The 100 most‐cited articles about the role of neurovascular unit in stroke 2001–2020: A bibliometric analysis

Abstract Background The neurovascular unit (NVU) is emerging as a potential therapeutic target in neurological conditions, such as stroke, brain injury, Alzheimer's disease, and Parkinson's disease; meanwhile, stroke is the second leading cause of death globally. The purpose of the study is to analyze the most influential articles, authors, countries, and topics in the role of NVU in stroke. Methods The Web of Science (WoS) database was used for bibliometric analysis using the search terms “Stroke” and “Neurovascular unit” on January 1st, 2021. Data were extracted from the WoS database to identify collaborations between authors, countries, organizations, and keywords using VOSviewer (1.6.16 mac). Two bibliometric indicators, the activity index (AI) and category normalized citation impact (CNCI), were computed. The keywords of bursts were also identified by CiteSpace. Results A total of 770 articles were analyzed by VOSviewer. AIs and CNCIs were computed of the eighteen countries according to VOSviewer co‐authorship analysis results. The majority of authors mainly came from the United States and Japan. Romania, Hungary, and Poland have emerged as rising‐star countries. In the 100 most‐cited articles, the number of citations ranged from 1873 to 69, with a total of 15,758 citations. Most articles were published in 2011 and 2012 (n = 13 each), followed by 2009 (n = 11) and 2013, 2014, and 2015 (n = 8 each). Stroke and Journal of Cerebral Blood Flow and Metabolism were the two top journals. EH Lo from Harvard University/ Massachusetts General Hospital was the top first author and corresponding author. Harvard University/Massachusetts General Hospital was the most productive affiliated institution with 15 publications. Conclusion There has been growing attention and efforts made in the field of stroke and NVU. The merit of the above findings may help to shape the research policy in ischemic stroke both at the country and institutional level.


| INTRODUC TI ON
Stroke is the second leading cause of death globally 1 and has become the fifth leading cause of death in the United States, which leaves an enormous burden on patients' families and the society at large. 2 The incidence and mortality of stroke decreased in high-income countries between 1990 and 2010. However, no significant change has been seen in low-and middle-income countries. 1,3,4 Stroke can be divided into ischemic stroke and hemorrhagic stroke, and our studies include both stroke types. Nowadays, with standard treatments such as tissue plasminogen activator (tPA) or thrombolytic therapy and mechanical thrombectomy, 5 more ischemic stroke patients survive the stroke but with complications such as hemorrhagic transformation, cerebral edema, epilepsy, and pneumonia. [6][7][8][9] Microvascular reperfusion injury following mechanical thrombectomy is also an urgent problem to be solved. Thrombolytic therapy requires a narrow time window and is only used in about 7% of patients after an acute ischemic stroke in the United States. 10 One novel thrombolytic, desmoteplase, has been reported to have failed the Phase IIb/III trial with no significant improvement in functional outcome at 3 months, 11 but other thrombolytics and reperfusion agents, such as tenecteplase and stachybotrys microspore triprenyl phenol-7 (SMTP-7), remain in development. 12 Basic studies and clinical trials may uncover nextgeneration thrombolytic drugs or agents that could reduce the risk of thrombolysis-associated hemorrhagic transformation that may allow an extension of the current narrow therapeutic window and reduce the risk of catastrophic brain hemorrhage after stroke. The emergence of the neurovascular unit (NVU) concept provides a new foothold for that research in this regard.
The concept of the NVU, which is comprised of neurons, astrocytes, pericytes, microglia, endothelial cells, and vascular smooth muscle cells that components of the NVU in the central nervous system communicated dynamically with each other and maintained hemostasis of the brain. 13 The interaction and signaling between different components of the NVU are very complicated, and latest advances have shown that the NVU might regulate cerebral blood flow and maintain brain homeostasis through neurovascular coupling or vasculoneuronal coupling. [13][14][15] Meanwhile, it was recently suggested that astrocytes or microglia, which have multiple phenotypes, have controversial effects on the regulation of neuroinflammation or neurovascular coupling and require further investigation. [16][17][18][19] Due to the complexity of the NVU, there has been an increasing number of studies on the NVU in stroke.
However, currently, none of these studies have translated into new stroke treatments. [20][21][22][23][24] Considerable efforts have been devoted to finding effective therapeutic targets and pathways in the NVU for not only ischemic stroke, but also a number of other neurological diseases, such as Alzheimer's disease and Parkinson's disease.
The latest progress and the most vital contributions in stroke and the NVU can be found in the surging number of publications in the field of NVU, including reviews, basic studies and clinical trials.
However, there is no bibliometric analysis of stroke and NVU. It is of great importance to look into the distribution of articles and authors in this field, which would give readers a vivid overview of the most important works in the past two decades.

| ME THODS
We performed a bibliometric analysis on January 1st, 2021 by using the Web of Science (WoS) database using the search terms "Stroke" and "Neurovascular unit" in the title/abstract/keywords between 2001 and 2020. Total citation number and average number of citations for each report of all results were collected in the WoS analysis tool.
Data were extracted from the WoS database to identify collaborations between authors, countries, organizations and keywords within the boundaries of the aforementioned search terms using VOSviewer (1.6.16 mac). Co-authorship analysis and co-occurrence analysis were performed, and the number of authors, countries, organizations, and keywords was based on the choice of a minimum number of documents or occurrences. Two bibliometric indicators, the activity index (AI) and category normalized citation impact (CNCI), were computed. AI indicates the relative research effort of a country to a research field based on publications. The CNCI of an article is the ratio of the observed number of citations to the expected number of citations. If AI or CNCI was greater than 1, then the research power or the academic influence of a country was higher than the global average, and vice versa.
The initial results were then filtered in descending order of the number of citations in WoS to find the 100 most-cited articles. The article title, number of citations, publication year, journal, journal impact factor (IF), first author, corresponding author, country/institution of the corresponding author, and study type were collected.
Eight articles were excluded after reviewing the title, abstract, and whole text of these papers by two experienced anesthesiologists in our group. Study type was accessed by the two doctors mentioned above reading the full text. These data were then imported to Microsoft Excel for analysis manually. The keywords of bursts were also identified by CiteSpace.

| S E ARCH RE SULTS
We found 774 articles in the initial search of the WoS database under the search terms "Stroke" and "Neurovascular unit." Of these papers, 20 176 reports had cited these articles, with a total citation number of 28141. The average number of citations for each report was 36.26.
Seven-hundred and seventy articles were analyzed by VOSviewer after excluding one withdrawn article and three patent documents.
The result of co-authorship analysis, which includes 27 authors with >9 reports, is shown in Figure 1A. Among the 27 authors, two of them were not connected to each other. Two different clusters of authors were identified, which represented American and Japanese authors. The result of country co-authorship analysis is shown in Figure 1B. A minimum of 8 publications per country was required for the country to be included in the analysis. Three different clusters of countries were identified, which represented the USA, European, and East Asian countries. We also performed organization co-authorship analysis and keywords co-occurrence analysis.
Nineteen organizations and 20 keywords that met the threshold are shown in Figure S1. The size of the circle is weighted by documents or occurrences of the author, country, organization, and keyword.
The thickness of the connecting lines reflects the strength of collaborations. The color of each circle represents the order of time, the more yellow the color is the closer the time, whereas purple is the farthest in time.
We computed AIs and CNCIs of the eighteen countries accord-

| Characteristics of the 100 most-cited reports
The top 10 most-cited articles-reviews and the top 10 most-cited articles-basic studies are listed in Tables 2 and 3. Details of the 100 most-cited articles are listed in descending order of the total number of citations (Table S1)  In terms of the publication form, the articles could be divided into the following categories (Table 6) The impact of microglial activation on blood-brain barrier in brain diseases 223 ACC da Fonseca book chapter (n = 1), and editorial material (n = 1). In the 70 reviews, seven articles discussed the topic of blood-brain barrier (BBB), fol-   give readers a more in depth understanding of current development of the field. were likely to contribute their articles to more influential journals in one field. Thus, we searched the latest papers in these two journals for progress in stroke and the NVU. One paper suggested that caveolin-1 might have a potential protective role in neovascularization, astrogliosis, and scar formation. 27 Meanwhile, nitroxide radicalcontaining nanoparticles (RNPs) could preserve the endothelial tight junctions and BBB integrity, improving oxygen species scavenging capacity. 28 The total citation number of "stroke" and "neurovascular unit" related publications in these two journals adds up to 5161 between 2004 and 2016.
Since the majority of the publications related to "stroke" and "neurovascular unit" were from the United States, we also analyzed the specialties of these authors. We found that most of the authors were also prominent in the field of traumatic brain injury, 29 vascular cognitive impairment, 30,31 and neuroimaging, 32,33 suggesting that the NVU is a field that is getting multidisciplinary attention.
In terms of the publication types, most of the 100 most-cited articles were reviews, and one-third were basic studies. The red blocks represented the begin, the end, and the duration of citation bursts microRNA, and PPARγ were also investigated in these basic studies, providing pre-clinical insights into the development of potential therapeutic strategies.
Although many of the above treatments have proved effective in animal stroke models, none have proved effective in treating stroke patients in clinical trials until now, 34 perhaps due to differences between animal models and humans. Meanwhile, stroke patients often have comorbid disease, such as hypertension, diabetes, hyperlipemia, and even aging, 2,14,35,36 which might impact the effectiveness of the therapy. Accurate animal models that better match with the stroke population should be established and the role of NVU in stroke requires further investigation. The above findings may help to shape research policy both at the country and institutional level.

| Limitations
One of the major limitations of the current study is that we used only "stroke" and "neurovascular unit" as search terms; thus, a lot of studies that did not use the NVU term may have been missed. Another limitation is that given the fact that citations gradually reach a peak

CO N FLI C T O F I NTE R E S T
We declare there is no conflict of interest among all the authors.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding author.