Cerebral Small Vessel Disease: A Bibliometric Analysis

Cerebral small vessel disease is a common neurological disease, and its incidence is increasing year by year worldwide. In recent years, research on cerebral small vessel disease has gained more and more attention. Our research aims to visualize publications to identify the hotspots and frontiers of cerebral small vessel disease research, and to provide reference and guidance for further research. Publications related to cerebral small vessel disease were searched from the Web of Science Core Collection and screened according to inclusion criteria. CiteSpace 5.8.R3 was used to evaluate and visualize results, including generating web maps and analyzing annual publications, countries, institutions, bibliographic and co-cited references, and keywords; in this article, we use CiteSpace and VOSviewer for the 2012 Cerebral small vessel disease and bibliometric analysis from January 1, 2022 to April 30, 2022. A total of 3037 papers related to cerebral small vessel disease were retrieved, and the number of published papers showed a steady upward trend. Among them, Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration, the most symbolic references in the field of cerebral small vessel disease have been cited a total of 438 times. Stroke is the most active journal (227 articles) and USA publishes up to 800 articles. Harvard Med SchUniv Edinburgh (133 papers) and Charidimou (85 papers) are the institutions and authors who have made the most contributions in this field, respectively. Among the keywords, most of them are related to the pathogenesis of cerebral small vessel disease. After 2018, gut-brain axis and cortex are the keywords with the strongest number of cited outbreaks. There is increasing evidence that cerebral small vessel disease is a research frontier and may remain a research hotspot in the future.


Introduction
Cerebral small vessel disease (CSVD) is a common neurological disease, a group of diseases with small perforating arteries and arterioles (diameter 40-200 μm), capillaries, and venules of the brain as the main lesions. It is the most common cause of vascular dementia, accounting for 25% of ischemic strokes and most hemorrhagic strokes (Agirman et al. 2021). It is commonly associated with Alzheimer's disease and exacerbates the resulting cognitive impairments, which are responsible for approximately 50% of dementias worldwide (Arba et al. 2019;Bai et al. 2022). In China, lacunar infarction caused by cerebral microvascular disease accounts for 25 to 50% of ischemic stroke, which is higher than that in Western countries (Bordes et al. 2022). It is foreseeable that CSVD will be a major disease affecting the quality of life of the elderly in the future (Thrippleton et al. 2019). Therefore, CSVD will be a great challenge in the field of encephalopathy, and its underlying pathogenesis needs to be further studied.
In recent years, cerebral small vessel disease has gained more attention in various research fields, and numerous academic journals have published articles related to CVSD research. However, few studies have systematically investigated the scientific achievements and current state of the field from a worldwide perspective (Du et al. 2022). Therefore, it is extremely important to use visual analysis to reveal the global status, future research trends, and hotspots of CSVD research. Bibliometric science not only provides quantitative and statistical analysis of publications in a specific field but also accurately reveals the most representative studies. In addition, by presenting massive data in the form of knowledge graphs, researchers can comprehensively analyze the development of a discipline and intuitively understand cutting-edge trends. Through CiteSpace, our surveys are based on the following: national networks, authors, institutions, annual publications, categories and references, and co-occurrence keyword analysis and clustering. Findings can benefit researchers by shaping future research directions and informing policy formulation (Ma et al. 2021;Sabe et al. 2022). Bibliometrics, first defined by Pritchard in 1969, is a visualization method that quantitatively evaluates the contributions of research fields using methods such as mathematics and statistics (Ma et al. 2021). Bibliometrics can not only accurately reveal research trends in a certain field but also an important method to predict research hotspots and frontiers (Sabe et al. 2022). Therefore, we used CiteSpace and VOSviewer to conduct the bibliometric analysis of the research on small vessel disease from 2012 to 2022 to investigate the research progress and hotspots in the field of cerebral small vessel disease and to help researchers quickly understand the research of cerebral small vessel disease The status quo and the development of research strategies to provide some literature data support for researchers' research on cerebral small vessel disease (Shen et al. 2022).

Source of Bibliometric Data and Search Strategies
Selecting the Web of Science Core Collection (WOSCC) as the main data source for data retrieval, WOSCC is a canonical online database which is considered to be the most suitable database for bibliometric analysis (Yao et al. 2020). The data retrieval time was from January 1, 2012 to April 30, 2022, and the set retrieval formula is [subject = (cerebral small vessel disease)] and [language = (English)] and [year range = (2012-2022)], the search results were de duplicated, and the inclusion criteria were the following: according to the document type, only articles were included, and the language was limited to English. Exclusion criteria were the following: delete conference calls, comments, news, reviews, errata, etc., and delete studies not related to cerebral small vessel disease (Guo et al. 2021). With reference to other studies, the title and abstract were reviewed by two independent researchers. As of April 30, 2022, 3037 publications were finally screened in the Web of Science database. Since the set time span does not include the literature for the 8 months after 2022, the data for 2022 is not complete, and the research analysis does not represent the whole year. Considering that the database is updated regularly, all data are obtained within 1 day to avoid potential discrepancies. The flow chart of the research data analysis is shown in Fig. 1. The data used in this study were downloaded directly from public databases without further animal experiments, so the approval of the ethics committee or informed consent was not required.

Data Export and Extraction
The WoSCC database is considered the most suitable one for bibliometric analysis and is widely used for biometric analysis and visualization of scientific literature. The search parameters are set as follows: time slice (years per slice) is January 1, 2012 to April 30, 2022, years per slice (1), links (strength = cosine; scope = within slices); selection criteria (g-index, k = 25), pruning (pathfinder + pruning sliced network); node types select "Author," "Keyword," "Institution," "Country," "Reference," "Cited Author," "Cited Journal"; selection criteria (g-index, k = 25). CiteSpace 5.8.R3 is used for visual data analysis analyzing keywords, co-cited references, and trends. A visual map created by the VOS viewer (Leiden University Science and Technology Research Centre, Leiden, The Netherlands) has nodes representing countries, institutions, authors, or keywords, which can be connected by co-authors, citations, co-citations, and co-occurrence analysis. We use the VOS viewer to perform a similar analysis of countries or regions, map their evolution, classify keywords with high co-occurrence frequencies into clusters, and create density visualization (Zhan et al. 2022).

Publication Outputs and Trends
A total of 3037 articles related to cerebral small vessel disease were retrieved. In order to investigate the research trend of cerebral small vessel disease, as shown in Fig. 2, the number of papers published each year was displayed in the form of a histogram. From 2012 to 2021, the number of related publications has increased year by year, which indicates that the research on cerebral small vessel disease is paying more and more attention. As of April 30, 2022, 143 papers have been published in 2022. The sum of the citation frequency is 53,506, and the average citation frequency of each article is 17.6.

Fund Source
The ten major funding sources are shown in Table 1

Countries and Institutions
A map of the geographic distribution of global publications shows that articles on cerebral small vessel disease are mainly published in Europe, North America, and Asia ( Fig. 3). All publications were published in 78 countries. Table 2 lists the top 10 countries and institutions for cerebral small vessel disease publications; USA is the country with the largest number of publications (800), followed by China (662 articles), and the Netherlands (424 articles), USA was cited the most (23,608 times) and reached the highest H-index (71). Figure 4 shows that USA attaches great importance to cooperation and has close cooperation with China, France, South Korea, and Italy. The top 10 institutions

Journal Analysis
A total of 3037 articles related to cerebral small vessel disease were published in 74 journals.

Author Analysis
Among the 3037 papers related to cerebral small vessel disease research, Table 4 lists the top 10 authors with the most published papers. Andreas and Charidimou published the most papers (85 papers), followed by Joanna M. Wardlaw and Hugh S. Markus, There are 78 and 76 papers, respectively; all of them are authors who have a certain influence in the field of cerebral small vessel disease. Figure 6 shows the co-occurrence map of authors in the study of cerebral small vessel disease.

Reference
From 2012 to 2022, a total of 3037 publications were visually analyzed using CiteSpace 5.8.R3, and a co-citation analysis of references was performed. After setting parameters, a visual co-citation map of the identified documents was generated. Table 5 lists the 10 most cited references during the study period, which not only laid the foundation for further research on the mechanism of cerebral small vessel disease but also provided a theoretical basis for the study of cerebral small vessel disease. The most cited paper is "Neuroimaging standards for research into small vessel disease and its contribution to aging and neurodegeneration" published by Wardlaw et al. (2013), with 438 citations. Figure 7 shows the co-occurrence map of the first author of the literature.  (Fig. 8). Through the network visualization analysis of keywords through VOS viewer, a keyword co-occurrence map of cerebral small vessel disease is generated, as shown in Fig. 9, and it is determined that synonyms and similar keywords will be merged in the research on cerebral small vessel disease from 2012 to 2022. After combining synonyms and similar keywords, the top 20 ranked keywords in terms of frequency can be seen (Table 6).

Keyword Cluster Analysis
Cluster analysis is performed on the basis of keyword cooccurrence analysis, and tag clustering is performed by the likelihood ratio (LLR) algorithm (Yao et al. 2020). As shown in Fig. 10, the cluster modularity Q value is 0.3935, while the mean contour value S value is 0.711. Generally speaking, a Q value > 0.3 represents a significant clustering structure; if the average cluster contour value S > 0.5, the clustering is generally considered to be reasonable. If the S value > 0.7, the clustering result is considered convincing. A total of 9 clusters were formed by keywords in this study, which to a certain extent demonstrated the knowledge structure and dynamic change process in the field of cerebral small vessel disease. Cluster analysis was conducted according to the similarity of keywords. The results showed that the current research on cerebral small vessel disease mainly focuses on three aspects: ① #0 and #7 are disease research fields, mainly related to the sequelae caused by cerebral small vessel disease, including keywords such as stroke, dementia, cognitive impairment, etc.; ② #1, #3, and #4 are pathological changes of cerebral small vessel disease, mainly   (Harshfield et al. 2022), including lacunar cerebral infarction, white matter lesions, cerebral microbleeds, enlarged perivascular space, and brain atrophy and recent small subcortical infarct (see Table 7).

Keyword Co-occurrence Analysis
According to the detection of emerging words with high frequency and fast growth rate within a period of time, keywords with high-burst intensity are an important indicator reflecting research hotspots, frontiers, and latest trends (Fig. 11). A total of 25 emergent words were detected, Fig. 7 Reference co-occurrence map Fig. 8 Timeline view of reference clustering. Nodes represent keywords (the bigger the circle, the more frequently it appears), and the labels of the clusters are listed on the right, where # 1 is cerebral microbleeds, # 2 is perivascular spaces, # 3 is cerebral amyloid angiopathy, # 4 is cerebral amyloid angiopathy, # 7 is arterial stiffness, # 8 is diffusion tensor imaging, and # 9 is Alzheimer's disease and the Rotterdam scan had the highest burst intensity (intensity = 15.42), followed by white matter lesion (intensity = 7.94), and outcm (intensity = 7.33). It is worth noting that "national institute" (2018-2022, 5.04), "outcm" (201--2022, 7.33), "gut-brain axi" (2019-2022, 5.95), "connectivity" (2019-2022, 5.81), "cortex" (the citation burst of keywords such as 2020-2022, 5.26) continued until 2022, indicating that these research directions are likely to become new research hotspots in the future.

General Information
We performed a bibliometric analysis of 3037 articles related to cerebral small vessel disease. As shown in Fig. 2, the number of global publications on cerebral small vessel disease has shown a steady upward trend. Currently, 143 articles have been published in 2022, although the  data for 2022 is incomplete, and it is expected that the production of articles in 2022 will increase, which indicates that research related to cerebral small vessel disease is increasingly attracting the attention of scholars. Bibliometric analysis takes the global literature pattern and literature characteristics as research objects, including countries, institutions, authors, and journals over a period of time (Liu et al. 2019). In terms of country/ regional analysis, research centers in this field are concentrated in Europe, North America, and Asia. The USA is the most productive country, with a much higher number of publications than other countries/regions, which is closely linked to funding sponsorship by funding agencies. In terms of research institutions, strengthening the cooperation between different institutions or teams is extremely important for future basic or clinical trials of cerebral small vessel disease. Among the published journals, Stroke, Neurology, and Journal of Stroke Cerebrovascular Diseases are the top 3 journals with the most publications. Andreas, Charidimou, Joanna M. Wardlaw, and Hugh S. Markus are among the top 3 authors in the field of cerebral small vessel disease by volume. Fig. 10 Timeline view of keywords. Nodes represent keywords (the bigger the circle, the more frequently it appears), and the labels of the clusters are listed on the right, where # 0 is a blood brain barrier, # 1 is perivascular space, # 2 is cognitive impairment, # 3 is cerebral microbleeds, # 5 is cerebral blood flow, # 7 is an atomic fiber, and # 8 is artistic stiffness

Bibliography Analysis
Co-citation analysis is generally used as a method to evaluate the academic influence of journals or scholars (Di Donato et al. 2017), who are all authors with certain academic influence (Dong et al. 2022). Wardlaw et al. published the most influential papers with the most citations (438 times). Through further research, it was found that Wardlaw et al. (Dong et al. 2022) published several articles mainly on the mechanism, clinical significance, and aging and neurodegeneration of cerebral small vessel disease. Lau et al. (2017) found that a higher total CSVD score was associated with an increased risk of recurrent ischemic stroke. In therapy, Wardlaw et al. (2019), (Lau et al. 2017) found emerging targets for new therapies including brain barrier integrity, vascular reactivity, vascular compliance, perivascular inflammation, or myelin repair. Shi and Wardlaw (2016) believed that new research should consider drugs targeting the endothelium and blood-brain barrier to prevent and treat CSVD. At the same time, changing traditional risk factors and healthy lifestyles are also an important prevention and treatment method.

Hotspots and Frontiers
In terms of different forms of coexisting disease of CSVD, as Alzheimer's disease and cerebral small vessel disease (CSVD) often coexist (Chojdak-Lukasiewicz et al. 2021), the interaction between the two is unclear (Kim et al. 2020). Pathologically, wall damage can lead to external expansion of microaneurysms due to fibrosis and proximal lumen stenosis or obstruction (Chou et al. 2021). Ultimately, impaired autoregulation of the involved small vessels results in decreased cerebral blood flow and chronic cerebral hypoperfusion (Litak et al. 2020), and occlusion of the arterial lumen leads to acute ischemia, leading to lacunar infarction (Tang and Liu 2021;Kim and Lee 2015). Severe stenosis and hypoperfusion involving multiple arterioles, mainly deep white matter, leading to incomplete ischemia, are seen on neuroimaging as "white matter hyperintensity" (WMH) Biesbroek et al. 2017). The two pathophysiological pathways above may often overlap, so lacunar and white matter lesions often coexist. CSVD studies the coexistence of different forms, and this field has received less attention and should be strengthened.

Research on Cerebral Small-Vessel Disease and White Matter Disease
The main symptoms of CSVD patients include lower extremity motor dysfunction characterized by gait disturbance and cognitive dysfunction characterized by impaired executive function Biesbroek et al. 2017). White matter lesions (WMLs) are more common in the elderly. The symptoms of WMLs are subtle, such as cognitive impairment, dementia, and depression (Manyangu et al. 2019;Putilina 2019). They are usually symmetrically distributed in the white matter including the pons and brain stem on imaging, and also in the deep gray matter Hashimoto et al. 2016). White matter hyperintensity (WMH) is the most important predictor of gait dysfunction, and more severe WMH-related defects are located in the internal capsule, hemi-egg center, periventricular frontal lobe, etc. (Kang et al. 2022;Wang et al. 2022). The number of lacunar infarcts is a predictor of executive dysfunction, presumably due to damage to the frontal-subcortical circuit, reduced connectivity and metabolism within the prefrontal cortex, and ultimately executive dysfunction (de Laat et al. 2011). However, the pathogenesis of white matter disease (WML) and lacunar infarction has not yet been fully explained. The role of cortical thickness remains unknown. There is a lack of attention in this area, and cortical studies in cerebral small vessel disease should be strengthened (de Leeuw et al. 2002).

The Effect of Brain-Gut Axis on Cerebral Small-Vessel Disease
Gut-brain axis is a bidirectional pathway between the gastrointestinal system and the central nervous system (He et al. 2018), involving nerves, endocrinology, immunity, etc. The gut microbiota has a symbiotic relationship with enterocytes and plays an important role in digestion (Markus 2021). The gut microbiota maintains bidirectional interactions with major parts of the central nervous system through direct and indirect pathways (Tonomura and Gyanwali 2021;Nelson et al. 2021). Microbial components may enhance systemic inflammation and amyloid fibril formation, ultimately leading to amyloid deposition and brain microvascular systemic inflammation caused by gut microbiome or microbiome metabolites may affect brain parenchyma (Camara-Lemarroy et al. 2018). Studies have shown that the gut microbiome is associated with characteristics suggestive of the presence of CSVD, and that the gut microbiome or its metabolites may influence the presence of CSVD through the microbiome gut-brain axis (Niemarkt et al. 2019). The influence of the brain-gut axis on cerebral small vessel disease is a new direction. At present, there are few studies in this field, and more attention should be paid to this field.

Study on Drug Intervention of Intestinal Flora in the Treatment of Cerebral Small-Vessel Disease
We found a role for chronic systemic inflammation in the pathophysiology of CSVD. Systemic and vascular inflammatory states have been found to be associated with the development and prognosis of CSVD (Bouasquevisque et al. 2019). The peripheral immune system, including innate and adaptive immune cells, plays a crucial role in the pathophysiology of CSVD (Cardona and Escrig 2018). Neutrophils infiltrate CSVD lesions across the blood-brain barrier (BBB), and their sustained release of the BBB to disrupt matrix metalloproteinase 9 (MMP9) has been identified (Tonomura and Gyanwali 2021). The researchers found that circulating monocytes in patients with CSVD had increased cytokine production capacity . The release of central nervous system (CNS) antigens into the peripheral circulation leads to the development and activation of CNS antigen-specific lymphocytes. Multiple inflammatory mediators derived from activated immune cells contribute to the development of CSVD (Zanon et al. 2021;Zhou et al. 2021). Systemic and vascular inflammatory factors synergistically drive the progression of small vessel disease (Tonomura and Gyanwali 2021). Addressing the immune response of injured brain endothelium and the BBB may be a promising therapeutic strategy . Ongoing interactions between the gut microbiota and the host immune system have important implications for the induction, functional modulation, or suppression of local and systemic immune responses (Jian et al. 2020). The field of drug intervention of intestinal flora in the treatment of cerebral small vessel disease is almost blank, and it is also one of the main research trends in the future. Research in this field should be strengthened. The treatment of small vessel disease has more options and may have breakthrough effects.

Conclusion
We analyzed the research progress, hotspots, and frontiers in this field; studied cerebral small vessel disease through bibliometric analysis; and revealed the future research prospects. Currently, research on cerebral small vessel disease is in a rapid development stage, and since 2012, publications related to cerebral small vessel disease have steadily increased. At the same time, we identified leading countries, institutions, and leading scholars in the field and analyzed journals and representative literature. Cortex and gut-brain axis are the latest research hotspots through keyword cooccurrence analysis and burst graph emergence detection. It is worth noting that the mechanism of cerebral small vessel disease is still unclear and needs further study. While this study searched the largest database, it may have missed some studies beyond the scope of the database. Future reviews may search multiple databases. Despite its limitations, this novel study is the first to synthesize nearly 10 years of cerebral small vessel disease research and will serve as an important addition to the existing knowledge base. In conclusion, bibliometric analysis provides objective insights into the research of cerebral small vessel disease, full of opportunities and challenges.

Declarations
Ethics Approval This paper has been approved by the ethical review board of the Guangxi University of Chinese Medicine.

Conflict of Interest
The authors declare no competing interests.
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