Validity and Reliability of Event Related Potential in Subacute Stroke

The aim of this study was assess the test-retest reliability of the ERP and resting EEG test in subacute stroke patients. Additionally, we compared the validity of the EEG, ERP test to MMSE (Mini-Mental State Exam) and MoCA (Montreal Cognitive Assessment) to use it as an objective tool to evaluate cognitive function. We recruited 20 patients with subacute ischemic stroke who were 19 years of age or older and had an MMSE score of 20 or higher. All participants were tested K-MMSE (Korean Mini Psychostatistics Test) and K-MoCA (Korea-Montreal Cognitive Assessment). The resting-state EEG and P300 wave using an auditory and visual oddball paradigm were measured at baseline and once again in 24 hours. We calculated the brain symmetry index (BSI) and directional BSI (BSIdir) over different frequency bands and delta/alpha ratio (DAR). The intra-rater reliability and validity of the P300 latency, amplitude, BSI, BSIdir and DAR were measured by intra-class correlation (ICC) analysis and by Pearson`s correlation coecient analysis, respectively. P300 latency showed excellent ICC level (auditory P contralesional, ICC = 0.918, visual P contralesional, ICC = 0.972, visual Pz, ICC = 0.945). In the visual ERP (latency), there was a signicant correlation between Cz, C ipsilesional and Mini-Mental State Exam (MMSE) and C ipsilesional and Montreal Cognitive Assessment (MoCA). The P contralesional and Pz latency of visual ERP showed signicant reliability, and the Cz and C ipsilesional of visual latency showed effectiveness in reecting the cognitive function. Thus, these montages could be used as a basis for future studies. observed reliable and constant results for resting-state EEGs, and the auditory and visual P300 amplitude and latency, our sample size was small. Furthermore, this study was conducted on patients with subacute supratentorial ischemic stroke. Therefore, the ndings cannot be generalized to patients with chronic or infratentorial ischemic stroke. Further studies on different patient populations are warranted.


Introduction
Cognitive impairment is observed in 12%-56% of stroke patients, and one in three patients exhibit persistent cognitive impairment despite adequate treatment [1]. Cognitive impairment after stroke may disrupt functional recovery and rehabilitation [2]. In clinical settings, cognitive impairment after ischemic stroke is usually diagnosed using neuropsychiatric examinations (e.g., Korean Wechsler Adult Intelligence Scale). However, these examinations yield different results depending on patient compliance, and are often complex and time-consuming. Therefore, researchers need an objective method that can help assess cognitive impairment regardless of patient compliance [3]. Event-related potential (ERP) is a potential derived from the electrical activities of the cerebrum, which appears for a certain time after auditory or visual stimulation [4]. ERP allows non-invasive analysis of the electrophysiological phenomena induced by cerebral cortex stimulation for the evaluation of brain function [5]. ERP is a reproducible electrophysiological response to external stimuli and indicates the

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The analysis results were noted as IL and CL according to the lesion. P3 maximum latency was de ned as the time from the start of the stimulus to the point of positive amplitude [14]. The peak amplitude was chosen as the amplitude [14], and the time window was chosen based on the average of the overall data of all sessions.
Cognitive test K-MMSE and Korean-Montreal Cognitive Assessment (K-MoCA) were conducted when participants were transferred to the Department of Rehabilitation Medicine. K-MMSE comprises 30 criteria to evaluate orientation, memory, attention and calculation ability, language, and spatial-temporal construction ability. The test was conducted one-on-one with the examiner. There was no time limit. Each item was worth one point. If the given task was performed correctly, one point was assigned. A point of 0 was assigned when the participant failed to conduct the given task. The K-MoCA was developed to evaluate mild cognitive impairment. K-MOCA evaluated cognitive functions such as executive ability, attention, concentration, memory, vocabulary, visual-spatial ability, abstraction, calculation, and orientation. The maximum score was 30 points. A score of 23 points or higher was considered normal. If the participant had less than six years of education, an extra point was given.
Ethical procedure This study was approved by the Chungnam National University Hospital institutional review board (IRB number: 2020-03-014-001). The study's purpose and method were explained to all participants in detail. A written consent form was obtained from every participant. All studies were performed in accordance with relevant guidelines/regulations. In addition, research was conducted in accordance with the Declaration of Helsinki.

Statistics
The amplitude and latency of each montage of auditory and visual ERP were recorded. The mean and standard deviation for each montage from the results of the two measurements were calculated. In the reliability analysis, Pearson sc or relationcoefficientwasmeasuredf or DAR, BSI, audi → ry, visualP300amplitude, and latency, whichweremeasuredtwice → evaluateth s correlation coe cient, K-MMSE, and K-MoC were used for DAR, BSI, auditory, visual P300 amplitude, and latency.

Demographic and clinical characteristics
A total of 20 participants with seven men and 13 women were included in this study. The mean age of the participants was 63.2±10.3 years. A total of 14 and 6 patients stroked on the right and left side, respectively, and 6 and 14 patients had cortex and subcortex lesions, respectively. The mean score for K-MMSE was 25.8±3.1. The mean score for K-MoCA was 22.4±3.0. MMSE, MoCA, EEG, and ERP were conducted on an average of 17.05±5.0 days after stroke onset (Table 1). We calculated the mean and standard deviation of latency and amplitude of the rst and second tests for auditory and visual ERP ( Table 2, 3).
In the auditory ERP, latency was not signi cantly correlated to the rst ERP. In the second ERP, F CL was signi cantly correlated with MMSE language, and C CL was signi cantly correlated with MoCA total, MoCA abstraction, and MoCA recall.
In the rst auditory ERP (amplitude), there was a signi cant correlation between C CL and MMSE recall, between Cz and MMSE recall, between C CIL and place. In the second auditory ERP, there was a signi cant correlation between C CL and MMSE place, between C CL and MMSE recall, between Cz and MMSE total, between Cz and MMSE recall, between C IL and MMSE place, between C IL and MMSE recall, and between C IL and MoCA abstraction. (Table 13, 14,15,16,17,18,19,20) In the rst visual ERP (latency), there was a signi cant correlation between Cz and MMSE (sum) and between C IL and MMSE (sum), attention & calculation, language, MoCA (sum), visuospatial and executive (MoCA), and attention (MoCA). In the second visual ERP, there was a signi cant correlation between C IL and visuospatial and executive (MoCA) and between P IL and attention (MoCA).

Discussion
In this study, we conducted resting-state EEGs, auditory ERPs, and visual ERPs in ischemic stroke patients to assess test-retest reliability of the three tests. We assessed the correlation between cognitive function and signi cantly reliable montages to evaluate concurrent validity.
In test-retest reliability, excellent ICC level was observed for P CL (ICC = 0.918), visual ERP latency P CL (ICC = 0.972), and Pz (ICC = 0.945) of auditory ERP latency. In addition, test-retest reliability was higher in the visual ERP than in the auditory ERP.
In the visual ERP (latency), Cz and MMSE (sum) were negatively correlated, showing higher MMSE (sum) for short latency. Moreover, C IL was negatively correlated with MMSE (sum) and MoCA (sum). Thus, the shorter the latency, the higher the MMSE and MoCA scores. Thus, measuring these montages of visual ERP showed high correlations with cognitive function in stroke patients. In the concurrent validity test with MMSE, C IL had higher values than Cz, more correlated with Cz than C IL.
In a study conducted by Hall et al. in 2006, latency and amplitude of auditory P300 were measured in 40 healthy monozygotic twin pairs. ICC of latency and amplitude was 0.88 and 0.86, respectively, with latency having a higher ICC level. Similarly, in this study, we compared the latency and amplitude of auditory and visual ERPs. There were 6 and 4 reliable channels for the latency and amplitude of auditory ERP, respectively. Conversely, there were 9 and 7 reliable channels for the latency and amplitude of visual ERP, respectively, showing a higher number of reliable channels. Additionally, the ICC level was higher for latency than for amplitude.
Cognitive decline after ischemic cerebral infarction is a common sequela and manifests as a de cit in attention, memory, information process speed, language, conceptual thinking, working memory, and executive functions [17]. As there is a lack of studies that have conducted multi-modal EEG and evaluated each montage and cognitive function, our ndings can suggest directions for future studies.
The mean age of the participants was 63.2 ± 10.3 years. The mean Fz, Cz, and Pz latencies of the auditory ERP were 252.3 ± 72.3, 273.4 ± 55.6, and 320.8 ± 76.4 ms, respectively. In a previous study conducted by Kim et al. in 1997, the mean Fz, Cz, and Pz in participants aged 60-69 years was 378.44 ± 32.9, 378.44 ± 32.99, and 378.63 ± 33.02 ms, respectively, which was longer than that in our study [18]. Similarly, Hong et al. in 2013 reported an auditory P300 latency of 311.3 ± 37.0 ms in healthy individuals, which was longer than our nding. In our study, the Cz amplitude of the auditory ERP was 1.5 ± 0.85 µV, which is greater than 4.95 ± 3.35 µV for the auditory P300 amplitude in healthy individuals in a study by Hong et al [19]. This suggests that patients with subacute stroke have smaller amplitudes of Cz compared to those in healthy individuals.
In another study by Dejanovic, M., et al. in 2015, the Fz, Cz, and Pz latencies of the auditory ERP were 423.5 ± 37.6, 429.9 ± 40.6, and 433.8 ± 35.0 ms, respectively, which were delayed compared to those in our study. Moreover, the Fz, Cz, and Pz amplitudes of the auditory ERP were 8.17 ± 3.47, 8.44 ± 3.16, and 6.76 ± 2.74 µV, respectively, with greater potentials than those in our study [3].

Limitations and Future directions
Although we observed reliable and constant results for resting-state EEGs, and the auditory and visual P300 amplitude and latency, our sample size was small. Furthermore, this study was conducted on patients with subacute supratentorial ischemic stroke. Therefore, the ndings cannot be generalized to patients with chronic or infratentorial ischemic stroke. Further studies on different patient populations are warranted.
The study participants had K-MSSE scores of greater than 20 points. Thus, the ndings may not be applicable to patients with lower MMSE scores. In future studies, patients with more severe stroke need to be evaluated to assess the neuronal correlation between the resting-state EEG, ERP, and cognitive function.
Lastly, we maintained the temperature and humidity at constant levels.

Conclusion
Herein, we evaluated the consistency and reliability of cognition-related EEG data in stroke patients. The P CL and Pz latency of visual ERP showed signi cant reliability, and the Cz and C IL of visual latency showed effectiveness in re ecting the cognitive function. Thus, these montages could be used as a basis for future studies.

Declarations Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. All data generated during this study are included in this published article.      Table 7 is not available with this version.            Caption not included with this version.

Figure 2
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