Effect of Repetitive Transcranial Magnetic Stimulation on Depression and Cognition in Individuals With Traumatic Brain Injury: A Meta-Analysis

Repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved therapy in major depressive disorder. However, its treatment efficacy on depression after traumatic brain injury (TBI) remains inconclusive. We conducted a meta-analysis to assess the effectiveness of executing rTMS over dorsolateral prefrontal cortex (DLPFC) on depression, cognitive impairment and post-concussion syndrome in individuals with traumatic brain injury. This study contained seven randomized controlled trials that published before April 5, 2020 in PubMed, Embase, Scopus, Cochrane, and Web of Science databases. The rTMS had significant anti-depressant effect (SMD = 1.03), but the effects dissipated at one-month follow-up (SMD = 0.39). In the subgroup analysis, only applying rTMS to left DLPFC area of post-TBI patients showed significant anti-depressant effect (SMD = 0.98). Moreover, current data observed that rTMS on post-TBI patients possessed substantial improvement in visuospatial memory (SMD = 0.39), but wasn’t in processing speed (SMD = -0.18) and selective attention (SMD = 0.21). In addition, the effect of rTMS on postconcussion syndrome was insignificant. In conclusion, the short-term antidepressant effect of left DLPFC rTMS in patients with TBI was significant. Furthermore, the effectiveness of rTMS on cognition and post-concussion syndrome in patients with post-TBI depression was limited .


Introduction
Traumatic brain injury (TBI) has been recognized as a global health concern in recent years. Every year, 27-69 million people worldwide experience TBI 1,2 . TBI not only is a major cause of death and disability but also leads to many neurological and psychological sequelae that increase global burden, including depression and cognitive impairment 3,4 . Within the first year after TBI, the prevalence rate of major depressive disorder ranges from 25% to 53% 5,6 . From 2007 to 2017, depressive disorder was the third leading burden-causing disease 7 . Cognitive impairment, characterized by alterations in judgment, memory, attention, planning, processing speed, and executive functions, is another complication that limits daily activities following TBI 8 . Approximately 33% of patients with mild TBI have experienced short-term functional impairment, 80% of which has resolved within 6 months 9 .
Moderate to severe TBI may lead to persistent impairment in cognitive function at 6 months 10 . Although one-third of patients with severe TBI have normal neuropsychological test performance at 3 months, patients with TBI with cognitive impairment have high future disability risk 10 . Therefore, early therapeutic intervention for post-TBI depression and cognitive impairment has become increasingly critical.
Functional neuroanatomy provides insight into the pathomechanism of depression and cognitive impairment. Left dorsolateral prefrontal cortex (DLPFC) hypoactivity and right DLPFC hyperactivity are involved in depression pathogenesis. Depression severity is associated with right DLPFC hyperactivity 11 . The DLPFC is responsible for emotional judgement as well as cognitive and executive function 12 . The functional connections between the prefrontal cortex and other regions of the brain form different networks, including the default mode network and cognitive control network 13,14 . TBI leads to diffuse axonal injury that disrupts network synchrony 15 . To restore functional connectivity, a functional magnetic resonance imaging-based approach was used to target and modulate specific cortical areas in TBI-induced depression 16 .
Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation approach; in rTMS, electric current is targeted at a specific area by using time-dependent magnetic fields. Studies have demonstrated that a high frequency of rTMS facilitates neuronal activity, whereas a low frequency suppresses neuronal excitement. Neuronal activity can be modulated through pulse frequency adjustment 17 . For clinical application, rTMS has been proved effective in improving symptoms of several diseases, including Parkinson disease 18 , Alzheimer disease 19 , stroke 20 , and treatment-resistant depression (TRD) 21 . Thus, rTMS has been proposed for treating people with TBI. Nevertheless, the effect of rTMS on TBI-induced depression or cognitive impairment remains controversial, although related publications have increased from 2018 to 2020. Thus, a systematic review with metaanalysis is crucial to validate the effectiveness of rTMS in treating post-TBI complications. A meta-analysis by Gao et al. revealed that high-frequency rTMS (HF rTMS) over the left DLPFC and low-frequency rTMS over the right DLPFC exhibited similar effects on major depressive disorder 22 . However, to our knowledge, no systematic review with meta-analysis has been conducted to ascertain the effectiveness of rTMS on TBI-induced depression or cognitive impairment. Therefore, the principle aim of this meta-analysis is to determine the efficacy of rTMS over DLPFC in treating TBI-induced depression. Next, our secondary purpose is to investigate whether rTMS can improve cognitive decline and post-concussion syndrome in patients with depression. Final, current study also evaluates the stimulation parameters of rTMS and the quality of the past studies to make suggestions for future researches.

Study selection
Through the initial database search, 1467 articles were identified. After removing duplicate studies, 876 articles were obtained, and after further review of titles and abstracts, we obtained 65 articles. The 65 studies were thoroughly reviewed, and most of them were excluded due to their non-RCT design and other outcomes. Finally, seven RCTs that compared the effects of rTMS treatment with sham on post-TBI depression, cognitive impairment, or postconcussion syndrome (PCS) were included ( Figure 1a). Table 1 presents the characteristics of the selected studies. In total, 136 participants were included in our research; 79 participants who had experienced TBI and had post-TBI depression were included in five studies; 57 participants with a diagnosis of posttraumatic headache or PCS had moderate to severe depression on average in two studies. The participants in the included articles had a mean age of 34.1-46.3 years and a higher percentage of men (73; 54%) than women. The rTMS protocols were summarized in Table 2.

Depression
Four studies reported depression severity according to the MADRS 16,23-25 , and two articles used the HAMD to assess depression 26,27 . Another study by Stilling et al.

Cognition and attention
Three studies used the Trail Making Test (TMT), a neuropsychological test of processing speed, attention, and task shifting to examine cognitive function. The TMT can be further divided into TMT-A and TMT-B. In TMT-A, participants must connect 25 circles numbered 1-25 in numerical order. In TMT-B, participants must alternate between numbers (1-13) and letters (A to L) in an ascending order (1-A-2-B-3-…) 29 .
Two studies examined cognitive function by using TMT-A and TMT-B 24 The Stroop Color Word Test (SCWT) is a test of selective attention. A conflict is created through presenting a mismatch between the name of a color ("green") and the color of the printed word (e.g., the word green printed using red ink) 30 . To examine the ability to overcome the cognitive interference, the time required for the SCWT was measured in three studies [24][25][26] . In the Brief Visuospatial Memory Test (BVMT), the participants were asked to memorize and reproduce six types of shapes 31 . After three learning trials, the scores of all rounds were summed (max = 2 × 6 × 3 = 36; 2 points for each figure in three trials). Two articles used the BVMT 24,26 .
The RPQ-3 inquires into the symptoms of headache, nausea/vomiting, and dizziness, three early postconcussion symptoms. The RPQ-13 questionnaire inquires into 13 self-reported conditions, namely noise sensitivity, sleep disturbance, fatigue, being irritable, feeling depressed, feeling frustrated, forgetfulness, poor concentration, taking longer to think, blurred vision, light sensitivity, double vision, and restlessness, to measure cognitive and emotional symptoms 32 .

Study quality
The baseline imbalance of patient characteristics in three articles 16

Discussion
Several studies have attempted to use rTMS to enhance the recovery of individuals with post-TBI depression. However, insufficient evidence was discerned regarding the effect of TMS on people with post-TBI depression. Hence, this study was designed to investigate the effectiveness of rTMS in treating post-TBI depression.
Our results demonstrated that rTMS has a significant on post-TBI depression immediately after administration. Nevertheless, the effect size decreased over time.
We observed no significant effect 1 month after rTMS treatment compared with the sham group. However, sample sizes of previous studies were small. In addition, few studies have performed a follow-up assessment, making it difficult to determine longterm efficacy (e.g., 4 weeks) of rTMS intervention in the present study. Therefore, recruiting a sufficient number of participants and having a long follow-up period in future studies is essential.
Relevant studies have proved that both unilateral and bilateral rTMS are effective in individuals with depression. Moreover, their results did not conclude that bilateral rTMS was superior to unilateral stimulation in remitting TRD 33 . A study by

Conclusion
Our study demonstrated that rTMS has a short-term effect on post-TBI depression, whereas the effects of rTMS on cognitive impairment and PCS in patients with TBI remained inconclusive. In addition, RCT studies revealed that rTMS has a significant antidepressant effect only when applied to the left DLPFC area. However, previous studies were limited by small sample sizes and heterogenous methodologies.
Further large sample sizes and well-designed trials are necessary to confirm the antidepressant and cognition-enhancing effects of rTMS and to establish optimal stimulation protocols for administering rTMS to patients with post-TBI depression.

Literature search
Multiple databases, including PubMed, Embase, Scopus, Cochrane, and Web of Science, were searched for randomized controlled trials (RCTs) published before April 5, 2020. The search terms were "traumatic brain injury [mesh]" AND "transcranial magnetic stimulation [mesh]." The meta-analysis was registered as CRD42020200348 in Prospero.

Study selection
Two authors independently screened the titles and abstracts of articles. Then, a full-text review was performed and eligible studies were included. In the case of discrepancy between two reviewers, the conflict was resolved through discussion among the two reviewers and a third reviewer to reach consensus. Studies fulfilling the following criteria were included: (1) patient with TBI, (2)

Data extraction and analysis
Reviewers extracted the following data: (1) patient characteristics, (2) number of patients receiving sham or rTMS treatment, (3) study design, (4) outcome measured, (5) rTMS protocol, and (6) standardized mean difference and standard error of change scores after interventions. Since current study used different scores or scales, we combined the effect size by the standardized mean difference, calculated from mean difference divided by standard deviation. Data extracted from the selected studies were analyzed using RevMan 5.3. We used the I 2 test to examine heterogeneity. Data were synthesized using a random-effects model.