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Non-invasive brain stimulation for treating psychiatric symptoms in Parkinson’s disease: A systematic review and meta-analysis

      Highlights

      • NIBS, especially rTMS, improved the depression and depressive mood in PD patients.
      • Combined use of NIBS and antidepressant were effective for PD depression and anxiety.
      • No significant therapeutic differences between NIBS and antidepressant alone.

      Abstract

      Background

      Non-invasive brain stimulation (NIBS), especially repetitive transcranial magnetic stimulation (rTMS), is a promising therapeutic tool for managing the psychiatric symptoms of Parkinson’s disease (PD). This meta-analysis aims to assess the effect of NIBS on psychiatric symptoms in patients with PD.

      Methods

      Several electronic databases were systematically searched for relevant literature from inception to October 18, 2021. The therapeutic effects of NIBS were evaluated using a random-effects meta-analysis based on the standard mean difference (SMD) and multivariable-adjusted effect estimates and subgroup analyses. Publication bias and sensitivity analyses were used to explore the sources of heterogeneity.

      Results

      Finally, 57 and 15 studies with 4,010 participants were obtained from the meta-analysis and systematic review, respectively. Significant differences were found between NIBS and sham-stimulation/placebo participants for depression (SMD = −0.75, 95 % confidence interval [CI]: −0.99 to −0.50, I2 = 79 %), and rTMS combined with antidepressant therapy and antidepressant alone for depression (SMD = −0.98, 95 % CI: −1.37 to −0.59, I2 = 87 %) and anxiety (SMD = −1.46, 95 % CI: −2.44 to −0.48, I2 = 95 %). Meanwhile, lower risks were observed for post-treatment compared with pre-treatment for depression (relative risk [RR] = 0.66, 95 % CI: 0.57–0.76, I2 = 96 %) and anxiety (RR = 0.66, 95 % CI: 0.60–0.73, I2 = 67 %).

      Conclusions

      NIBS can be considered an effective non-pharmacological option for treating PD depression; moreover, rTMS combined with antidepressants was demonstrated to be a useful tool against depression and anxiety in PD.

      Keywords

      1. Introduction

      Parkinson’s disease (PD), which is the second most common neurodegenerative disease worldwide, is characterized by a broad spectrum of motor and non-motor features [
      • Poewe W.
      • Seppi K.
      • Tanner C.M.
      • Halliday G.M.
      • Brundin P.
      • Volkmann J.
      • et al.
      Parkinson disease.
      ]. Besides depression, anxiety and psychoses are the major psychiatric complications of non-motor symptoms in patients with PD, which contribute to significant functional impairment and adversely affect motor and social function [
      • Aarsland D.
      • Larsen J.P.
      • Cummins J.L.
      • Laake K.
      Prevalence and clinical correlates of psychotic symptoms in Parkinson disease: a community-based study.
      ,
      • Reijnders J.S.
      • Ehrt U.
      • Weber W.E.
      • Aarsland D.
      • Leentjens A.F.
      A systematic review of prevalence studies of depression in Parkinson’s disease.
      ]. For patients and families, these neuropsychiatric disturbances are often more challenging and distressing than the motor aspects of PD [
      • Hely M.A.
      • Morris J.G.
      • Reid W.G.
      • Trafficante R.
      Sydney multicenter study of Parkinson’s disease: non-L-dopa-responsive problems dominate at 15 years.
      ], which result in a poor quality of life and increased burden to the caregiver [
      • Jones J.D.
      • Butterfield L.C.
      • Song W.
      • Lafo J.
      • Mangal P.
      • Okun M.S.
      • et al.
      Anxiety and depression are better correlates of Parkinson’s disease quality of life than apathy.
      ]. Therefore, early detection and optimal therapy for psychiatric symptoms are crucial in the management of PD.
      Related studies have demonstrated that non-invasive brain stimulation (NIBS) is a treatment that uses magnetic pulses or weak currents to reverse brain activity and physiological disturbances that are believed to be caused by clinical defects. NIBS could also be used as an adjunct intervention to current PD treatment, a potential combination that could improve the efficacy of PD management, especially in patients with refractory symptoms [
      • Madrid J.
      • Benninger D.H.
      Non-invasive brain stimulation for Parkinson’s disease: clinical evidence, latest concepts and future goals: a systematic review.
      ,
      • Jenkins B.
      • Tepper S.J.
      Neurostimulation for primary headache disorders, part 1: pathophysiology and anatomy, history of neuromodulation in headache treatment, and review of peripheral neuromodulation in primary headaches.
      ,
      • Dayan E.
      • Censor N.
      • Buch E.R.
      • Sandrini M.
      • Cohen L.G.
      Noninvasive brain stimulation: from physiology to network dynamics and back.
      ,
      • De Risio L.
      • Borgi M.
      • Pettorruso M.
      • Miuli A.
      • Ottomana A.M.
      • Sociali A.
      • et al.
      Recovering from depression with repetitive transcranial magnetic stimulation (rTMS): a systematic review and meta-analysis of preclinical studies.
      ,
      • Miniussi C.
      • Paulus W.
      • Rossini P.M.
      Transcranial brain stimulation.
      ].
      This review focuses on the most commonly used NIBS techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). rTMS depolarizes neurons via a strong and relatively focal electromagnetic field that is generated beneath a coil positioned over the scalp of the patients [
      • Brunoni A.R.
      • Teng C.T.
      • Correa C.
      • Imamura M.
      • Brasil-Neto J.P.
      • Boechat R.
      • et al.
      Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting.
      ]. The generated pulsed magnetic field can also significantly alter the reactivity of the molecules and free radicals [
      • Chervyakov A.V.
      • Chernyavsky A.Y.
      • Sinitsyn D.O.
      • Piradov M.A.
      Possible mechanisms underlying the therapeutic effects of transcranial magnetic stimulation.
      ], thereby affecting the level of various neurotransmitters [
      • Cho S.I.
      • Nam Y.S.
      • Chu L.Y.
      • Lee J.H.
      • Bang J.S.
      • Kim H.R.
      • et al.
      Extremely low-frequency magnetic fields modulate nitric oxide signaling in rat brain.
      ,
      • Gorelick D.A.
      • Zangen A.
      • George M.S.
      Transcranial magnetic stimulation in the treatment of substance addiction.
      ], promoting plasticity of neural synapses [
      • Li Y.
      • Li L.
      • Pan W.
      Repetitive transcranial magnetic stimulation (rTMS) modulates hippocampal structural synaptic plasticity in rats.
      ], regulating the expression of genetic material in the brain [
      • Ikeda T.
      • Kobayashi S.
      • Morimoto C.
      Effects of repetitive transcranial magnetic stimulation on ER stress-related genes and glutamate, γ-aminobutyric acid and glycine transporter genes in mouse brain.
      ], and enabling anti-neuronal apoptosis and glial cell activation [
      • Sasso V.
      • Bisicchia E.
      • Latini L.
      • Ghiglieri V.
      • Cacace F.
      • Carola V.
      • et al.
      Repetitive transcranial magnetic stimulation reduces remote apoptotic cell death and inflammation after focal brain injury.
      ]. tDCS uses electrodes placed on the scalp to apply a weak direct current to the brain to depolarize the neurons, which not only alters nerve excitability but also changes the cerebral blood flow [
      • Brunoni A.R.
      • Teng C.T.
      • Correa C.
      • Imamura M.
      • Brasil-Neto J.P.
      • Boechat R.
      • et al.
      Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting.
      ,
      • Feng W.
      • Bowden M.G.
      • Kautz S.
      Review of transcranial direct current stimulation in poststroke recovery.
      ]. For 20 years, studies have suggested rTMS to be a valid treatment option for major depression and other psychiatric indications [
      • Lefaucheur J.-P.
      • Aleman A.
      • Baeken C.
      • Benninger D.H.
      • Brunelin J.
      • Di Lazzaro V.
      • et al.
      Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014–2018).
      ,
      • George M.S.
      • Taylor J.J.
      • Short E.B.
      The expanding evidence base for rTMS treatment of depression.
      ]; moreover, rTMS shows a certain therapeutic effect on PD depression [
      • Hai-jiao W.
      • Ge T.
      • Li-na Z.
      • Deng C.
      • Da X.
      • Shan-Shan C.
      • et al.
      The efficacy of repetitive transcranial magnetic stimulation for Parkinson disease patients with depression.
      ,
      • Randver R.
      Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex to alleviate depression and cognitive impairment associated with Parkinson’s disease: a review and clinical implications.
      ,
      • Lesenskyj A.M.
      • Samples M.P.
      • Farmer J.M.
      • Maxwell C.R.
      Treating refractory depression in Parkinson’s disease: a meta-analysis of transcranial magnetic stimulation.
      ,
      • Xie C.-L.
      • Chen J.
      • Wang X.-D.
      • Pan J.-L.
      • Zhou Y.i.
      • Lin S.-Y.
      • et al.
      Repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression in Parkinson disease: a meta-analysis of randomized controlled clinical trials.
      ]. Although the evidence for the clinical efficacy of rTMS for PD depression is largely inadequate, a growing number of randomized controlled trials (RCTs) suggests that these methods may improve PD symptoms with mild adverse effects and at a low cost [
      • Miniussi C.
      • Paulus W.
      • Rossini P.M.
      Transcranial brain stimulation.
      ].
      Previous studies have demonstrated that rTMS can safely alleviate depression in patients with PD [
      • Hai-jiao W.
      • Ge T.
      • Li-na Z.
      • Deng C.
      • Da X.
      • Shan-Shan C.
      • et al.
      The efficacy of repetitive transcranial magnetic stimulation for Parkinson disease patients with depression.
      ,
      • Chen J.
      • He P.
      • Zhang Y.
      • Gao Y.
      • Qiu Y.
      • Li Y.
      • et al.
      Non-pharmacological treatment for Parkinson disease patients with depression: a meta-analysis of repetitive transcranial magnetic stimulation and cognitive-behavioral treatment.
      ]; however, these studies are unable to provide strong evidence owing to the small sample size and non-systematic evaluation. Furthermore, few studies have explored and elucidated the therapeutic effect of combination therapy of NIBS and other antidepressant treatment, which is an up-to-the-moment treatment for managing the psychiatric symptoms of PD.
      Thus, a systematic review and meta-analysis are warranted to assess the efficiency of NIBS techniques for treating psychiatric disorders in patients with PD. Therefore, we conducted this study to systematically evaluate the effects of NIBS for managing the psychiatric symptoms of PD.

      2. Methods

      2.1 Search strategy

      The protocol was published in the International Prospective Register of Systematic Reviews (PROSPERO), CRD42021289212. Following the Preferred Reporting Items for Systematic Reviews and meta-Analyses (PRISMA) 2009 guidelines (Supplementary Table 1) [
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gotzsche P.C.
      • Ioannidis J.P.A.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
      ], we systematically searched electronic databases (PubMed, EMBASE, Cochrane Library, Web of Science, Ovid, ProQuest, and PsycInfo databases for English, and Chinese National Knowledge Infrastructure [CNKI] and Wanfang databases for Chinese) for relevant literature from inception to October 18, 2021, that reported on NIBS for the treatment of psychiatric symptoms in PD. The complete search strategy is presented in Supplementary Table 2. Further studies were identified by manually searching for all relevant reviews and meta-analyses.

      2.2 Selection criteria

      Articles were included if they simultaneously met the following inclusion criteria: a) the patients conformed to the diagnosis of idiopathic PD, b) studies employed NIBS alone or combined with other treatments when compared with sham-stimulation, placebo, antidepressant drugs, or other psychological treatments, and c) psychiatric symptoms were evaluated using relative rating scales. Articles were excluded if they did not include available data for the calculation of the effect sizes. There were no restrictions on the trial designs, including RCTs, cross-sectional trials, and self-contrast trials.

      2.3 Data extraction

      Two authors independently extracted the data on the study characteristics (first author, publication year, and study design), stimulation parameters (NIBS type, position, intensity, frequency, sessions, and therapy duration), and psychological assessments (psychiatric symptoms, evaluation time, and rating scales). Outcome measures are presented as scale scores with mean (standard deviation [SD]), median (interquartile range [IQR]) or median (range), and the data of the latter were converted to the former by a new estimation method [
      • Luo D.
      • Wan X.
      • Liu J.
      • Tong T.
      Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range.
      ]. If the reported data for an article were insufficient for data analysis, we attempted to contact the corresponding author via email to request access to additional data. The third researcher double-checked all the entered data for accuracy.

      2.4 Quality assessment of studies

      The potential bias of the included studies was evaluated according to the Cochrane handbook 5.1.0 [

      Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0, https://handbook-5-1.cochrane.org/; 2011.

      ]. The tool classifies studies as having a low, high, or unclear risk of bias across 6 domains: selection (random sequence generation and allocation concealment), performance (blinding of the participants and personnel), detection (blinding of the outcome assessment), attrition (incomplete outcome data), reporting (selective reporting bias), and other bias.

      2.5 Risk of bias

      Considering the inconsistency in the NIBS interventions and outcome measures, in our meta-analysis, we primarily preferred the most used methods, for instance, the Hamilton Depression Scale (HAMD) as a depression rating scale, >1 Hz as the stimulation frequency, and the first time after treatment as the evaluation time. On the other hand, the NIBS stimulation parameters included frequency and location. The stimulation locations were divided into the bilateral primary motor cortex (M1) and left or right dorsolateral prefrontal cortex (DLPFC), and the stimulation parameter was defined as the frequency combined with the location.

      2.6 Statistical analysis

      For all the RCTs, the standardized mean difference (SMD) with 95 % confidence interval (CI) were used to measure the overall effect sizes of outcomes owing to different rating scales; meanwhile, the ratio of means (RoM) method was used to evaluate pre- and post-therapy psychiatric changes for self-contrast trials, and the 95 % CI was calculated using the delta method [
      • Friedrich J.O.
      • Adhikari N.K.J.
      • Beyene J.
      The ratio of means method as an alternative to mean differences for analyzing continuous outcome variables in meta-analysis: a simulation study.
      ].
      Heterogeneity between studies was calculated using I2, and random effects meta-analyses were used in all the analyses for robust results. Publication bias was adopted to evaluate if the pooled effect values were impacted by part of the studies’ positive results and assessed using Egger’s test and funnel plots. Sensitivity analyses were employed to inspect if the pooled effect estimates were influenced by eliminating a single study or by the characteristics of the study design or population; thus, one study was eliminated at a time to discover the effect of this study on the result. Subgroup analyses were employed to test the source of the heterogeneity and the effect differences between different NIBS treatment protocols.
      All analyses were performed using R version 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria) and Review Manager (RevMan) version 5.4 (Cochrane Collaboration, London, UK). A probability value of <0.05 was considerate statistically significant.

      3. Results

      A total of 12,208 papers were found following the literature search, selection, and deduplication; 12,054 were excluded after reviewing the titles and abstracts. Thus, 154 papers with full-text availability were included in the review. Another 13 potential papers were further identified based on the references of relevant reviews. Finally, 57 and 15 studies were included in the meta-analysis and systematic review, respectively (Fig. 1). We included 44 RCTs and 13 non-RCTs in the meta-analysis. The characteristics of the included studies are listed in Supplementary Tables 3 and 4. A total of 44 and 13 studies were classified as high and medium quality, respectively, based on the results of the quality assessment (Fig. 2).
      Figure thumbnail gr2
      Fig. 2Study quality assessment of included studies.

      3.1 RCTs on NIBS and sham-stimulation/placebo

      A total of 29 eligible RCTs included 823 and 737 patients for NIBS and sham-stimulation/placebo, respectively; the results are shown in Fig. 3. Moreover, 28 trials demonstrated a significant difference between the participants for NIBS and sham-stimulation for depression (SMD = −0.75, 95 % CI: −0.99 to −0.50, I2 = 79 %). There were no significant differences for anxiety (SMD = -0.29, 95 % CI: −0.76 to 0.17, I2 = 61 %) or apathy (SMD = -0.05, 95 % CI: −0.39 to 0.50, I2 = 0 %).
      Figure thumbnail gr3
      Fig. 3Forest plot of effect sizes for NIBS and sham-stimulation/placebo in PD psychiatric symptoms. Individual SMDs and their corresponding 95%CIs are indicated by filled squares with lines attached to it. The size of the shadow indicates the weight of the study in each analysis. The overall estimate of SMDs and its 95%CI is indicated by a rhombus.Abbreviations: CI, confidence interval; NIBS, non-invasive brain stimulation; PD, Parkinson’s disease; SMD, standard mean difference.

      3.2 RCTs on NIBS and antidepressant treatment

      Thirteen RCTs with 497 and 495 participants were merged for the comparison between NIBS combined with antidepressant treatment and antidepressant treatment alone (Fig. 4A), respectively. An obvious improvement was observed for combination therapy compared with single antidepressant therapy for depression (SMD = −0.98, 95 % CI: −1.37 to −0.59, I2 = 87 %) and anxiety (SMD = −1.46, 95 % CI: −2.44 to −0.48, I2 = 95 %).
      Figure thumbnail gr4
      Fig. 4Forest plot of effect sizes for rTMS and antidepressant treatment in PD psychiatric symptoms. Forest Plot of effect sizes for rTMS combined with antidepressant treatment and antidepressant alone in PD psychiatric symptoms (4A); Forest Plot of effect sizes for rTMS and antidepressant treatment alone in PD psychiatric symptoms (4B). Individual SMDs and their corresponding 95%CIs are indicated by filled squares with lines attached to it. The size of the shadow indicates the weight of the study in each analysis. The overall estimate of SMDs and its 95%CI is indicated by a rhombus. Abbreviations: CI, confidence interval; NIBS, non-invasive brain stimulation; PD, Parkinson’s disease; rTMS, repetitive transcranial magnetic stimulation; SMD, standard mean difference.
      Nine RCTs with 231 and 228 participants were included for the comparison between NIBS and antidepressant treatment alone (Fig. 4B), respectively; no significant difference was observed for depression or anxiety.

      3.3 Non-RCTs on pre- and post-treatment of NIBS

      A total of 12 self-contrast trials for NIBS therapy were qualitied, which included 394 patients (Fig. 5). Lower risks were proven following NIBS treatment compared with pre-treatment for depression (RR [relative risk] = 0.66, 95 % CI: 0.57–0.76, I2 = 96 %) and anxiety (RR = 0.66, 95 % CI: 0.60–0.73, I2 = 67 %).
      Figure thumbnail gr5
      Fig. 5Forest plot of effect sizes for pre- and post-rTMS stimulation in PD psychiatric symptoms. Individual RRs and their corresponding 95%CIs are indicated by filled squares with lines attached to it. The size of the shadow indicates the weight of the study in each analysis. The overall estimate of RRs and its 95%CI is indicated by a rhombus. Abbreviations: CI, confidence interval; NIBS, non-invasive brain stimulation; PD, Parkinson’s disease; RR, relative ratio; rTMS, repetitive transcranial magnetic stimulation.

      3.4 Subgroup analyses

      Subgroup analyses were conducted according to the NIBS type (rTMS or tDCS), stimulation location (DLPFC or M1), scale (Beck Depression Inventory [BDI], HAMD, or Montgomery–Asberg Depression Rating Scale [MADRS]), stimulation frequency (>or ≤ 1 Hz), therapy duration (>or ≤ 2 weeks), evaluation time (after treatment, ≤1, 1–3, or 6 months after treatment), and depression diagnosis (yes or no). The results of the stimulation parameters illustrated the effects of various frequencies and locations (Fig. 6).
      Figure thumbnail gr6
      Fig. 6Subgroup forest plot of the effects for NIBS in PD psychiatric symptoms based on NIBS stimulate parameters. Subgroup Forest Plot of NIBS and sham-stimulation/placebo (6A); Subgroup Forest Plot of rTMS combined with antidepressant treatment and antidepressant alone (4B); Subgroup Forest Plot OF pre- and post-rTMS stimulation (4C); Subgroup Forest Plot of rTMS and antidepressant treatment alone (4D). Abbreviations: CI, confidence interval; DLPFC, dorsolateral prefrontal cortex; M1, primary motor cortex; NIBS, non-invasive brain stimulation; PD, Parkinson’s disease; RR, relative ratio; rTMS, repetitive transcranial magnetic stimulation; SMD, standard mean difference.
      Notably, significant differences were observed between rTMS and sham-stimulation for anxiety upon using HAMD (SMD = −0.61, 95 % CI: −1.18 to −0.03, I2 = 61 %). Furthermore, all the rTMS treatments combined with antidepressant drugs, Chinese traditional drugs, or other therapy (bio-feedback therapy, rehabilitation training, and cognitive behavioral therapy) resulted in a significant improvement in depression. High-frequency and short-term rTMS seemed more effective for anxiety improvement (SMD = −2.24, 95 % CI: −4.21 to −0.28, I2 = 95 %) (Supplementary Figs. 1-45).

      3.5 Publication bias and sensitivity analyses

      No publication bias was found, which suggested robustness of the results. Likewise, the sensitivity analysis did not show that the results were influenced by a single study (Supplementary Figs. 46-59). However, no factors could explain the reason for the existing high heterogeneity in our analyses; we suspect that it could be attributed to the inconformity of the included studies.

      3.6 Systematic review

      A total of 15 studies were included in our systematic review, including 12 RCTs, 2 case reports, and 1 non-RCT. Most of the studies concluded that rTMS could reduce the scores of various depression rating scales; however, whether tDCS could improve depressive symptoms or rTMS was effective for the treatment of anxiety and apathy was inconclusive owing to insufficient evidence. Notably, rTMS was reportedly used as a therapeutic tool for PD complex visual hallucinations in a case study.

      4. Conclusions

      We identified that compared with pre-treatment, the scores of depression and anxiety rating scales decreased following NIBS treatment. NIBS, especially rTMS, improved depression and depressive mood in patients with PD compared to sham-stimulation or placebo; however, it did not improve anxiety or apathy. Compared with antidepressant treatment alone, the combined use of NIBS and antidepressant treatment was an equally favorable option for the management of depression and anxiety in patients with PD. Moreover, there was no significant difference between NIBS and antidepressant treatment alone. Our meta-analysis could provide powerful evidence for the therapeutic efficacy of NIBS for depression and anxiety in patients with PD, which supports the guideline for disease treatment.
      Based on the available statistical data, we found that the number of tDCS samples was small, and the data types were different; therefore, the included studies on the treatment of PD psychiatric symptoms used rTMS, which showed good performance according to our analysis.
      First, most studies focused on the management of depression or depressive symptoms in patients with PD, which support the use of the rTMS technique as an effective tool; moreover, no significant therapeutic difference was observed compared with antidepressants. The current treatments of depression in patients with PD include oral antidepressants, behavioral therapy, or electroconvulsive therapy [
      • Ghazi-Noori S.
      • Chung T.H.
      • Deane K.
      • Rickards H.E.
      • Clarke C.E.
      Therapies for depression in Parkinson’s disease.
      ]. However, the therapeutic efficacy of antidepressants for PD depression has not yet been adequately evaluated [
      • Weintraub D.
      • Morales K.H.
      • Moberg P.J.
      • Bilker W.B.
      • Balderston C.
      • Duda J.E.
      • et al.
      Antidepressant studies in Parkinson’s disease: a review and meta-analysis.
      ], and numerous potential adverse reactions have been reported for the combined use of antidepressants and anti-PD drugs [
      • Burn D.J.
      Beyond the iron mask: towards better recognition and treatment of depression associated with Parkinson’s disease.
      ,
      • Schneider F.
      • Althaus A.
      • Backes V.
      • Dodel R.
      Psychiatric symptoms in Parkinson’s disease.
      ]. Therefore, the treatment of PD psychiatric symptoms is especially worth considering; hence, exploring supplementary therapy is warranted. rTMS was used alone or in combination with commonly-used antidepressants in several studies, and the results demonstrated that rTMS effectively improves the depressive symptoms of PD when used in combination with antidepressants and traditional Chinese medicines, with a higher therapeutic effect than when used alone. However, the related mechanism is unclear. Previous studies have shown that this antidepressant effect is similar to that of selective serotonin reuptake inhibitors (SSRIs) [
      • Boggio P.S.
      • Fregni F.
      • Bermpohl F.
      • Mansur C.G.
      • Rosa M.
      • Rumi D.O.
      • et al.
      Effect of repetitive TMS and fluoxetine on cognitive function in patients with Parkinson’s disease and concurrent depression.
      ].
      Opting for an optimal stimulation plan is particularly important in clinical treatment. The major targets for rTMS in the treatment of PD include the M1, supplementary motor area (SMA), and DLPFC. Moreover, dysfunction of the prefrontal-limbic system is one of the pathogenic mechanisms of PD depression, and neuroimaging reveals that the hypoactivated left DLPFC was mainly associated with mood changes in PD [
      • Cardoso E.F.
      • Fregni F.
      • Martins Maia F.
      • Boggio P.S.
      • Luis Myczkowski M.
      • Coracini K.
      • et al.
      rTMS treatment for depression in Parkinson’s disease increases BOLD responses in the left prefrontal cortex.
      ]. Therefore, the DLPFC has become a common target for rTMS in the treatment of PD depression. Stimulation of the motor cortex, which corresponds to the cortico-striatal projections associated with dopamine release in the caudate and putamen, plays an important role in the therapeutic effects of rTMS on motor symptoms in PD [
      • Santos L.
      • Opris L.
      • Hampson R.
      • Godwin D.W.
      • Gerhardt G.
      • Deadwyler S.
      Functional dynamics of primate cortico-striatal networks during volitional movements.
      ]. As pointed out by a guideline, sufficient evidence and recommendations exist for the use of high-frequency rTMS of the left DLPFC (Level A, definitely effective or ineffective) and low-frequency rTMS of the right DLPFC (Level B, probably effective or ineffective) [
      • Lefaucheur J.-P.
      • André-Obadia N.
      • Antal A.
      • Ayache S.S.
      • Baeken C.
      • Benninger D.H.
      • et al.
      Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS).
      ]. Besides, the stimulation of the M1 and the M1 combined with the DLPFC has been recognized as effective for managing the overall motor symptoms in PD (Level B) [
      • Madrid J.
      • Benninger D.H.
      Non-invasive brain stimulation for Parkinson’s disease: clinical evidence, latest concepts and future goals: a systematic review.
      ], which has also been proven useful for depression; this is consistent with the findings of our meta-analysis. A previous study presumes that rTMS does not have any significant effect on non-motor symptoms by M1 stimulation [
      • Maruo T.
      • Hosomi K.
      • Shimokawa T.
      • Kishima H.
      • Oshino S.
      • Morris S.
      • et al.
      High-frequency repetitive transcranial magnetic stimulation over the primary foot motor area in Parkinson’s disease.
      ]; we found that bilateral M1 stimulation was beneficial for PD depression. Previous studies have also reported that different DLPFC stimulation locations and frequencies have diverse consequences on the psychiatric symptoms of patients with PD, which is consistent with our results. Further evaluation cannot be performed owing to lack of studies or inconclusive results; additional trials are required to examine the combined bilateral stimulation of the M1 and DLPFC. Simultaneously, the DLPFC region is a promising stimulation location [
      • Lefaucheur J.-P.
      • Aleman A.
      • Baeken C.
      • Benninger D.H.
      • Brunelin J.
      • Di Lazzaro V.
      • et al.
      Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014–2018).
      ,
      • McClintock S.M.
      • Reti I.M.
      • Carpenter L.L.
      • McDonald W.M.
      • Dubin M.
      • Taylor S.F.
      • et al.
      National Network of Depression Centers rTMS Task Group; American Psychiatric Association Council on Research Task Force on Novel Biomarkers and Treatments. Consensus recommendations for the clinical application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression.
      ]; future studies should further discuss the appropriate location (unilateral/bilateral) and frequency parameters on this basis [
      • Zhang W.
      • Deng B.
      • Xie F.
      • Zhou H.
      • Guo J.-F.
      • Jiang H.
      • et al.
      Efficacy of repetitive transcranial magnetic stimulation in Parkinson’s disease: a systematic review and meta-analysis of randomised controlled trials.
      ].
      Further, rTMS plays a role by modulating cortical excitability, with high-frequency rTMS (>1 Hz) being facilitatory whereas low-frequency rTMS (≤1 Hz) is inhibitory. In fact, both frequencies greatly improve depression. Cerebral blood flow and metabolism in the left DLPFC reportedly decrease in patients with depression, as evidenced by brain single-photon emission computed tomography perfusion and functional magnetic resonance imaging, while those in the right DLPFC increase. This suggests that abnormal functioning of the left and right DLPFC in emotion processing and regulation may be one of the pathogenic mechanisms [

      He J, Su W. Application of repeated transcranial magnetic stimulation in the treatment of depression in Parkinson’s disease [Chinese]. Chinese J Neuroimmunol Neurol 2017:362–5. https://doi.org/10.3969/.j.

      ]. Therefore, increasing cortical excitability using high-frequency stimulation of the left DLPFC or decreasing cortical excitability using low-frequency stimulation of the right DLPFC could alter the brain asymmetry thereby attaining therapeutic effects. When treating depressive symptoms in patients with PD using rTMS, high-frequency rTMS of the left side and low-frequency rTMS of the right side should be performed simultaneously. In addition, we concluded that the BDI, HAMD, and MADRS achieved the highest diagnostic accuracy and were sufficient to screen the depressive symptoms of patients with PD [
      • Lauterbach E.C.
      • Freeman A.
      • Vogel R.L.
      Correlates of generalized anxiety and panic attacks in dystonia and Parkinson disease.
      ]. Most of the included studies used the HAMD, and these scales showed similar results. Further, long-term treatment duration (>2 weeks) reportedly had a more significant effect than short-term treatment (≤2 weeks), and the therapeutic effects lasted for several months following rTMS therapy, which could serve as a guideline in the future.
      Second, anxiety affects >60 % of patients with PD, and presents as generalized anxiety disorder, social phobia, and panic disorder [
      • Walsh K.
      • Bennett G.
      Parkinson’s disease and anxiety.
      ]. It is commonly, but not always, accompanied by depression [
      • Lin C.H.
      • Lin J.W.
      • Liu Y.C.
      • Chang C.H.
      • Wu R.M.
      Risk of Parkinson’s disease following anxiety disorders: a nationwide population-based cohort study.
      ,
      • Chaudhuri K.R.
      • Schapira A.H.
      Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment.
      ]. Similar to depression, anxiety in PD can be attributed to the interactions between dopaminergic deficits and variable deficits in norepinephrine and serotonin [
      • Schneider F.
      • Althaus A.
      • Backes V.
      • Dodel R.
      Psychiatric symptoms in Parkinson’s disease.
      ]. Currently, evidence for the efficacy and safety of anxiolytic agents for the treatment of anxiety in patients with PD is lacking, and benzodiazepines should be prescribed to older adults with care, considering their increased risk of falls and oversedation [
      • Walsh K.
      • Bennett G.
      Parkinson’s disease and anxiety.
      ]. Additionally, our study finds no significant therapeutic difference between NIBS and antidepressants. SSRIs are reportedly effective for treating anxiety symptoms in patients with PD [
      • Chen J.J.
      Anxiety, depression, and psychosis in Parkinson’s disease: unmet needs and treatment challenges.
      ]. Owing to the lack of relevant studies, no significant therapeutic effects of rTMS for treating anxiety in patients with PD were observed. Nevertheless, our results suggest that rTMS combined with antidepressant therapy is effective; however, this should be further verified in more clinical trials.
      Lastly, only a few studies focusing on apathy and other psychiatric symptoms were included in our systematic review and meta-analysis. Apathy occurs in 60 % of individuals with PD and has been increasingly recognized as a distinct non-motor component in addition to depression and anxiety [
      • Marin R.S.
      • Fogel B.S.
      • Hawkins J.
      • Duffy J.
      • Krupp B.
      Apathy: a treatable syndrome.
      ]. A recent study demonstrated that participants with PD and apathy show reductions in gray matter density in the cingulate gyrus and inferior frontal gyrus, which may involve the ventral striatal and limbic brain areas [
      • Dujardin K.
      • Langlois C.
      • Plomhause L.
      • Carette A.-S.
      • Delliaux M.
      • Duhamel A.
      • et al.
      Apathy in untreated early-stage Parkinson disease: relationship with other non-motor symptoms.
      ]. Psychosis in PD typically takes place in the later course of the illness, and its common symptoms include visual hallucinations and delusions, which are present in up to 40 % of cases [
      • Diederich N.J.
      • Goetz C.G.
      • Stebbins G.T.
      Repeated visual hallucinations in Parkinson’s disease as disturbed external/internal perceptions: focused review and a new integrative model.
      ,
      • Bodis-Wollner I.
      Visual deficits related to dopamine deficiency in experimental animals and Parkinson’s disease patients.
      ]. rTMS can be considered as a therapeutic tool for visual hallucinations in patients with PD based on a case report [
      • Hanoğlu T.
      • Hanoğlu L.
      • Güntekin B.
      • Aktürk T.
      • Yulug B.
      The therapeutic role of repetitive transcranial magnetic stimulation (rTMS) in parkinsonian visual hallucinations: electrophysiological correlates.
      ], which provides a new direction for the treatment of non-motor symptoms. Considering the complexity of psychotropic drugs, the efficiency and safety of rTMS should be further verified before its application to broader fields.
      There are several strengths to our meta-analysis. First, this study included 73 records, which, to our knowledge, is the largest sample size compared with previous studies. Second, this study evaluated the efficacy of NIBS combined with antidepressants for the first time, and conducted detailed subgroup analyses. Inevitably, several limitations should be noted in this work. First, Chinese RCTs accounted for a large proportion, which could result in population bias. Second, recent studies are urgently warranted to further explore the relationship between NIBS and other psychiatric symptoms. Third, a detailed analysis should be conducted to investigate more precise parameters of NIBS applicable to the psychiatric condition of patients with PD.
      In summary, our results suggest that NIBS, especially rTMS, can be considered an effective non-pharmacological option for treating PD depression. However, no sufficient evidence demonstrating its effectiveness for anxiety and apathy exists. Additionally, the data shows no significant therapeutic difference between NIBS and antidepressants. Notably, rTMS combined with antidepressants is demonstrated as an effective tool for treating depression and anxiety in PD. More up-to-date studies are warranted to further investigate the optimal NIBS protocols for treating psychiatric symptoms in patients with PD.

      Funding

      This work was funded by the Medical Research Project of Wuhan, Hubei Province, China (Grant No of WX19D12).

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      This study was supported by grants from Wuhan Wudong Hospital (The Second Mental Hospital of Wuhan).

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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