Efficacy of Non-Invasive Brain Stimulation for Treating Depression in Patients with Traumatic Brain Injury: A Meta-Analysis and Meta-Regression of Randomized Controlled Trials

Abstract

Objective: This meta-analysis aimed to ascertain the efficacy of non-invasive brain stimulation (NIBS)-comprising repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS)-for depression in traumatic brain injury (TBI) patients.

Methods: Comprehensive searches were conducted in PubMed, Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials up to 28 January 2023. Random-effects models assessed the treatment effects, and heterogeneity was evaluated through I² statistics and funnel plot inspection.

Results: From 10 trials (234 participants; 8 rTMS, 2 tDCS), NIBS was found significantly more effective than sham in alleviating depressive symptoms (SMD: 0.588, 95% CI: 0.264-0.912; p < 0.001). rTMS, specifically, showed higher efficacy (SMD: 0.707, 95% CI: 0.306-1.108; p = 0.001) compared to sham, whereas tDCS outcomes were inconclusive (SMD: 0.271, 95% CI: -0.230 to 0.771; p = 0.289). Meta-regression found no correlation with the number of sessions, treatment intensity, or total dose. Notably, while post-treatment effects were significant, they diminished 1-2 months post intervention. Adverse events associated with NIBS were minimal, with no severe outcomes like seizures and suicide reported.

Conclusions: rTMS emerged as a potent short-term intervention for depression in TBI patients, while tDCS findings remained equivocal. The long-term efficacy of NIBS is yet to be established, warranting further studies. The low adverse event rate reaffirms NIBS's potential safety.

Keywords: depression; non-invasive brain stimulation; transcranial direct current stimulation; transcranial magnetic stimulation.

Figure 1

PRISMA flowchart for study selection. Databases: PubMed (n = 470), Cochrane Central Register of Controlled Trials (n = 655), and Cochrane Database of Systematic Reviews (n = 18). Keywords: (traumatic brain injur* OR TBI OR head injur* OR brain injur* OR brain trauma OR concussion OR concussive) AND (tDCS OR transcranial direct current stimulation OR non-invasive stimulation OR transcranial magnetic stimulation OR TMS OR rTMS OR brain stimulation) AND controlled trial. Date: Up to January 2023. Abbreviations: NIBS, non-invasive brain stimulation; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; rTMS, repetitive transcranial magnetic stimulation; TBI, traumatic brain injury; tDCS; transcranial direct current stimulation.

Figure 2

Summary of quality assessment of studies included in the meta-analysis using version 2 of the Cochrane Risk-of-Bias Tool for Randomized Trials.

Figure 3

Meta-analysis results of all studies in terms of SMDs in depression scores. (Note: in the graph, the square represents the effect size of each study. The bigger the square, the more participants in the study. A horizontal line represents the 95% confidence intervals of the study result, with each end of the line representing the boundaries of the confidence interval. The diamond represents the combined effect). Franke et al., 2022 [25]; Stilling et al., 2020 [36]; Rushby et al., 2020 [33]; Siddiqi et al., 2019 [22]; Rao et al., 2019 [37]; Moussavi et al., 2019 [38]; Hoy et al., 2019 [26]; Lee et al., 2018 [23]; Leung et al., 2018 [24]; Sacco et al., 2016 [27].

Figure 4

Meta-analysis results of studies stratified by NIBS type in terms of SMDs in depression scores. (Note: in the graph, the square represents the effect size of each study. The bigger the square, the more participants in the study. A horizontal line represents the 95% confidence intervals of the study result, with each end of the line representing the boundaries of the confidence interval. The diamond represents the combined effect). Franke et al., 2022 [25]; Stilling et al., 2020 [36]; Siddiqi et al., 2019 [22]; Rao et al., 2019 [37]; Moussavi et al., 2019 [38]; Hoy et al., 2019 [26]; Lee et al., 2018 [23]; Leung et al., 2018 [24]; Rushby et al., 2020 [33]; Sacco et al., 2016 [27].

Figure 5

Meta-analysis results of studies stratified by stimulation frequency in terms of SMDs in depression scores. (Note: in the graph, the square represents the effect size of each study. The bigger the square, the more participants in the study. A horizontal line represents the 95% confidence intervals of the study result, with each end of the line representing the boundaries of the confidence interval. The diamond represents the combined effect). Rao et al., 2019 [37]; Lee et al., 2018 [23], Franke et al., 2022 [25]; Stilling et al., 2020 [36]; Leung et al., 2018 [24]; Moussavi et al., 2019 [38]; Siddiqi et al., 2019 [22]; Hoy et al., 2019 [26].

Figure 6

Meta-analysis results of studies stratified by brain target, in terms of SMDs in depression scores. (Note: in the graph, the square represents the effect size of each study. The bigger the square, the more participants in the study. A horizontal line represents the 95% confidence intervals of the study result, with each end of the line representing the boundaries of the confidence interval. The diamond represents the combined effect). Siddiqi et al., 2019 [22]; Hoy et al., 2019 [26]; Stilling et al., 2020 [36]; Moussavi et al., 2019 [38]; Leung et al., 2018 [24]; Franke et al., 2022 [25]; Rao et al., 2019 [37]; Lee et al., 2018 [23].

Figure 7

Meta-analysis results of studies stratified by baseline TBI severity in terms of SMDs in depression scores. (Note: in the graph, the square represents the effect size of each study. The bigger the square, the more participants in the study. A horizontal line represents the 95% confidence intervals of the study result, with each end of the line representing the boundaries of the confidence interval. The diamond represents the combined effect). Stilling et al., 2020 [36]; Moussavi et al., 2019 [38]; Leung et al., 2018 [24]; Franke et al., 2022 [25]; Rao et al., 2019 [37]; Lee et al., 2018 [23]; Hoy et al., 2019 [26]; Siddiqi et al., 2019 [22]; Rushby et al., 2020 [33]; Sacco et al., 2016 [27].

Figure 8

Meta-regression results of the association between the efficacy of rTMS and the total number of sessions.

Figure 9

Meta-regression results of the association between the efficacy of rTMS and the total pulses.

Figure 10

Meta-regression results of the association between the efficacy of rTMS and treatment intensity.

Figure 11

Forest plot indicating the efficacy of NIBS versus sham treatment for the treatment of depression. The depression outcome was evaluated immediately, 1 month, and 2 months after NIBS treatment. (Note: in the graph, the square represents the effect size of each study. The bigger the square, the more participants in the study. A horizontal line represents the 95% confidence intervals of the study result, with each end of the line representing the boundaries of the confidence interval. The diamond represents the combined effect). Franke et al., 2022 [25]; Rushby et al., 2020 [33]; Siddiqi et al., 2019 [22]; Moussavi et al., 2019 [38]; Hoy et al., 2019 [26]; Lee et al., 2018 [23]; Leung et al., 2018 [24]; Stilling et al., 2020 [36]; Sacco et al., 2016 [27]; Rao et al., 2019 [37].

Figure 12

Forest plot of adverse event rates for NIBS treatment versus sham treatment. (Note: in the graph, the square represents the effect size of each study. The bigger the square, the more participants in the study. A horizontal line represents the 95% confidence intervals of the study result, with each end of the line representing the boundaries of the confidence interval. The diamond represents the combined effect). Rao et al., 2019 [37].; Hoy et al., 2019 [26]; Siddiqi et al., 2019 [22].

Figure 13

Funnel plot constructed for SMDs among patients’ depression scores.