Introduction

Vascular cognitive impairment (VCI) is an umbrella term for a range of cognitive impairments primarily caused by cerebrovascular disorders [1, 2], generally considered to include mild VCI, vascular dementia (VaD), and vascular-related Alzheimer’s disease (AD) [3, 4]. The three categories of VCI are cognitive impairment following stroke and cognitive impairment caused by invisible cerebrovascular lesions that can only be detected by autopsy or imaging [5]. The main clinical manifestations of VCI have impaired thinking and executive abilities, including memory, behavioural and emotional dysfunctions, and other neurological deficits such as dysarthria(difficulty with speech), parkinsonism and reflex asymmetry [6]. According to statistics, VCI is the second leading cause of dementia worldwide after AD, accounting for approximately 20% of people with dementia [7]. Modern autopsy studies show that the risk of vascular brain injury accounts for 33% of dementia [8]. The primary pathological basis of VCI is a deficiency of cholinergic transmitters in patients [9], and clinical drug therapy is mainly based on acetylcholine inhibitors. The main drugs approved by the US FAD for VCI treatment are Donepezil, Rivastigmine and Galantamine, and the first two of which have been recommended as Level A evidence [10]. Other drugs commonly used in Vad treatment include Memantine, Citicoline, Cilostazol, Naftidrofuryl, Sertraline, and Vinpocetine [9]. However, the clinical evidences of these drugs are currently insufficient. In terms of neurological mechanisms, VCI patients’ recovery depends mainly on neuroplasticity which is the functional rebuilding of the central nervous system, especially the cortex, following injury and stimulation. Neuroplasticity relies on the regeneration of brain tissue vasculature and the enhancement of synaptic connections to regulate related gene expression, the release of trophic factors and changes in cerebral blood flow [11]. Neuroplasticity has been shown to underpin the recovery of cognitive function [12, 13]. As modern rehabilitation is moving towards community-based and home rehabilitation, the efficacy of non-invasive neuromodulation techniques in the later stages of VCI rehabilitation is expected.

At this stage, the most common non-invasive neuromodulation techniques include Transcranial Magnetic Stimulation (TMS), Transcranial Direct Current Stimulation (tDCS) and Transcutaneous Vagus Nerve Stimulation (TVNS), all of which can promote neuroplasticity. Repetitive Transcranial Magnetic Stimulation (rTMS), which involves repeated TMS stimulation at a target, can excite or inhibit cortical electrical activity through magnetic field stimulation depending on the different parameters [14], which has been widely used in cognitive-related rehabilitation [15, 16]. On the other hand, tDCS has also been shown to improve cognition. It is generally accepted that the tDCS anode increases the excitability of the subcortical layers [17] and can facilitate cognitive recovery by stimulating striatal dopamine release [18]. TVNS is a non-invasive vagal modulation technique that has been promoted in recent years,. It has been shown to produce vagally mediated pathways similar to those of invasive vagal electrical stimulation, including mainly transcutaneous auricular vagus nerve stimulation and transcutaneous cervical vagus nerve stimulation. Recent studies have shown that TVNS can improve cognitive function [19]. The mechanism of TVNS is unclear and may be related to the induction of NE and GABA. All three of these non-invasive neuromodulation techniques have been used in clinical VCI rehabilitation, and all have some theoretical basis and clinical efficacy. A network meta-analysis of non-invasive neuromodulation techniques for intervention in Alzheimer’s disease and mild cognitive impairment noted that HFrTMS was superior to atDCS in improving overall cognitive function [20]. In another systematic evaluation and meta-analysis of noninvasive neuromodulation techniques to intervene in behavioral and psychological symptoms of dementia, it was noted that pharmacological treatment had significant side effects, non-pharmacological treatment with rTMS was effective and safely tolerated, and the efficacy of tDCS was inconclusive [21]. In a network meta-analysis of similar Chinese and Western rehabilitation tools for intervention of post-stroke motor dysfunction, rTMS was found to be superior to tDCS and conventional therapy in improving Fugl Meyer Assessment (FMA) scale scores [22]. The network meta-analysis is expected to include all clinical studies on TMS, tDCS and TVNS interventions in VCI in the future to conduct a network meta-analysis of all relevant clinical data available. We hope to provide further scientific evidence and data which can support the application of non-invasive neuromodulation techniques in the rehabilitation of clinical VCI patients.

Materials and methods

The network meta-analysis is conducted following the PRISMA Statement and Cochrane Reviews Handbook 5.1 for protocol development and study evaluation. In addition, the network meta-analysis has been registered on the international perspective systematic review register (PROSPERO): CRD42022308580.

Data sources and search strategy

The network meta-analysis will search eight databases, including PubMed, Embase, Cochrane Library, Web of Science, China Knowledge Infrastructure Library (CNKI), China Biology Medicine disc (CBM)), Wanfang Data Knowledge Service Platform, and Vipshop Journal Service Platform (VIP). The search period is from the establishment of the database to January 30, 2022. The keywords include VCI, MCI, VaD, AD, TMS, rTMS, tDCS, TaVNS, TcVNS, vagus nerve and related terms. Table 1 summarized the search details for the relevant terms on PubMed. Table 2 is a summary of the characteristics of some of the published studies in relation to this research. For duplicate publications, we chose to include in this study the literature with the earliest publication date.

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Table 1. Search strategy used in Pubmed database.

https://doi.org/10.1371/journal.pone.0284447.t001

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Table 2. Characteristics of the partially included studies.

https://doi.org/10.1371/journal.pone.0284447.t002

Studies inclusion

Two reviewers will search relevant studies individually based on the studies search strategy, and the results will be compared and supplemented after the search. The two reviewers will eliminate duplicate studies using the NoteExpress check function and read the title, abstract and keywords to eliminate studies which are not relevant to the network meta-analysis, read the full text according to the nadir criteria, and finally include the studies that meet the criteria in the study. We created a PRISMA flow chart to show the whole process Fig 1.

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Fig 1. PRISMA flow chart of study and exclusion.

https://doi.org/10.1371/journal.pone.0284447.g001

Discussion

The trend of modern rehabilitation is not only towards better rehabilitation outcomes, but also the need for non-invasive, simple, inexpensive, home or community-based rehabilitation. Non-invasive neuromodulation technology, as a cutting-edge medical technology whose mechanism of action to promote neuroplasticity, should not be overlooked in the rehabilitation of VCI. Although some of the access mechanisms are not yet clear, they have shown some efficacy in the clinical rehabilitation of VCI. In the network meta-analysis, we will systematically compare the efficacy and safety of various non-invasive neuromodulation techniques and corresponding drug combinations in the rehabilitation of VCI. The results of this network meta-analysis will synthesise direct and indirect evidence [30] to provide a preferred protocol for the intervention of non-invasive neuromodulation techniques in the rehabilitation of VCI [31]. Therefore, we hope that a rigorous network meta-analysis will provide more evidences to support the clinical application of non-invasive neuromodulation interventions in VCI. However, there are some potential weaknesses in the network meta-analysis: on the one hand, the lack of quality of the original studies directly affects the final effect of the network meta-analysis; on the other hand, the difference in the dose of medication administered to the patients and the corresponding parameters in the non-invasive neuromodulation technique may also lead to differences in the outcome. Therefore, we will strictly control the quality of the included studies to provide reliable clinical evidence to support the development of non-invasive neuromodulation techniques in the rehabilitation of VCI.

Supporting information

Acknowledgments

We are grateful to all those who participated in this study.