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Thematic analysis of multiple sclerosis research by enhanced strategic diagram

This bibliometric review summarised the research trends and analysed research areas in multiple sclerosis (MS) over the last decade. The documents containing the term"multiple sclerosis"in the article title were retrieved from the Scopus database. We found a total of 18003 articles published in journals in the English language between 2012 and 2021. The emerging keywords identified utilising the enhanced strategic diagram were"covid-19","teriflunomide","clinical trial","microglia","b cells","myelin","brain","white matter","functional connectivity","pain","employment","health-related quality of life","meta-analysis"and"comorbidity". In conclusion, this study demonstrates the tremendous growth of MS literature worldwide, which is expected to grow more than double during the next decade especially in the identified emerging topics.


Introduction
Multiple sclerosis (MS) is an autoimmune chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. 1 MS is characterised by inflammation, demyelination, astroglial growth (gliosis) and neurodegeneration. 2 Reversible neurological deficits occur in the early phases of MS, characterised by clinically isolated syndrome and relapsing-remitting MS (RRMS), whereas secondary progressive MS (SPMS) is hallmarked by progressive neurological deficits and clinical disability. 1 Less than 10% of MS patients have primary progressive MS (PPMS), which means the disease has progressed from the outset. 1,2 Across developed and developing countries, MS prevalence has climbed since 2013. 3   VOSviewer software (1.6.17) was used to map the author's keywords, which used data in .csv format. It is a popular application with a simple graphic interface that can be used to build coauthorship network maps of authors, countries, citation analysis, and keywords co-occurrence. 9 This method is especially beneficial for this study since its keyword co-occurrence analysis enables the identification of key research subjects and the detection of major research clusters linked to MS research. VOSviewer supports the introduction of a thesaurus file that can be used for data cleaning by integrating multiple forms of terms (e.g. biomarker and biomarkers, experimental autoimmune encephalitis and eae) to improve the correctness of the analysis. 10 The median values for occurrence, total link strength (TLS) and average publication year were calculated based on the data obtained from VOSviewer.

Database: Scopus
Theme networks, an overlay network and enhanced strategic diagrams (ESDs) were the three key results of our study. We have plotted the enhanced strategic diagram with the x-axis representing centrality, the y-axis representing density and the z-axis representing time, which is a three-dimensional plane based on a study by Feng et al. 11 The degree of interaction between networks is measured by centrality. 11,12 A theme with a higher centrality score has more external connections to other themes (external strength), thus has a greater impact on the field's development and evolution. 11-13 A node having 10 social connections, for example, would have a degree centrality of 10. 14 The higher the centrality score, the more central a topic is within the whole study field under consideration. 15 Thus, the mean strength value of external linkages to other subjects such as TLS was used in this study to determine centrality. The TLS values that were equal or higher than its median value were considered as high while those lower than its median values were considered as low centrality.
In contrast, the density of a topic is used to determine its internal strength or degree of interaction within a network. 11,12 In this study, co-occurrences of the author's keywords were used to determine the density. As for centrality, the median value was calculated and the cooccurrence values equal or higher than its median value were considered as high while those below it were considered as low density. The novelty of the topic, however, is represented by time 11 and in this study, the average publication year was used. In terms of novelty, the median value of average publication year was determined, and average publication years equal to or more than its median was deemed novelty, while those below it were considered old.

The trend of annual publications from 2012 to 2021
During the 2012-2021 period, 18003 articles on MS were retrieved from Scopus. In the first five years, 44.7% of these articles were published, while 55.3% were published in the second five years. There was a steady growth in the number of publications from 2012 through 2018 but rapid growth was observed in 2019. As to date, the highest number of articles was published in 2020 with a total of 7171 citations. Figure       However, the overall growth rate of publications was similar i.e. around 82%.
Science mapping capability to portray the conceptual structure of scientific subjects is unique. 16 In this study, we found five conceptual clusters (themes) in MS literature: management, psychosocial rehabilitation, animal experiment, neuroimaging, and epidemiology. Cluster 1 (management) has the most terms (28), followed by Cluster 3 (animal experimentation, 22), Cluster 2 (neuropsychological rehabilitation, 19), Cluster 5 (epidemiology, 18) and Cluster 4 (neuroimaging, 11 keywords). This could indicate that MS management research is currently the most popular and has the biggest volume. 17 Our results identified several core topics in each cluster/theme of MS research. These topics were the most frequent and had strong external links. For example, "fingolimod", diseasemodifying therapies" and "safety" were the core topics under management theme. Many studies related to these topics were published recently. [18][19][20] Under animal experiment theme, "multiple sclerosis", "biological marker", and "inflammation" were the core topics. Biological markers were useful in the context of inflammatory disorders to precisely describe the immune response and prospective therapeutic targets, as well as to better understand the etiopathogenesis and monitoring of disease activity and treatment response. 21 They play a diagnostic role 22 as well as predict disability progression, monitor ongoing disease activity and assess treatment response in MS. 23 Under the neuropsychological rehabilitation theme, the core keywords were "fatigue", "anxiety" and "exercise". While new disease-modifying medications are useful in slowing disease progression and neurological decline, there is no effective pharmacological treatment for fatigue. 24 Physical exercise significantly reduces fatigue 26 in MS patients, but there is insufficient data support for anxiety. 26 The core keywords under neuroimaging theme were "cognition", "cognitive impairment", and "brain atrophy". Cognitive impairment is present in all MS phenotypes, 27 with a prevalence of 43-70% depending on phenotype and cognitive diagnostic criteria utilised. 28 Structural correlates of cognitive impairment include white matter and grey matter damage, brain atrophy and network modifications. 29 Under the epidemiology theme, the core keywords were "epidemiology", and "edss". Expanded Disability Status Scale (EDSS) is a commonly used measure of disability for MS in various studies including epidemiology studies. 30,31 The emerging keywords in MS literature include "covid-19", "teriflunomide", "clinical trial", "microglia", "b cells", "myelin", "brain", "white matter", "functional connectivity", "pain", "employment", "health-related quality of life", "meta-analysis" and "comorbidity", while "pregnancy" was the emerging keyword with higher density. These keywords has the potential to expand. For example, coronavirus disease-19 (COVID-19) has become a major concern for medical professionals across the board including management of MS patients who are often on immunosuppressive drugs. With the pandemic, the therapeutic landscape for MS has shifted, and it will undoubtedly continue to do so in the near future. 32 While clinical trial and teriflunomide were the emerging topics under management theme, based on the case reports, teriflunomide was safe and used as the first-line treatment for MS patients with COVID-19. 33 The emerging keywords in the animal experiment theme include "B cells", that has recently been identified as the main mechanism in the pathogenesis of MS, 34 and "microglial", which has a role in rescuing oxidized phosphatidylcholines (oxPC)-induced neurotoxicity 35

in MS.
Under the psychosocial rehabilitation theme, the emerging keywords were "health-related quality of life", "pain", and "employment". Various symptoms including pain affect the employment status and quality of life of working-age adults with MS. 36 Furthermore, according to a recent study, the impact of MS on health-related quality of life (HRQOL) in real-world patients may be underestimated. 37 A new review also emphasises the need for rehabilitation in fostering daily life involvement in MS patients, as part of a comprehensive plan to address present and future issues. 38 "Brain", "white matter" and "functional connectivity" were the emerging keywords under neuroimaging theme. Several diffusion magnetic resonance imaging (MRI) studies have found that MS patients have lower structural connectome, 38 which is best explained by the disruption of long-range white matter tracts 39 and the disconnection of the major hubs such as the thalamus and nodes of the default-mode brain network. 40 A functional connection such as resting-state functional MRI (rs-fMRI) was another growing area under this theme and is increasingly being employed to investigate the aetiology of cognitive impairment in MS patients. 41 Finally, under the epidemiology theme, the most frequent keywords were "meta-analysis" and "comorbidity". In recent years, comorbidities in patients with MS have piqued researchers'