Efficacy of non-pharmacological interventions for depression in individuals with Parkinson's disease: A systematic review and network meta-analysis

<jats:sec><jats:title>Background</jats:title><jats:p>Depression in Parkinson's disease (PD) is a major health concern worldwide. Recently, an increasing number of non-pharmacological interventions have been used in PD to alleviate depressive symptoms. However, it is uncertain which intervention is the best, and related evidence is limited. This network meta-analysis was performed to compare and rank non-pharmacological interventions for PD and analyze their effects on depression to provide evidence for clinicians to choose appropriate non-pharmacological management options.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>The PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, China National Knowledge Infrastructure (CNKI), and Wanfang databases were searched from inception to April 7, 2022. Two authors screened all studies, extracted the data, and evaluated the methodological quality. STATA software version 16.0 was used to conduct the network meta-analysis.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Our network meta-analysis included 62 studies involving 3,050 participants and 35 non-pharmacological interventions. Although most non-pharmacological interventions showed non-significant effects, the surface under the cumulative ranking curve (SUCRA) values indicated that the best non-pharmacological intervention for depression was dance (82.3%), followed by LSVT-BIG therapy (77.4%), and CBT (73.6%).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Dance can be considered as an effective therapy for improving depression in patients with PD. In the future, more strictly designed trials are needed to verify the conclusions of this network meta-analysis.</jats:p></jats:sec>

section_content: Parkinson's disease (PD), the second most common neurodegenerative disease, is a chronic senile disease (Hirtz et al., 2007). The prevalence of PD increases with age and affects 1% of individuals older than 60 years (Tysnes and Storstein, 2017). PD is characterized by dyskinesia; however, the nonmotor symptoms (NMS) of PD have gradually attracted more attention from researchers over the past 10-20 years (Garcia-Ruiz et al., 2014). Neuropsychiatric disturbances and cognitive impairment are the main features of NMS in PD patients (Zhang et al., 2020), while depression is the most common psychiatric symptom. The prevalence of clinically significant depression in patients with PD is reported to be 40-50% (Reijnders et al., 2008). Depression often increases the incidence of disability and dysfunction in PD patients; in addition, it can affect patients' quality of life and the burdens of their caregivers. Moreover, a study by Wu et al. indicated that PD patients with depression had a higher incidence of dementia (Wu et al., 2018). Therefore, early detection and appropriate intervention are extremely important. Currently, the clinical management of depressive disorders in PD includes pharmacological and non-pharmacological treatments. However, studies on the tolerability, safety, and efficacy of antidepressant drugs in PD patients are limited (Assogna et al., 2020). Additionally, pharmacological treatments with side effects can exacerbate the motor symptoms and NMS of PD patients and lead to complications (Uhrbrand et al., 2015; Deuel and Seeberger, 2020). 

Owing to the limitations of pharmacological treatments, non-pharmacological treatments have been developed and have gradually gained popularity. Many non-pharmacological treatments have been used to relieve depressive symptoms in patients with PD, and these can be roughly categorized into complementary therapies (e. g., yoga, acupuncture, auricular pressure, massage, music therapy, and dance therapy), traditional Chinese exercises (e. g., tai chi and qigong), physical exercise (e. g., aerobic exercise, resistance exercise, and balance training), virtual reality, cognitive behavioral therapy (CBT), psychotherapy, cognitive training (CT), bright light therapy (BLT), deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) (Jin et al., 2019; Zhang et al., 2019; Deuel and Seeberger, 2020; Triegaardt et al., 2020; Chen et al., 2021; Hong et al., 2021; Huang et al., 2021). Previous studies (Troeung et al., 2014; Ryan et al., 2019; Assogna et al., 2020) have paid more attention to the effects of CBT and TMS on depression in PD patients and indicated that these two therapies are supportive for improving depression. The efficacy of other non-pharmacological treatments for depression in patients with PD remains controversial. 

Previous systematic reviews have evaluated the effects of various non-pharmacological interventions on depression in individuals with PD (Cusso et al., 2016; Jin et al., 2019; Hai-Jiao et al., 2020; Triegaardt et al., 2020; Cartmill et al., 2021; Hong et al., 2021; Huang et al., 2021; Takamiya et al., 2021). However, some reviews included non-randomized controlled trials (RCTs) or lacked quantitative analyses (Cusso et al., 2016; Triegaardt et al., 2020; Cartmill et al., 2021; Takamiya et al., 2021) ; thus, these systematic reviews did not provide strong evidence. In addition, most RCTs compared nonpharmacological interventions with placebo, waiting list, or usual treatments, and only a few RCTs compared two different non-pharmacological interventions (Modugno et al., 2010; Kalbe et al., 2020; Schmidt et al., 2021). To our knowledge, only one systematic review has reported the efficacy of nonpharmacological interventions on depression in PD subjects (Chen et al., 2021). In that study, a population with idiopathic PD was selected, and the interventions included repetitive TMS (rTMS) and CBT. The review also included limited interventions and small sample sizes and excluded some patients with PD. Consequently, a systematic review evaluating the effects of different non-pharmacological interventions and the exploration of more effective interventions is required. 

Network meta-analysis (NMA) is a general technique for comparing several interventions simultaneously (e. g., A vs. B, B vs. C) (Lu and Ades, 2004). NMA can compare multiple interventions by incorporating direct and indirect comparisons to select the best intervention based on the relative effects of different interventions from a network of evidence (Catalá-López et al., 2014). Therefore, we performed this systematic review with a NMA of RCTs to provide further evidence to clinicians when choosing appropriate non-pharmacological management options.
section_name: Introduction

section_name: Methods

section_content: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension statement for reporting systematic reviews incorporating network metaanalyses of health care interventions (Hutton et al., 2015) 4 ) randomized controlled trial, randomized, placebo. MeSH and free words were linked by "OR" in each group and searched by "AND" to link each group. 

In addition, we retrieved data from the U. S. National Library of Medicine Clinical Trial Registry Platform and the Chinese Clinical Trial Registry Platform for trials in progress or ready for publication. The gray literature was also considered in the search. The reference lists of the included literature and related articles were also manually searched to identify eligible studies. The search strategies for all databases are listed in Supplementary Data Sheet 1.
section_name: Search strategy

section_content: Eligible studies met the following criteria:

(1) Population: Adults (>18 years) diagnosed with PD according to sex, Hoehn and Yahr stage, or disease duration with no restrictions. All participants in the intervention and control groups who were stably taking antidepressants and/or antiparkinsonian medications were also eligible.
section_name: Eligible criteria

section_content: Two authors (YW, XS) independently extracted data including the first author, country, year, sample size, baseline characteristics of participants, duration of disease, Hoehn-Yahr stage, intervention details (type, frequency, and duration), comparison, and outcomes based on a predesigned form within Microsoft Excel. The methodological quality of the eligible studies was independently assessed using the Cochrane risk of bias (RoB 2. 0) tool (Sterne et al., 2019) by two authors (YW, XS). The scale consists of five domains: the randomization process, deviations from the intended interventions, missing outcome data, outcome measurement, and selection of the reported result. In terms of the domain algorithm, the risk of bias for each domain was rated as low risk, some concerns, or high risk. If the assessment of risk bias in all domains was "low risk, " then the overall risk bias was considered as "low risk"; if the assessment of risk bias indicated "some concerns" in some domains and there was no "high risk" result in any domain, the overall risk bias was "some concerns"; if the assessed risk of bias was "high risk" in at least one domain, the overall risk bias was "high risk. " The results of the data extraction and quality assessment were cross-checked, and the divergences were resolved through discussion with a third author (YJ). To comprehensively compare the effects of non-pharmacological interventions on depression in PD subjects, we did not exclude medium-and low-quality studies.
section_name: Data extraction and quality assessment

section_content: The network analysis was conducted using STATA 16. 0 (StataCorp, College Station, TX) and a frequentist framework with a random-effects model. For all eligible trials, postintervention measurements were selected for comparison. Continuous variables were analyzed using standardized mean differences (SMD) with 95% percentile intervals, and the significance was set at α = 0. 05. We examined the global consistency and used the node-split model to determine the local consistency. P > 0. 05 indicated no significant inconsistency between direct and indirect comparisons, and in these cases, the consistency model was adopted; otherwise, the inconsistency model was used. In addition, the inconsistency of closed loops was evaluated using a loop-specific method, and a 95% confidence interval (CI) of 0 indicated no significant loop inconsistency. Each arm was included for comparison, and to discriminate the consistency between the two-arm and threearm trials, a league table was used to perform the pairwise analysis. The league table was used to analyze the results of the comparisons among the different interventions based on a NMA. To explore the best evidence for improving depression, the SUCRA was used to summarize the ranking probability values. Funnel plots were used to visually evaluate publication bias based on the symmetry criterion (Shim et al., 2017).
section_name: Statistical analysis

section_content: The process of selection of the eligible studies.
section_name: FIGURE

section_name: Results

section_content: A total of 2,755 studies were identified from six databases, while 9 studies were selected from other sources. Five trials were retrieved by screening the reference lists of the included studies and related articles. After removing 853 duplicates, 1,746 articles were excluded after screening their titles and abstracts. Subsequently, 156 articles were retrieved, 153 full-text articles were evaluated, and 63 were included in the systematic review. However, one study did not meet the quantitative analysis
section_name: Study selection

section_content: Table 1 shows the characteristics of 62 eligible RCTs (Chinese = 6, English = 56) published from 2002 to 2021 and involving 3,050 participants. In this NMA, non-pharmacological interventions included a variety of interventions such as BLT (n = 4), CBT (n = 9), dance (n = 3), massage (n = 3), music therapy (n = 1), DBS (n = 1), aerobic exercise (n = 2), resistance exercise (n = 5), balance training (n = 2), mindfulness intervention (n = 2), TMS (n = 9) including rTMS and rhythmic TMS, traditional Chinese exercise (TCE) (n = 5) including Qigong and Tai chi, tDCS (n = 1), virtual reality (VR) (n = 2), yoga (n = 3), CT (n = 7), psychotherapy (n = 3), acupuncture (n = 1), multidisciplinary rehabilitation (n = 1), and auricular pressure (n = 1). The comparison mainly consisted of placebo, waitlist, TAU including usual care and usual treatment, stretching exercises, supportive instruction (e. g., health education, sleep hygiene advice, regular social interactions, and active testing), and physiotherapy. Among all eligible studies, 60 RCTs were two-arm trials (Wade et al., 2003; Craig et al., 2006; Paus et al., 2007; Veazey et al., 2009; Modugno et al., 2010; Pal et al., 2010; Smania et al., 2010; Sproesser et al., 2010; Dobkin et al., 2011 Dobkin et al.,, 2021;; Edwards et al., 2013; Naismith et al., 2013; Okai et al., 2013; Rios Romenets et al., 2013, 2015; Shirota et al., 2013; Peña et al., 2014; Petrelli et al., 2014; Troeung et al., 2014; Calleo et al., 2015; Dashtipour et al., 2015; Lee et al., 2015 Lee et al.,, 2018;; Bega et al., 2016; Brys et al., 2016; Patel et al., 2016; Picelli et al., 2016; Fan et al., 2017; Ghielen et al., 2017; Tröster et al., 2017; Videnovic et al., 2017; Xu and Xia, 2017; Yu et al., 2017; Cheung et al., 2018; Cohen et al., 2018; Kong et al., 2018; Michels et al., 2018; Pérezde la Cruz, 2018; Tollár et al., 2018; Willis et al., 2018; Kwok et al., 2019; Rodgers et al., 2019; Rutten et al., 2019; Sacheli et al., 2019; Solla et al., 2019; Wuthrich and Rapee, 2019; Fellman et al., 2020; Kalbe et al., 2020; Kraepelien et al., 2020; Li et al., 2020; Moon et al., 2020; Wu et al., 2020 Wu et al.,, 2021;; You and She, 2020; Zheng et al., 2020; Zhuang et al., 2020; Aftanas et al., 2021; Han et al., 2021; Schmidt et al., 2021; Bogosian et al., 2022) and 2 RCTs (Stallibrass et al., 2002; Wu et al., 2019) were multi-arm trials.
section_name: Study characteristics

section_content: The methodological quality assessments of the eligible RCTs are shown in Figure 2, ranging from low to high risk. All eligible RCTs met the criteria for deviation from the intended interventions, missing outcome data, and outcome measurements. Three trials had obvious flaws in the domain of randomization; thus, their risk of bias was rated as high. Fortyfive RCTs were rated as "some concerns" due to weaknesses in the randomization process or selection of the reported result domains. Supplementary Table S1 shows the relative effects of the different interventions on depression. The league table shows the pairwise comparisons of 35 non-pharmacological interventions for depression in PD subjects. Compared to occupational group activities, dance (SMD: -3. 23; 95% CI: -6. 05--0. 41), LSVT-BIG therapy (SMD: -3. 36; 95% CI: -6. 27--0. 45), CBT (SMD: -2. 76; 95% CI: -5. 31--0. 21), aerobic exercise (SMD: -2. 69; 95% CI: -5. 07--0. 30), mindfulness intervention (SMD: -2. 31; 95% CI: -4. 06--0. 56), TCE (SMD: -2. 14; 95% CI: -4. 10--0. 18), DBS (SMD: -2. 17; 95% CI: -4. 07--0. 27), CT (SMD: -1. 85; 95% CI: -3. 16--0. 53), waitlist (SMD: -1. 76; 95% CI: -3. 26--0. 26), and physiotherapy (SMD: -1. 72; 95% CI: -3. 29--0. 14) all showed significant improvement effects on depression. Compared to stretching exercises, dance (SMD: -2. 67; 95% CI: -4. 91--0. 44), CBT (SMD: -2. 2; 95% CI: -4. 09--0. 31), and TCE (SMD: -1. 58; 95% CI: -2. 52--0. 63) showed significant improvement effects on depression. Compared to TAU, dance (SMD: -1. 70; 95% CI: -3. 25--0. 14) and CBT (SMD: -1. 23; 95% CI: -2. 22--0. 23) had significantly positive effects.
section_name: Quality assessment

section_name: Network meta-analysis

section_content: The SUCRA plot and values are shown in Figure 4 and Table 2
section_name: Rank probability

section_content: The global inconsistency analysis of this NMA showed a Pvalue of 0. 0038, indicating significant inconsistency. Moreover, the results of the node-splitting analysis indicated that the four indirect comparisons had inconsistencies (P < 0. 05). The results are summarized in Supplementary Table S2. Therefore, we used an inconsistency model to perform the NMA. Considering that two triangular loops were formed by the multi-arm trials, I 2 quadratic loop consistencies were examined if they were inconsistent. The 95% CI of the four closed loops included 0, indicating significant inconsistency (Figure 5 ). However, the lower CI was close to 0, which indicated low consistency. . Although the NMA revealed an obvious overall inconsistency, the comparisons of inconsistency using node-splitting analysis and the loop-specific method both included a small number of studies and sample sizes. Therefore, the inconsistencies were not significant. Inconsistency tests can be affected by limited numbers of studies and small sample sizes, making accurate evaluation difficult. Due to the low heterogeneity of the data (τ < 0. 5), a meta-regression analysis of potential effects was not performed (Turner et al., 2012).
section_name: Consistency analysis

section_content: A comparison-adjusted network funnel plot with a random model was constructed for the outcome (Figure 6 ). The funnel plot was symmetric, demonstrating that there was no significant risk of publication bias in our study.
section_name: Publication analysis

section_content: This NMA was conducted to synthesize existing evidence from 62 RCTs involving 35 non-pharmacological interventions for depressive symptoms using a comprehensive search. Direct and indirect comparisons were conducted to analyze the efficacy of different non-pharmacological interventions on depressive symptoms. The SUCRA values revealed that the best nonpharmacological intervention was dance, followed by LSVT-BIG therapy and CBT. Despite the lack of strong evidence, current guidelines recommend ECT, physical exercise, and psychotherapy to treat depression in PD patients (Olanow et al., 2001; Goodarzi et al., 2018). However, our NMA did not include RCTs on the effect of ECT on depression. 

Although two conventional meta-analyses showed that dance had no significant effect on depression (Zhang et al., 2019; Wang et al., 2022), most original trials indicated a supportive effect of dance on depression compared to no intervention or TAU. In addition, our study demonstrated that dance was the best non-pharmacological intervention based on its high SUCRA value (82. 3%). Dance is a multicomponent activity that involves moving one's muscles, maintaining one's balance, maintaining auditory, visual, and sensory reactions, memory, perception, expression, and social interactions (Kattenstroth et al., 2010). Dance can create a sense of pleasure by combining physical exercise and mental regulation, which contributes to increased compliance and continued attendance (Earhart, 2009; Hackney and Earhart, 2010; Goodarzi et al., 2018). The sense of pleasure may evoke positive emotions by stimulating basal ganglia loops and reward systems (Hackney and Earhart, 2009). Meanwhile, music used in dance can increase the release of dopamine from the ventral striatum and ventral tegmental area to alleviate depressive symptoms (Weintraub et al., 2005). However, this ranking has an underlying uncertainty and may not fully reflect reality. 

LSVT-BIG therapy is a type of exercise model that focuses on training of amplitude together with sustained attention and perception of a single movement during exercise, thus enabling patients to participate physically and mentally in functional activities with great sustainability (Fox et al., 2012). Our study indicated that LSVT-BIG therapy is the second-ranked nonpharmacological intervention according to its SUCRA value (77. 4%), whereas only one RCT showed a positive effect of LSVT-BIG therapy on depression compared with general exercise (Dashtipour et al., 2015). However, the small sample sizes of the studies limited the accuracy and generalization of the conclusions; therefore, more large-scale and strictly designed trials are needed. The mechanism by which LSVT-BIG therapy is effective in reducing depressive symptoms remains unclear. Additionally, current trials lack focus on the long-term effects of LSVT-BIG therapy. Thus, the maintenance of long-term effects and exploration of the underlying mechanisms should be given more attention in future studies. 

CBT, as a psychotherapy, is the third-ranked nonpharmacological intervention according to its SUCRA value (73. 6%), which is similar to the recommendations of the guidelines and results of conventional meta-analyses (Goodarzi et al., 2018; Zhang et al., 2020; Hong et al., 2021). CBT is a problem-oriented approach that aims to enhance a patient's coping skills. This approach involves both therapists and patients and aims to help patients overcome negative moods, dysfunctional thoughts, and behaviors by modifying their way of thinking and behaving (Farley and Koshland, 2005; Schrag et al., 2007; O'cleirigh et al., 2019; Sahranavard et al., 2019). Among the conventional meta-analyses that demonstrated that CBT had a significant positive effect on the improvement of depression (Troeung et al., 2013; Xie et al., 2015; Zhang et al., 2020; Hong et al., 2021), a meta-analysis showed that CBT had a larger effect size than antidepressant treatments (Troeung et al., 2013). To date, most trials have indicated that CBT plays a beneficial role in depression disorders in patients with PD. One review suggested that CBT is more appropriate for patients with PD without dementia, as patients with dementia are usually excluded from trials (Egan et al., 2015). In short, CBT can be considered an important approach for first-line or adjunctive treatment of depression in PD. 

Interestingly, our results indicate that most nonpharmacological interventions examined in our study had no significant effect on alleviating depressive disorders. This may be due to the use of antidepressant medications and the progression of PD (Schrag et al., 2001; Bhattacharjee et al., 2018; Demarco et al., 2021). Moreover, depression in PD patients is associated with cognitive impairment. As the disease progresses, cognitive deficits negatively affect depressive symptoms (Van Uem et al., 2018). Although most included trials in our study excluded PD patients with dementia, the impact of mild cognitive impairment cannot be ignored. In addition, it is difficult for short-term non-pharmacological interventions to improve neuroanatomical degeneration (Mcdonald et al., 2003). According to their SUCRA values, some non-pharmacological interventions were ranked below placebo and waitlist. This may be due to a lack of sufficient evidence showing the efficacy of these interventions for depression in PD. Although a global inconsistency was present in our NMA, the local inconsistency was found to be weak in the node-split test, and inconsistencies were mainly due to the triangular loops from two multiarm trials. Therefore, related results should be interpreted with caution. Conventional meta-analyses, including RCTs, showed that yoga, BLT, rTMS, and psychotherapy significantly improved depression (Ban et al., 2021; Chen et al., 2021; Hong et al., 2021; Huang et al., 2021) ; however, the evidence was relatively weak. Although a previous systematic review showed that physical exercise is beneficial for depression, it did not provide a quantitative analysis of the intervention effects (Cusso et al., 2016). Guidelines and reviews suggest that ECT may be an effective therapy for depression (Bhattacharjee et al., 2018; Goodarzi et al., 2018) ; however, the current systematic review with meta-analysis did not identify any relevant RCTs of ECT (Takamiya et al., 2021). Therefore, our study did not compare ECT with the other non-pharmacological interventions. Recently, a systematic review and meta-analysis by Xie et al. revealed that psychodynamic psychotherapy was superior to CBT (Xie et al., 2015). According to the eligibility criteria of our study, we did not include RCTs on the effect of psychodynamic psychotherapy on depression in patients with PD. Psychotherapy in combination with non-CBT requires further high-quality evidence to explore its efficacy for treating depression in PD patients. 

This NMA has several limitations. First, only RCTs that focused on PD patients with mean Hoehn-Yahr stage values of 1-3 were included in our NMA; thus, the results of this NMA may not be generalizable to all PD patients. Second, there was heterogeneity in the frequencies, durations, and periods of the non-pharmacological interventions. Third, although we comprehensively searched for non-pharmacological interventions for depression in patients with PD, the language was restricted to Chinese and English, which may have contributed to selection bias. Fourth, our NMA had obvious global inconsistencies, which may be related to the small sample size, short-term effects, discrepancies in eligibility criteria, different baseline characteristics, various measurement tools, different severities of depression, and different severities of PD. Thus, the accuracy and generalization of the conclusions are limited. Fifth, many comparisons of the interventions included only a small number of trials, which may have affected the accuracy of the conclusions. Lastly, most studies did not report concealed allocation, which may have led to selection and performance biases. Therefore, strictly designed RCTs with larger sample sizes are needed in the future.
section_name: Discussion

section_content: To the best of our knowledge, this is the first NMA to comprehensively summarize the existing RCTs of 35 different non-pharmacological interventions used for depressive symptoms. The results showed non-significant effects of most non-pharmacological interventions on depression. According to its SUCRA values, dance may be the preferred non-pharmacological intervention for improving depression, followed by LSVT-BIG therapy and CBT. Consequently, a larger sample size and stronger high-quality trials are required to draw more reliable results regarding the efficacy of Fan, J., Liu, X. L., Kong, M., Wang, X. Y., Yi, L. Y., and Zhang, Y. (2017). Effect of health qigong on mood state and cognition of patients with moderate Parkinson's disease. Chin. J. Sports Med. 36, 143-146+149. Farley, B. G., and Koshland, G. F. (2005). Training BIG to move faster: the application of the speed-amplitude relation as a rehabilitation strategy for people with Parkinson's disease. Exp. Brain Res. 167, 462-467. doi: 10. 1007/s00221-005-0179-7 Fellman, D., Salmi, J., Ritakallio, L., Ellfolk, U., Rinne, J. O., and Laine, M. (2020). Training working memory updating in Parkinson's disease: a randomised controlled trial. Neuropsychol. Rehabil. 30, 673-708. doi: 10. 1080 /09602011. 2018. 1489860 Fox, C., Ebersbach, G., Ramig, L., and Sapir, S. (2012). LSVT LOUD and LSVT BIG: behavioral treatment programs for speech and body movement in Parkinson disease. Parkinsons. Dis. 2012 Dis., 391946. doi: 10. 1155 Dis. /2012/ 391946 / 391946 Garcia-Ruiz, P. J., Chaudhuri, K. R., and Martinez- Martin, P. (2014). Non-motor symptoms of Parkinson's disease A review. . . from the past. J. Neurol. Sci. 338, 30-33. doi: 10. 1016 /j. jns. 2014. 01. 002 Frontiers in Aging Neuroscience frontiersin. org
section_name: Conclusion

section_name: Data availability statement

section_content: The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.
section_name: Data availability statement

section_name: Author contributions

section_content: YW, XS, and YJ conceived and designed the study. YW and XS searched the literature and contributed to writing of original manuscript, data acquisition and analysis, and responsible for the software. FL, QL, and YJ were responsible for revising and reviewing. All authors contributed to the article and approved the submitted version.
section_name: Author contributions

section_content: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
section_name: Conflict of interest

section_content: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
section_name: Publisher's note

section_content: The Supplementary Material for this article can be found online at: https://www. frontiersin. org/articles/10. 3389/ fnagi. 2022. 1050715/full#supplementary-material
section_name: Supplementary material