. Biol Psychiatry 90:689-700. https://doi.org/10.1016/j.biopsych.2020.05.033.

[10] Chand GB, Wu J, Hajjar I, et al. (2017) Interactions of the salience network and its subsystems with the default-mode and the Centralexecutive networks in normal aging and mild cognitive impairment. Brain Connect 7:401-12. https://doi.org/10.1089/brain.2017.0509.

[11] Chen FJ, Gu CZ, Zhai N, et al. (2020) Repetitive transcranial magnetic stimulation improves amygdale functional connectivity in major depressive disorder. Front Psychiatry 11:732. https://doi.org/10.3389/fpsyt.2020.00732.

[12] Chrysikou EG, Wing EK, van Dam WO. (2019) Transcranial direct current stimulation over the prefrontal cortex in depression modulates cortical excitability in emotion regulation regions as measured by concurrent functional magnetic resonance imaging: an exploratory study. Biol Psychiatry Cogn Neurosci Neuroimaging 7:8594 https://doi.org/10.1016/j.bpsc.2019.12.004.

[13] Cirillo G, Di Pino G, Capone F, et al. (2017) Neurobiological aftereffects of non-invasive brain stimulation. Brain Stimul 10:1-18. https://doi.org/10.1016/j.brs.2016.11.009.

[14] Cohen J. (1992) A power primer. Psychol Bull 112:155-9. https://doi.org/10.1037//0033-2909.112.1.155.

[15] Cole EJ, Stimpson KH, Bentzley BS, et al. (2020) Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression. AmJ Psychiatry 177:716-26. https://doi.org/10.1176/appi.ajp.2019.19070720.

[16] Dandekar MP, Fenoy AJ, Carvalho AF, et al. (2018) Deep brain stimulation for treatment-resistant depression: an integrative review of preclinical and clinical findings and translational implications. Mol Psychiatry 23:1094-112. https://doi.org/10.1038/mp.2018.2.

[17] Delaveau P, Jabourian M, Lemogne C, et al. (2011) Brain effects of antidepressants in major depression: a meta-analysis of emotional processing studies. J Affect Disord 130:66-74. https://doi.org/10.1016/j.jad.2010.09.032.

[18] Deng Y, Li W, Zhang B. (2020) Neuroimaging in the effect of transcranial magnetic stimulation therapy for patient with depression: a protocol for a coordinate-based meta-analysis. BMJ Open 10:e038099. https://doi.org/10.1136/bmjopen-2020-038099.

[19] Dichter GS, Gibbs D, Smoski MJ. (2015) A systematic review of relations between resting-state functional-MRI and treatment response in major depressive disorder. J Affect Disord 172:8-17. https://doi.org/10.1016/j.jad.2014.09.028.

[20] Downar J, Geraci J, Salomons TV, et al. (2014) Anhedonia and rewardcircuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression. Biol Psychiatry 76:176-85. https://doi.org/10.1016/j.biopsych.2013.10.026.

[21] Downar J, Siddiqi SH, Mitra A, et al. (2024) Mechanisms of action of TMS in the treatment of depression. Curr Top Behav Neurosci 66:233-77. https://doi.org/10.1007/7854_2024_483

[22] Egger M, Davey Smith G, Schneider M, et al. (1997) Bias in metaanalysis detected by a simple, graphical test. BMJ 315:629-34. https://doi.org/10.1136/bmj.315.7109.629.

[23] Eickhoff SB, Bzdok D, Laird AR, et al. (2012) Activation likelihood estimation meta-analysis revisited. Neuroimage 59:2349-61. https://doi.org/10.1016/j.neuroimage.2011.09.017.

[24] Ernst M, Torrisi S, Balderston N, et al. (2015) fMRI functional connectivity applied to adolescent neurodevelopment. Annu Rev Clin Psychol 11:361-77. https://doi.org/10.1146/annurev-clinpsy-032814112753.

[25] Eshel N, Keller CJ, Wu W, et al. (2020) Global connectivity and local excitability changes underlie antidepressant effects of repetitive transcranial magnetic stimulation. Neuropsychopharmacology 45:1018-25. https://doi.org/10.1038/s41386-020-0633-z.

[26] Esmaeilpour Z, Shereen AD, Ghobadi-Azbari P, et al. (2020) Methodology for tDCS integration with fMRI. Hum Brain Mapp 41:1950-67. https://doi.org/10.1002/hbm.24908.

[27] Felger JC, Li Z, Haroon E, et al. (2016) Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry 21:1358-65. https://doi.org/10.1038/mp.2015.168.

[28] Fitzgerald PB, Sritharan A, Daskalakis ZJ, et al. (2007) A functional magnetic resonance imaging study of the effects of low frequency right prefrontal transcranial magnetic stimulation in depression. J Clin Psychopharmacol 27:488-92. https://doi.org/10.1097/jcp.Ob013e318151521c.

[29] Follmann D, Elliott P, Suh I, et al. (1992) Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol 45:769-73. https://doi.org/10.1016/0895-4356(92)90054-q.

[30] Ge R, Downar J, Blumberger DM, et al. (2020) Functional connectivity of the anterior cingulate cortex predicts treatment outcome for rTMS in treatment-resistant depression at 3-month follow-up. Brain Stimul 13:206-14. https://doi.org/10.1016/j.brs.2019.10.012.

[31] Ghobadi-Azbari P, Jamil A, Yavari F, et al. (2021) fMRI and transcranial electrical stimulation (tES): a systematic review of parameter space and outcomes. Prog Neuropsychopharmacol Biol Psychiatry 107:110149. https://doi.org/10.1016/j.pnpbp.2020.110149.

[32] Higgins JPT, Thomas J, Chandler J, et al. (2019) Cochrane Handbook for Systematic Reviews of Interventions. 2nd Edn. Chichester (UK): John Wiley & Sons.

[33] Iwabuchi SJ, Auer DP, Lankappa ST, et al. (2019) Baseline effective connectivity predicts response to repetitive transcranial magnetic stimulation in patients with treatment-resistant de-pression. Eur Neuropsychopharmacol 29:681-90. https://doi.org/10.1016/j.euroneuro.2019.02.012.

[34] Jog MV, Wang DJJ, Narr KL. (2019) A review of transcranial direct current stimulation (tDCS) for the individualized treatment of depressive symptoms. Pers Med Psychiatry 17-18:17-22. https://doi.org/10.1016/j.pmip.2019.03.001.

[35] Junghofer M, Winker C, Rehbein MA, et al. (2017) Noninvasive stimulation of the ventromedial prefrontal cortex enhances pleasant scene processing. Cereb Cortex 27:3449-56. https://doi.org/10.1093/cercor/bhx073.

[36] Kaiser RH, Andrews-Hanna JR, Wager TD, et al. (2015) Large-scale network dysfunction in major depressive disorder: a meta-analysis of resting-State functional connectivity. JAMA Psychiatry 72:60311. https://doi.org/10.1001/jamapsychiatry.2015.0071.

[37] Kang JI, Lee H, Jhung K, et al. (2016) Frontostriatal connectivity changes in major depressive disorder after repetitive transcranial magnetic stimulation: a randomized sham-controlled study. J Clin Psychiatry 77:e1137-43. https://doi.org/10.4088/JCP.15m10110.

[38] Kar SK. (2019) Predictors of response to repetitive transcranial magnetic stimulation in depression: a review of recent updates. Clin Psychopharmacol Neurosci 17:25-33. https://doi.org/10.9758/cpn.2019.17.1.25.

[39] Klomjai W, Katz R, Lackmy-Vallée A. (2015) Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS). Ann Phys Rehabil Med 58:208-13. https://doi.org/10.1016/j.rehab.2015.05.005.

[40] Kraus C, Kadriu B, Lanzenberger R, et al. (2020) Prognosis and improved outcomes in major depression: a review. Focus 18:220-35. https://doi.org/10.1176/appi.focus.18205.

[41] Kuehner C. (2017) Why is depression more common among women than among men? Lancet Psychiatry 4:146-58. https://doi.org/10.1016/S2215-0366(16)30263-2.

[42] Lai CH. (2021) Fronto-limbic neuroimaging biomarkers for diagnosis and prediction of treatment responses in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 107:110234. https://doi.org/10.1016/j.pnpbp.2020.110234.

[43] Lefaucheur JP, Aleman A, Baeken C, et al. (2020) Evidencebased guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014-2018). Clin Neurophysiol 131:474-528. https://doi.org/10.1016/j.clinph.2019.11.002.

[44] Lefaucheur JP, André-Obadia N, Antal A, et al. (2014) Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol 125:2150-206. https://doi.org/10.1016/j.clinph.2014.05.021.

[45] Lefaucheur JP, Antal A, Ayache SS, et al. (2017) Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS). Clin Neurophysiol 128:56-92. https://doi.org/10.1016/j.clinph.2016.10.087.

[46] Liston C, Chen AC, Zebley BD, et al. (2014) Default mode network mechanisms of transcranial magnetic stimulation in depression. Biol Psychiatry 76:517-26. https://doi.org/10.1016/j.biopsych.2014.01.023.

[47] Malhi GS, Mann JJ. (2018) Depression. Lancet 392:2299-312. https://doi.org/10.1016/S0140-6736(18)31948-2.

[48] Moher D, Liberati A, Tetzlaff J, et al.; PRISMA Group. (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151:264-9, W64. https://doi.org/10.7326/0003-4819-151-4-200908180-00135.

[49] Müller VI, Cieslik EC, Laird AR, et al. (2018) Ten simple rules for neuroimaging meta-analysis. Neurosci Biobehav Rev 84:151-61. https://doi.org/10.1016/j.neubiorev.2017.11.012.

[50] Nemeroff CB. (2020) The State of our understanding of the pathophysiology and optimal treatment of depression: glass half full or half empty? Am J Psychiatry 177:671-85. https://doi.org/10.1176/appi.ajp.2020.20060845.

[51] Nord CL, Halahakoon DC, Limbachya T, et al. (2019) Neural predictors of treatment response to brain stimulation and psychological therapy in depression: a double-blind randomized controlled trial. Neuropsychopharmacology 44:1613-22. https://doi.org/10.1038/s41386-019-0401-0.

[52] Pan PM, Sato JR, Salum GA, et al. (2017) Ventral striatum functional connectivity as a predictor of adolescent depressive disorder in a longitudinal community-based sample. AmJ Psychiatry 174:11129. https://doi.org/10.1176/appi.ajp.2017.17040430.

[53] Perera T, George MS, Grammer G, et al. (2016) The Clinical TMS Society Consensus Review and Treatment recommendations for TMS therapy for major depressive disorder. Brain Stimul 9:336-46. https://doi.org/10.1016/j.brs.2016.03.010.

[54] Persson J, Struckmann W, Gingnell M, et al. (2020) Intermittent theta burst stimulation over the dorsomedial prefrontal cortex modulates resting-state connectivity in depressive patients: a shamcontrolled study. Behav Brain Res 394:112834. https://doi.org/10.1016/j.bbr.2020.112834.

[55] Peters SK, Dunlop K, Downar J. (2016) Cortico-striatal-thalamic loop circuits of the salience network: a central pathway in psychiatric disease and treatment. Front Syst Neurosci 10:104. https://doi.org/10.3389/fnsys.2016.00104.

[56] Philip NS, Barredo J, van 't Wout-Frank M, et al. (2018) Network mechanisms of clinical response to transcranial magnetic stimulation in posttraumatic stress disorder and major depressive disorder. Biol Psychiatry 83:263-72. https://doi.org/10.1016/j.biopsych.2017.07.021.

[57] Pinna M, Manchia M, Oppo R, et al. (2018) Clinical and biological predictors of response to electroconvulsive therapy (ECT): a review. Neurosci Lett 669:32-42. https://doi.org/10.1016/j.neulet.2016.10.047.

[58] Rottschy C, Langner R, Dogan I, et al. (2012) Modelling neural correlates of working memory: a coordinate-based meta-analysis. Neuroimage 60:830-46. https://doi.org/10.1016/j.neuroimage.2011.11.050.

[59] Siddiqi SH, Taylor SF, Cooke D, et al. (2020) Distinct symptom-specific treatment targets for circuit-based neuromodulation. AmJ Psychiatry 177:435-46. https://doi.org/10.1176/appi.ajp.2019.19090915.

[60] Su L, Cai Y, Xu Y, et al. (2014) Cerebral metabolism in major depressive disorder: a voxel-based meta-analysis of positron emission tomography studies. BMC Psychiatry 14:321. https://doi.org/10.1186/s12888-014-0321-9.

[61] Taylor SF, Ho SS, Abagis T, et al. (2018) Changes in brain connectivity during a sham-controlled, transcranial magnetic stimulation trial for depression. J Affect Disord 232:143-51. https://doi.org/10.1016/j.jad.2018.02.019.

[62] Turkeltaub PE, Eden GF, Jones KM, et al. (2002) Meta-analysis of the functional neuroanatomy of single-word reading: method and validation. Neuroimage 16:765-80. https://doi.org/10.1006/nimg.2002.1131.

[63] Uddin LQ, Supekar KS, Ryali S, et al. (2011) Dynamic reconfiguration of structural and functional connectivity across core neurocognitive brain networks with development. J Neurosci 31:18578-89. https://doi.org/10.1523/JNEUROSCI.4465-11.2011.

[64] van Schouwenburg MR, O'Shea J, Mars RB, et al. (2012) Controlling human striatal cognitive function via the frontal cortex. J Neurosci 32:5631-7. https://doi.org/10.1523/JNEUROSCI.6428-11.2012.

[65] Vergallito A, Riva P, Pisoni A, et al. (2018) Modulation of negative emotions through anodal tDCS over the right ventrolateral prefrontal cortex. Neuropsychologia 119:128-35. https://doi.org/10.1016/j.neuropsychologia.2018.07.037.

[66] Whitton AE, Webb CA, Dillon DG, et al. (2019) Pretreatment rostral anterior cingulate cortex connectivity with salience network predicts depression recovery: findings from the EMBARC randomized clinical trial. Biol Psychiatry 85:872-80. https://doi.org/10.1016/j.biopsych.2018.12.007.

[67] Willner P, Scheel-Krüger J, Belzung C. (2013) The neurobiology of depression and antidepressant action. Neurosci Biobehav Rev 37:2331-71. https://doi.org/10.1016/j.neubiorev.2012.12.007.

[68] Xiao Y, Womer FY, Dong S, et al. (2024) A neuroimaging-based precision medicine framework for depression. Asian J Psychiatr 91:103803. https://doi.org/10.1016/j.ajp.2023.103803.

[69] Zheng A, Yu R, Du W, et al. (2020) Two-week rTMS-induced neuroimaging changes measured with fMRI in depression. J Affect Disord 270:15-21. https://doi.org/10.1016/j.jad.2020.03.038.

[70] Zhong X, Pu W, Yao S. (2016) Functional alterations of fronto-limbic circuit and default mode network systems in first-episode, drugnaïve patients with major depressive disorder: a meta-analysis of resting-state fMRI data. J Affect Disord 206:280-6. https://doi.org/10.1016/j.jad.2016.09.005.

[71] Zhou HX, Chen X, Shen YQ, et al. (2020) Rumination and the default mode network: meta-analysis of brain imaging studies and implications for depression. Neuroimage 206:116287. https://doi.org/10.1016/j.neuroimage.2019.116287.

[72] Zhuo C, Ji F, Lin X, et al. (2020) Global functional connectivity density alterations in patients with bipolar disorder with auditory verbal hallucinations and modest short-term effects of transcranial direct current stimulation augmentation treatment-baseline and follow-up study. Brain Behav 10:e01637. https://doi.org/10.1002/brb3.1637.