Bibliometric Analysis on Literature of Working Memory on the Patients with Epilepsy in China

Corresponding Author:

Qing Liu
Zhejiang University of Technology, Hangzhou, China

Abstract

In order to provide scientific support and pave new avenues for future studies of superior cognitive function in patients with epilepsy, we systematically sorted the data of working memory research about Chinese epileptics by using bibliometric analysis. Our analysis found: (1) studies in the working memory of Chinese patients with epilepsy were rarely reported; (2) these studies are related to working memory impairment of epileptics, its factors and neurobiological underpinnings; (3) questionnaires and laboratory experiments were the main methodology used in these studies. Though some valuable results were gained from studies involved in working memory of Chinese patients with epilepsy, further research should be devoted to improve cognitive function of epileptics by using working memory training, strengthen interdisciplinary collaboration, and explore how to conduct psychological intervention for epileptics who received working memory training.

Keywords

Epilepsy; Working memory; Bibliometric analysis; Chinese

Introduction

Epilepsy is a group of neurological disorders featured by epileptic seizures [1,2]. The characteristic of epilepsy is recurrent, unprovoked and transient dysfunction of central nervous system induced by neurons abnormal discharge (Guidelines to Chinese Epilepsy Diagnosis). The syndromes of epilepsy not only include commonly clinical epileptic seizures, but also contain different degrees of cognitive impairment characterized by impairments of memory, language, attention and executive function. Moreover, cognitive impairments could severely disrupt life of patients with epilepsy, and the severity of epilepsy is associated with the type of seizures, the age of onset and antiepileptic treatment [3].

Working memory, as the core of advanced cognitive functions, is defined as a system to temporarily store information during individuals executing cognitive tasks [4]. The formation of working memory requires complicated cohesive coordination of several brain areas [5]. As epilepsy tends to induce seizures in a long term, we can speculate that the damage of working memory in these patients might be physiological and functional. In the present bibliometric analysis study, we summarized articles and reports related to working memory of patients with epilepsy which published on Chinese professional journals, in order to systematically outline the research status of working memory studies in Chinese patients with epilepsy, provide scientific supports and pave new avenues for future studies of advanced cognition in epilepsy.

Methods

We conducted a retrieval of all documents involved in working memory and epilepsy by using China National Knowledge Infrastructure (CNKI) on 1st November 2019. Firstly, keywords (epilepsy, working memory) were used to search documents. Secondly, the index mode was precisely match. Thirdly, the index range was entire. These three index conditions yielded a list of 21 papers.

The selection of studies includes two steps. The first step was to read title and abstract of the research article. The second step was to read the full text. Both steps were conducted by a dedicated doctor of psychology. The search results were selected with following criteria: (1) empirical research reflecting research results by quantitative value; (2) research subjects including patients with epilepsy; (3) research method including working memory tasks; (4) published on Chinese professional journals. Finally, 13 documents were recruited for the quantitative analysis.

Results

• Publication details

The publication time of 13 documents ranged from 2009 to 2019. Specific content is shown in Table 1. Thirteen documents were published on three different types of journal. Four documents were published on journals of university (30.7%), seven documents were published on journals of medical science (53.8%), and the rest on journals of biophysics (15.4%). The specific information is shown in Figure 1.

Figure 1:Document type of research focused on epileptic working memory in China.

• Research methods

Authors of these 13 documents came from two kinds of institutions which is school of medicine in university (2, 15.4%) and hospitals (11, 84.6%). Methodology used in these working memory studies was based on behavioral research (7, 53.8%) and brain functional research which included functional magnetic resonance imaging (fMRI) study (5, 38.5%) and electroencephalography (EEG) study (1, 7.7%), the details are shown in Table 1.

Table 1: Participant demographics involved in cognitive capability test.

Table 2: Cognitive capability test of patients with epilepsy.

• Research subjects and tools

Subjects involved in these studies contained adult (12, 92.3%) and children (1, 7.7%) with epilepsy. Thereinto, five documents were related to idiopathic epilepsy (38.5%). Seven documents (53.8%) and one (7.7%) document were related to symptomatic epilepsy and cryptogenic epilepsy, respectively. As for research tools, the digit span task and verbal fluency test were the most common tool to measure the capacity of working memory (6, 46.2%). Two studies used the n-back task (15.4%) and other two studies used delayed match task and its variants (15.4%). Self-revised working memory/executive function test was also used in two studies (2, 15.4%). Besides, one research (7.7%) used restingstate MRI scanning to assess visual and spatial working memory network (Table 2).

• Research contents

Two research articles were related to the status of working memory in patients with epilepsy (15.4%). Research about pathophysiological basis of working memory impairment in patients with epilepsy accounted for the biggest part in these 13 documents (6, 46.2%). And five studies were involved in factors associated with working memory of epileptic patients (46.2%).

Discussion

• Working memory impairment of epileptic patients

Epilepsy is a common neurological disorder which characterized as neurons abnormal discharge inducing transient central nervous system dysfunction. Long-term epileptic seizures could result in cognitive impairment, such as working memory impairment. As working memory is the core of advanced cognition, its impairment could lead to dysfunction of cognitive activities such as reading, problem solving and logical thinking [6].

Studies involved in working memory of patients with epilepsy were still rare in China. The study of Ma and Zhou (2009) used basic cognitive capability test to investigate cognitive capability of children with primary or cryptogenic epilepsy and normal children [7]. Their results showed that there was no significant difference in intelligence between children with epilepsy and normal children. However, children with epilepsy got lower scores in basic cognitive capability test compared with normal children. Except the scores of the double-word recognition test, the average scores of other tests (number recognition test, Chinese characters rapid comparison test, mental arithmetic practice test, digit symbol test, meaningless images recognition test and rotation variant recognition of handprinted Chinese characters) also decreased. Yang et al. [8] conducted neuropsychological assessment for patients with temporal lobe epilepsy and patients with frontal lobe epilepsy by using working memory test, auditory verbal learning test and Rey-Osterrieth complex figure test. Their results demonstrated that the scores of frontal lobe epilepsy group and temporal lobe epilepsy group in working memory, attention and executive capability was lower than that of control group. Moreover, the performance of frontal lobe epilepsy group in attention, working memory, control/inhibition ability, verbal memory and nonverbal memory was worse than temporal lobe memory group.

Basic conclusions can be drawn from the above, cognitive impairment is an inevitable result for patients with temporal lobe epilepsy as well as clinical epileptic seizures. However, results showed that patients with epilepsy in remission may have the same opportunity to receive education and work as normal people, and the neuropsychological function of them is also at normal stage [9]. This indicated that the processes of cognitive impairment in epileptic patients may be reversible. Therefore, physicians should pay attention to basically cognitive capability of patients with epilepsy during therapeutic procedures so that side effects of treatment could be reduced.

• Influence factors in working memory research of epileptics

Epilepsy could damage brain neurons and morphological changes of synapses, which leads to impairment of memory [10,11]. For patients with epilepsy, the severity of working memory impairment is different from each patient due to type of seizure, causes of disease, usage of medication and individual variations [12]. In China, studies involved in the influence factors of working memory impairment of epileptic patients mainly included several aspects as follows:

Firstly, individual variations of epileptic patients influenced their working memory performance. Wu and Xiang used Hamilton depression scale, visual-object and visual-space working memory task to explore depression and visual working memory of patients with epilepsy. It found that patients with epilepsy had higher level of depression and worse performance of working memory in contrast to healthy people [13]. They also found that depression could influence performance of epileptics in visual working memory test. Besides, in the study of Zhou and Xiao, they recruited adult patients with idiopathic epilepsy or symptomatic epilepsy and healthy adults whose gender, age, marriage and education were matched with each patient as subjects [14]. After that, they used Behavior Rating Inventory of Executive Function-Adult version (BRIEF-A) to study characteristics of executive function and its effects in adult patients with idiopathic epilepsy or symptomatic epilepsy [15]. The results demonstrated that the executive function index of epileptics was worse than that of control group. Besides, the type of seizures, epileptic frequency and usage of antiepileptics were strongly related to the performance of executive function.

Secondly, antiepileptics could influence performance of working memory in patients with epilepsy. Specifically, the study of Song and colleagues (2014) [16] used adult patients with partial epilepsy as subjects to investigate the effects of levetiracetam on cognition and electrical activities of brain. Their results demonstrated that the EEG of these patients was the same before and after levetiracetam treatment. Epileptic discharge of patients diminished or decreased at least 50% after 12 weeks of levetiracetam treatment. Moreover, the performance of patients in cognition test was better than that of before treatment. In another study of Song, they used enzyme-linked immune sorbent assay (ELISA) to measure the serum level of glial fibrillary acidic protein (GFAP) combined with trail making test, digit symbol test, digit span test and verbal fluency test to investigate the relation between serum level of GFAP and cognition in patients with epilepsy [17]. The results showed that serum level of GFAP in patients with epilepsy was negatively correlated with patients’ performance in digit symbol test and verbal fluency test, while positively correlated with patients’ performance in trail making test.

Thirdly, subclinical epileptiform discharges have effects on cognition such as working memory. Song and Li recruited idiopathic epilepsy patients with generalized tonic-clonic seizure as subjects to investigate the relation between serum level of insulin-like growth factor 1 (IGF-1) and cognition [18]. The results demonstrated that serum level of IGF-1 in subclinical epileptiform discharges group was higher than normal EEG group. And serum level of IGF-1 in subclinical epileptiform discharge group was negatively correlated with performance of cognition in patients with epilepsy.

According to conclusions above, these studies not only investigated the effects of seizures type, etiology and psychological variations on working memory from perspective of individual differences, but also disclosed the effects of antiepileptics on working memory from the perspective of pathology.

• Pathophysiology of working memory impairments in epilepsy

In recent years, more and more studies showed that structural abnormality and abnormal intrinsic functional connectivity of brain are speculated as the causes of neuropathy and mental disorders [19-22]. As an advanced cognition, normal function of working memory requires working memory networks consisted of cerebral cortex (frontal lobe, parietal lobe and temporal lobe), cerebral subcortex and cerebella properly works [23]. Investigating the pathophysiology of epileptic’s working memory could be helpful to understand the mechanism of epileptic’s cognitive impairment and enrich the research of working memory networks. Studies related to mechanism of epileptic’s working memory in China mainly involved in several aspects as follows:

Firstly, from the perspective of structure and function, some studies used fMRI to reflect working memory impairment of patients with epilepsy. The study of Wei used fMRI to study working memory of epileptic patients when they were conducting the working memory task [24]. Compared with control group, the activities of dorsolateral prefrontal cortex, bilateral parietal lobe, thalamus, basal ganglia and hippocampus in TLE patients were down-regulated while the activities of some brain areas (precuneus and bilateral cingulate gyrus) were up-regulated. In Wang’s study, the results of fMRI showed that when conducting 2-back working memory task, TLE patients had a worse performance and lower activation level of forehead and parietal brain area than that of control group [25].

Some other studies used the resting-state fMRI to extract working memory networks and compare the differences between patients with epilepsy and normal group. Huang et al. used the resting-state fMRI combined with digit span test to study verbal working memory (VWM)’s functional connectivity and its relation with cognition in patients with left temporal lobe epilepsy (LTLE) [26]. They found that the scores of LTLE group in digit span test were lower than that of control group. And the strength of functional connectivity among left prefrontal cortex, bilateral parietal lobe and the right cerebellar cortex was significantly decreased in LTLE group, while the scores of LTLE group in digit span test was independent with the strength of functional connectivity. In study of Lv et al, they used resting-state fMRI to compare spatial distribution and functional connectivity of visuospatial working memory (VSWM) between groups based on group independent component analysis method. Patients with right temporal lobe epilepsy and normal group were recruited as subjects [27]. Results showed that there was no difference in distribution of VSWM related brain networks between RTLE group and healthy control. However, when RTLE group was under resting-state, the functional connectivity of brain networks of VSWM in right dorsolateral prefrontal, right parietal lobe (BA8) and left inferior parietal lobe was weaker than that of control group. As for the functional connectivity in BA10, left cerebellar lobe and right superior parietal lobule, RTLE group was stronger than healthy people.

Secondly, some studies recorded brain electrical activities to investigate the processes of working memory impairment in patients with epilepsy and damage severity of different components of working memory. Ni and colleagues [28] investigated the role of hippocampus in goal match enhancement and time processes of goal match enhancement by implanting deep brain stimulation in bilateral hippocampus of patients with epilepsy.The findings demonstrated that the left hippocampus played an important role in the goal match enhancement. Moreover, the enhancement effect was detected after 600-650ms of stimulation. Zhu and colleagues [29] they used EEG to study properties of theta oscillations of working memory in patients with frontal lobe epilepsy (FLE). They collected signals of theta oscillations under resting-state state and delayed match task. The results showed that FLE group had a delayed response in working memory task in contrast to control group. In addition, in FLE group, the energy density of Fz electrode and frontal theta oscillations in resting-state were significantly increased compared with control group while decreased in delayed match task.

The studies above indicated that studies related to the pathophysiology of working memory on Chinese epileptic patients gave us a holistic map of working memory impairment in these patients to some extent. Specifically, the neural basis of working memory is a network which includes frontal lobe as dominant component combined with several brain areas of parietal lobe and temporal lobe. Patients with epilepsy have different damage severity of impairment on working memory brain areas and networks when performing working memory tasks or staying at resting state. The absence of theta oscillations in latency of working memory might be one of the mechanisms. Besides, hippocampus plays a vital role in working memory tasks related to spatial locations. Goal match enhancement effect happened after perceptual processes, which indicated that different components of working memory were separated in hippocampus. However, it is also required more studies involving in properties and mechanisms of working memory impairment so that working memory impairment in epilepsy could be prevented or decreased.

According to studies above, controlling seizures, avoiding multi-drug therapy, selecting new antiepileptics with little side effects and monitoring therapeutic effect by recording brain electrical activity regularly might be the effective methods to prevent or decrease working memory impairment in epileptic patients. At the same time, The role of diet and food quality has been shown to be important with relevance to working memory performance and the control of epilepsy. Dietary activators are important to the activation of genes that are important to memory performance and the prevention of epilepsy. Controlling seizures by avoiding multidrug therapy, use of new antiepileptics and monitoring therapeutic effects may be linked to diet and food quality to decrease working memory impairment in epileptic patients in China [30-33].

Declaration of Interest

The authors have declared that no competing interests exist.

References

1. Falco-Walter JJ, Scheffer IE, Fisher RS. The new definition and classification of seizures and epilepsy. Epilepsy. Research 139(1), 73-79 (2018).
2. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia55(4), 475-482 (2014).
3. Jehi L. The epileptogenic zone: concept and definition. Epilepsy.Currents 18(1), 12-16 (2018).
4. Quigg M, Gharai S, Ruland J, et al. Insomnia in epilepsy is associated with continuing seizures and worse quality of life. Epilepsy. Res 122(1), 91-96 (2016).
5. Viteva EI. Seizure frequency and severity: How really important are they for the quality of life of patients with refractory epilepsy. Ann. Indian. Acad.Neur 17(1), 35-42 (2014).
6. Baddeley A. Working memory. Science 20(4), 136-140 (2010).
7. Baddeley A. Working memory: theories, models, and controversies. Annu. Rev. Psychol63(1), 1-29 (2012).
8. Engle RW. Role of working-memory capacity in cognitive control. Curr. Anthropol 51(1), 17-26 (2015).
9. Ma C, Zhou N. Study of the basis cognitive ability in children with idiopathic or cryptgenic epilepsy. Acta. Universitatis. Medicinalis. Anhui44(3), 389-391 (2009).
10. Yang E, Yu Q, Bai X, et al. Study of cognitive function features in temporal lobe and frontal lobe epilepsy. Journal. Of. Tianjin. Medical.University 19(1), 70-72 (2013).
11. Hessen E, Lossius MI, Reinvang I, et al. Predictors of neuropsychological impairment in seizure-free epilepsy patients. Epilepsia 47(11), 1870-1878 (2006).
12. Verrotti A, Matricardi S, Rinaldi VE, et al. Neuropsychological impairment in childhood absence epilepsy: Review of the literature. J.Neurol .Sci 359(1), 59-66 (2015).
13. Vlooswijk MC, Jansen JF, de Krom MC, et al. Functional MRI in chronic epilepsy: associations with cognitive impairment. Lancet.Neurol 9(10), 1018-1027 (2010).
14. Bell B, Lin JJ, Seidenberg M, et al. The neurobiology of cognitive disorders in temporal lobe epilepsy. Nat. Rev. Neurol 7(3), 154-164 (2011).
15. Wu C, Xiang Z. The study of depression and visual working memory on epilepsy. Chinese. Community. Doctors 14(4), 178-179 (2012).
16. Xiao GZ. Features and influencing factors concerning the ecological executive function of adult epileptics. Acta. Universitatis. Medicinalis. Anhui 52(2), 248-251 (2017).
17. Song Y, Zhao, X. The relation of GFAP level and cognition in epilepsy. Shandong.Medical. Journal 55(45), 91-92 (2015).
18. Li N, Song Y. Cognitive function and insulin-like growth factor-1 levels in patients with subclinical epileptiform discharges. Chin. J .Brain. Dis. Rehabil5(4), 10-13 (2015).
19. Doan NT, Kaufmann T, Bettella F, et al. Distinct multivariate brain morphological patterns and their added predictive value with cognitive and polygenic risk scores in mental disorders. NeuroImage: Clinical 15(1), 719-731 (2017).
20. Collin G, Scholtens LH, Kahn RS, et al. Affected anatomical rich club and structural–functional coupling in young offspring of schizophrenia and bipolar disorder patients. Biol. Psychiat 82(10), 746-755 (2017).
21. Chai XJ, Hirshfeld-Becker D, Biederman J, etal. Altered intrinsic functional brain architecture in children at familial risk of major depression. Biol. Psychiat 80(11), 849-858 (2016).
22. Itahashi T, Yamada T, Nakamura M, et al. Linked alterations in gray and white matter morphology in adults with high-functioning autism spectrum disorder: a multimodal brain imaging study. NeuroImage. Clinical 7(1), 155-169 (2015).
23. Darki F, Klingberg T. The Role of Fronto-Parietal and Fronto-Striatal Networks in the Development of Working Memory: A Longitudinal Study. Cerebral. Cortex 25(6), 1587-1595 (2015).
24. Wei F, Tao L, Lu G, et al. Impaired working memory in left medial temporal lobe epilepsy revealed by functional MRI. Acta. Biophysica.Sinica 27(10), 859-865 (2011).
25. Wang Y, Chen Zi, Wu X. Preliminary study of Bold-fMRI for dignital working memory of patients with temporal lobe epilepsy. Funct. Mol. Med. Imaging (Electronic Edition) 2(3), 187-194 (2013).
26. Huang W, Zheng J, Lu F, et al. Resting state fMRI study of the cerebral network of verbal working memory in patients with left temporal lobe epilepsy. Journal. of Clinical. Radiology2014; 33(5): 662-666.
27. Lv Z, Zheng J, Chen Z, et al. The cerebral network of visuospatial working memory in patients with rTLE: A resting state fMRI study. J. Apoplexy.And. Nervous. Diseases30(12),1098-1101 (2013).
28. Ni B, Qian C, Wu R, et al. Timing of goal match enhancement in the hippocampus revealed by human intracranial recording. Progress. In. Biochemistry.And. Biophysics38(11), 1027-1035 (2011).
29. Zhu J, Li H, Song Y. The study of the theta oscillation characteristic for working memory in frontal lobe epilepsy. Tianjin. Med. J 45(4), 393-397 (2017).
30. Adrian M. Dieting and Food Cue-Related Working Memory Performance. Front. Psychol 7(1), 1944 (2016).
31. Amy C. Reichelt, R. Fred W, Margaret JM. Editorial: Impact of Diet on Learning, Memory and Cognition. Front. Behav. Neurosci 11(1), 96 (2017).
32. Martins IJ. Antimicrobial activity inactivation and toxic immune reactions induce Epilepsy in human. J .Med .Discov; 2(4), JMD 17040.
33. Martins IJ. Food Quality and Advances in Pharmacological Management Prevent Mitochondrial Apoptosis and Epilepsy Induced Stroke. Research and Reveiws: Neuroscience 2(1), 7-9 (2018).