Behaviour test in chronic brain ischemia rats: A bibliometric approach

Introduction

Stroke causes severe disability and mortality. Moreover, stroke is considered the number one cause of disabilty and independency (Katan and Luft, 2018). Acute and subacute strokes have been targeted with medicines provided within 48 hours after onset, thanks to recent breakthroughs in stroke treatment. Thrombus breakdown using a tissue-type plasminogen activator (e.g, alteplase) within 4.5 hours of stroke onset or mechanical thrombectomy within six hours are two current treatment options. Both of these treatments, however, are only appropriate for a tiny percentage of patients, and not all of them work well (Wardlaw et al., 2014).

Despite the fact that the mechanism of acute stroke is widely recognized, publication on chronic stroke is still limited. Because glial scars mark the location of brain injury and the capacity for reorganization may be substantially reduced, finding new treatments for chronic stroke poses significant challenges. In recent investigations, a paracrine effect has been proposed as a mechanism for improving recovery, implying that when surviving, neurons surrounding the infarction are adequately activated, and have the ability to change function in ways that improve brain function. Replacement of destroyed brain tissue and restoration of missing connections may be necessary for greater improvement and maybe complete recovery. This would necessitate the replacement of neuron, endothelial cells, astrocytes, and supportive cells. Some of these challenges are currently being investigated in animal models, with the expectation of progressing rapidly toward the objective of finding viable treatments for chronic stroke patients (Wechsler et al., 2018).

In stroke research, rodent models are commonly utilized and behavior testing is a crucial tool (Saré et al., 2021). Rodents have various advantages over other species, including quick reproduction, minimal maintenance costs, and more ethical acceptance (Ruan and Yao, 2020). However, rats and humans have quite different neurological behaviors and higher brain processes. Rodents, for example, may only perform tasks that imitate their natural responses, whereas human patients can have their neurological processes tested by answering questions and following directions. This makes determining the outcome of a stroke, particularly in terms of cognitive function and consciousness, problematic.

In measuring stroke outcome and translating rodent findings to therapeutic trials, selecting relevant behavioral tests that fit the study purpose is critical. Although 30-minute temporary middle cerebral artery occlusion (30-min tMCAO) generates consistent infarct in subcortical areas of rats’ brains, the behavioral tests such as the rotarod test, adhesive-removal test, or narrow beam test make it difficult to assess the subsequent neurological loss. The development of a quantitative evaluation method would aid in the development of a unique cerebral infarction therapy approach (Wakayama et al., 2007).

Here, we’ll look at some of the recent publications that have focused on behavior testing in chronic stroke patients. Hopefully, we were able to provide additional information regarding the behavior test, allowing researchers to select the best test for their needs. A bibliometric analysis was used to examine global collaboration patterns, patterns in institutions and countries, as well as to determine trends in studies.

Methods

Results

Articles published

From 1996 to 2022, the Scopus database contained 18 entries relating to “behaviour test in chronic stroke rats”. Three articles were excluded (Macaca article, a Chinese article we were unable to translate, mice-related articles). Figure 1A illustrates the annual publication trend. In 1996, there was only one publication, which then gradually increased year after year until it peaked in 2021 (four publications). The study “behaviour test in chronic stroke rats” received funding from 23 different sources. The National Natural Science Foundation of China (frequency: 4), the National Institute of Neurological Disorders and Stroke (frequency: 3), and the National Institutes of Health (frequency: 2) were the top three primary funding sources (frequency: 3) (Figure 1B).

Figure 1. A. Yearly published articles in the Scopus database between 1996 and 2022. The peak year for publication was 2021. B. The top ten funding sources.

Origin of country and organization

In the 18 papers on “behaviour test in chronic stroke rats” that have been published so far, 12 nations and 49 organizations were identified. The top three countries/regions were China, the USA, and Brazil (Table 1 and Figure 2). With 99 citations, the USA led the pack, followed by Brazil with 63 and China with 52. With two papers and 62 citations, the Department of Neurology at the University of Texas at Houston Medical School in Houston, Texas, was the most productive (Table 1). There were six organizations that collaborated with each other during the publication and other organizations published by their own resource (Figure 3).

Table 1. The publication authors’ country and institutions. The United States, China, and Brazil were the top three countries.

Rank	Organization	Country	Papers	Citations	Connection with others author
1	Department of Neurology, University of Texas - Houston, medical school, Houston, TX, United States	United States	2	62	1
2	Department of Pharmacology and therapeutics, State University of Maringá, av. colombo, 5790, Maringá, Paraná, cep 87020-900, Brazil	Brazil	1	44	1
3	Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 50, Maastricht, 6229 er, The Netherlands	Netherlands	1	44	1
4	Department of Clinical Neurosciences, University of Edinburgh, Edinburgh, United Kingdom	United Kingdom	1	31	2
5	Department of Neurology, Xijing Hospital, Fourth Military Medical University, no. 17 Changle West Road, Xi’an, 710032, China	China	1	31	2
6	Department of Neurosurgery, Institute of Mini-invasive Neurosurgery and Translational Medicine, Xi’an Central Hospital, no. 185 Houzai Gate of North Street, Xi’an, 710003, China	China	1	31	2
7	Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, no. 17 Changle West road, Xi’an, 710032, China	China	1	31	2
8	Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Austin campus, Heidelberg, Australia	Australia	1	31	2
9	University of Tasmania, School of Medicine, Faculty of Health, Hobart, Australia	Australia	1	31	2
10	Department of Neurological Surgery, Neuroscience program, University of Miami Miller School of Medicine, Miami, FL, United States	United States	1	29	3

Figure 2. The top 10 countries of the author of publications.

Figure 3. Organizational co-author analysis using the VOSviewer 1.6.18 network visualization.

A. Six-organizations connected to each other. B. Other organizations that worked alone for their publication.

Authors of publications

In “behavior test in chronic stroke rats,” 96 authors contributed to 18 papers. Milani H placed first (63 citations) with two papers, followed by J Aronowski, J. C Grotta, and R Strong (Figure 4A). The study “behaviour test in chronic stroke rats” had Milani H as the lead author. Figure 4B illustrates that collaboration amongst active authors in this subject is still lacking.

Figure 4. Author co-occurrence analysis.

A. Authors that collaborated in publications. B. Other authors that published independently.

Citations

The circle size denotes the number of occurrences of phrases in the subnetwork of keywords and graph, as shown in Figure 5. The top ten keywords were “animals”, “brain ischemia”, “male”, “article”, “animal experiment”, “animal model”, “rats”, “controlled study”, “animal behaviour”, “animal tissue” (Figure 5A). In the overlaid visualization (Figure 5B), the keywords “animal behaviour” were related to “middle cerebral artery occlusion”, “brain ischemia”, “cognitive function” and “sensorimotor function”. Figure 5C shows the keyword connected with cognitive dysfunction such as “tumor necrosis factor”, “metabolism”, and “inflammation”.

Figure 5. Keywords occurence.

A. The top ten keywords were “animals”, “brain ischemia”, “male”, “article”, “animal experiment”, “animal model”, “rats”, “controlled study”, “animal behaviour”, “animal tissue”. B. Keyword related animal behaviour. C. Keyword related cognitive function.

Discussion

Stroke causes long-term impairment that is sometimes accompanied by debilitating deficits, necessitating immediate treatment. Stroke patients commonly experience motor, sensory, and cognitive impairments, but therapeutic options are limited. Functional results in animal models, in addition to histology measurements, have provided vital information into the molecular basis of experimental stroke and future rehabilitation initiatives. Expanding the development of translational medicines necessitates the creation and use of tests that can identify behavioral impairments.

Selecting relevant behavioral measures that meet the study goal is crucial when monitoring stroke outcome and transferring rodent findings into treatment trials. Although a 30-minute tMCAo generates consistent infarct in subcortical area in rats, behavioural tests like the rotarod test, adhesive-removal test, or narrow beam test make measuring the ensuing neurological damage difficult. The development of a new cerebral infarction therapy technique would benefit from the development of a quantitative evaluation method (Wakayama et al., 2007).

Choosing the appropriate behaviour test in chronic stroke research is difficult since rats’ brains recover well, and even though infarct pathology still exists, behaviour test findings are comparable to normal rats. This is the component about which researchers should ponder long and hard before beginning their study. It’s crucial to use tests that are able to detect the neurological deficits to the injury to the brain and the treatments used. Due to the loss of limb function following a stroke, many tests focus on motor and sensory testing (Lipsanen et al., 2011; Makkiyah et al., 2021; Sun et al., 2016; Wakayama et al., 2007). Because learning and memory problems are frequent after a stroke, cognitive testing is particularly important for determining the full extent of the difficulties (Barros et al., 2009; Dhaliwal et al., 2021; Hei et al., 2018; Yao et al., 2021). As a result, it’s critical to have sensitive behavioural approaches for detecting the wide range of deficits that might arise after a stroke. By recording functional improvements over time, behavioral assessments can also be used to measure the efficiency of pharmacological and cell-replacement treatments.

Since 1996, researchers have been using behaviour tests in chronic stroke patients, with a peak occurring in 2021. The literature was dominated by research from countries like the USA and China. In other areas of stroke research, such as the involvement of ferroptosis in stroke, a similar pattern emerged (Chen et al., 2021).

The MWM test, which is the most common test implemented in the literature has some limitations. It may be difficult to distinguish between a merely cognitive deficit and a possible sensorimotor insufficiency in tMCAO rats because of the unilateral ischemia impairment. There was no significant variation in swim speed or path length during the probing session, indicating that abilitity to swim did not have a role in the cognitive function deficit shown in tMCAO animals. As a result, while the water maze techniques used may provide useful assays for the efficacy of therapeutic interventions targeting the striatum area, other behavioural tests may be more appropriate for measuring rescue area or recovery in injured neocortex areas (Bingham et al., 2012).

Sensorimotor asymmetry is one of the most common signs of stroke, and it can be measured using a variety of behavioural tests, including cylinder test. After a central nervous system injury, the cylinder test was initially used to measure spontaneous forelimb motor performance. It has been used in many publications in research related to behaviour tests in chronic stroke rats (Barros et al., 2009; Huang et al., 2018; Lipsanen et al., 2011; Loris et al., 2017; Makkiyah et al., 2021; Shaafi et al., 2019). The cylinder task has been shown to be objective, simple to use and score, sensitive to chronic issues that other tests overlook, and has strong inter-rater reliability. Furthermore, no prior training is necessary, albeit baseline data is required to assess for pre-operative bias because some animals exhibit independent use of one limb on occasion (Schaar et al., 2010).

Conclusions

Clinical applications and therapeutic effectiveness against stroke could be improved with more collaboration amongst authors. When using a behavior test, researchers need to think about which neurological deficiency is being addressed and whether the test covers long-term evaluation.

Data (and Software) availability

Author contributions

Conceptualization: FD, TS, HM. Data collection and analysis: AI, MC. MA-formal analysis. CB, MB, AC, YH, AI, SW, FZ. methodology. Writing—original draft: YS, TR. Writing—review and editing: MST.