VISUAL EVENT-RELATED POTENTIALS UNDER EXTERNAL EMOTIONAL STIMULI AS EARLY SIGNS FOR MILD COGNITIVE IMPAIRMENT

 

C. Wang^1,2, W. Yu¹, T. Xu1, H. Zeng³, A. González-Cuello², E. Fernández-Villalba², F. Xu³, F. Chu¹, M.T. Herrero², M. Tao¹

 

1. The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China; 2. Clinical & Experimental Neuroscience (NiCE), Biomedical Research Institute of Murcia (IMIB), Institute for Aging Research (IUIE), UniWell, Campus Mare Nostrum, School of Medicine, University of Murcia, Murcia, Spain; 3. School of Computer Science and Technology, Hangzhou Dianzi University, Hangzhou, China

Corresponding Author: Dr. Ming Tao, M.D. The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Binwen Road 548, Hangzhou, 310053, Zhejiang, China, Email: taoming@zcmu.edu.cn, Dr. María Trinidad Herrero, M.D., Ph.D. Clinical & Experimental Neuroscience (NiCE), Biomedical Research Institute of Murcia (IMIB), Institute for Aging Research (IUIE), School of Medicine, University of Murcia, Murcia, 30120, Spain, Email: mtherrer@um.es

J Prev Alz Dis 2024;
Published online April 2, 2024, http://dx.doi.org/10.14283/jpad.2024.72

 

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Abstract

BACKGROUND: Alzheimer’s disease (AD) is a neurodegenerative disorder featured by progressive cognitive decline, which manifests in severe impairment of memory, attention, emotional processing and daily activities, leading to significant disability and social burden. Investigation on Mild Cognitive Impairment (MCI), the prodromal and transitional stage between normal aging and AD, serves as a key in diagnosing and slowing down the progression of AD. Numerous effects have been made up to date, however, the attentional mechanisms under different external emotion stimuli in MCI and AD are still unexplored in deep.
OBJECTIVE: To further explore the attentional mechanisms under different external emotion stimuli in both MCI and AD patients.
DESIGN/SETTING/PARTICIPANTS/MEASUREMENTS: In 51 healthy volunteers (Controls, 24 males and 27 females), 52 MCI (19 males and 33 females), and 47 AD (15 males and 32 females) patients, we administered the visual oddball event-related potentials (ERPs) under three types of external emotional stimuli: Neutral, Happiness and Sadness, in which the components N1, P2, N2 and P3 as well as the abnormal cortical activations corresponding to the significant ERP differences in the three groups were observed.
RESULTS: Under all three external emotions, in AD patients, N2 and P3 latencies were significantly prolonged compared to both Controls and MCI. In addition, under Happiness, in MCI, P3 latencies were significantly delayed compared to Controls. Meanwhile, under both Happiness and Sadness, in AD patients, P3 amplitudes were significantly decreased compared to Controls and MCI, respectively. During N2 time window, under Neutral emotion, significant hypoactivation in the right superior temporal gyrus was found in AD patients compared to Controls, and under Happiness, the activation of the right inferior frontal gyrus was significantly attenuated in MCI compared to Controls. Under Sadness, in AD patients, the activation of the right superior frontal gyrus was significantly decreased compared to MCI. During P3 time window, under both Happiness and Sadness, when AD patients compared to MCI, the significantly attenuated activations were located in the right fusiform gyrus and the right middle occipital gyrus, respectively.
CONCLUSION: Our results demonstrated visual attentional deficits under external emotional stimuli in both MCI and AD patients, highlighting the function of Happiness for early detecting MCI, in which the P3 latency and the hypoactivation of right inferior frontal gyrus during N2 time window can be early signs. The current study sheds further light of attentional mechanisms in MCI and AD patients, and indicates the value of emotional processing in the early detection of cognitive dysfunction.

Key words: Alzheimer’s disease, emotional stimuli, event-related potentials, P300, mild cognitive impairment.

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Introduction

Age related diseases are becoming more and more prominent worldwide due to the increased life expectancy. Alzheimer’s Disease (AD), the leading cause of dementia, accounts for 60-80% of all cases and is expected to influence 139 million population in 2050 (1). AD is characterized by deteriorated cognitive functions such as memory, language, and problem solving along with impaired daily activities (2), in which the senile plaques and neurofibrillary tangles combined with massive neuronal loss are particularly developed in hippocampus and neocortex (3). However, it might take at least 10-20 years from the presence of neuropathological hallmarks to the onset of clinical symptoms (4), leading to a huge challenge in its early diagnosis and prevention. Indeed, the diagnosis of AD and Mild Cognitive Impairment (MCI), the prodromal and transitional stage between normal aging and AD when cognitive dysfunctions have not significantly affected daily activities, are remains difficult due to the essence of disease itself or the limitation of present diagnostic methods (5). Since the noticeable conversion rate from MCI to AD compared to that from normal aging (10-15% vs. 1-2% per year) (6), increasing attention has been diverted to MCI and the research on this stage might provide a potential window in early detection of AD, in order to slow down its progression.
Despite numerous studies have demonstrated that episodic memory dysfunction is the most dominant manifestation of AD, attentional impairments significantly correlated with the decline in functional ability and decreased quality of life have also been observed early in AD (7). In addition, AD patients showed impaired emotional processing concerning identification, discrimination, labeling, or matching (8), which seems a major disturbance in AD and might provide hints for clinical diagnosis (9). For instance, previous studies have exhibited that the capacity to decode positive emotions is preserved in AD, whereas the ability to identify negative ones appears to be diminished (10). The atrophy and functional changes in medial temporal lobe including hippocampus which play a critical role in emotional processing and regulation (11), are among the earliest neural markers of MCI and AD (12, 13). Moreover, the difficulty in social interactions and neuropsychiatric symptoms such as agitation and aggression have been related to the impaired emotional processing in AD (10, 14).
Attention can be categorized into two neural networks: one is dorsal, top-down network responsible for voluntary and goal-directed selective process based on prior knowledge, current goal, and future plan; the other is ventral, bottom-up network activated by salient or unexpected stimuli with noticeable features (15). Damaged top-down but relatively preserved bottom-up attentional network has been exposed in AD (16). Meanwhile, it is well known that cognitive or attentional functions can be regulated by emotions, that is, emotional stimuli help to capture attentional resources and enhance memory (17). However, MCI and AD patients showed difficulty in spontaneously and rapidly orienting attention to emotionally salient features of facial expression (18-20). Similarly, in an eye-tracking study, impaired early emotional attention was reported in AD when exposed to emotional visual stimuli other than emotional faces (21). This study also argued that AD was still able to process emotional information in low attentional load conditions (e.g. with long presentation time or fixation) (21). Furthermore, Yiend (22) argued that emotional stimuli which biased the resource deployment of attention would exacerbate attentional blink, might resulting in the insufficient attention to subsequent target stimuli thereby.
Due to the characteristics of cost-effective, non-invasive, and superior temporal resolution, event-related potentials (ERPs) which reflect cortical synaptic function and brain neuronal activity have been successfully utilized in detecting attentional and cognitive variations of neuropsychiatric disorders. The ERP N1 and P2 components reflect primary sensory processing of incoming information and early allocation of attention to external stimuli, respectively (23, 24). N2 is involved with voluntary cognitive processes manifested in identification and discrimination to target or deviant stimuli (25). P3 which is one of the most studied components in cognitive decline correlates with central resource allocation and voluntary processing of attention, working memory, and decision making (26), where P3 latency indicates the speed of neural information processing and the amplitude denotes the ability to allocate top-down attentional resources (27). On the other hand, potential ERP biomarkers have been put forward in the early diagnosis of MCI and AD. The principal alterations of ERP components in MCI and AD were prolonged latency and declined amplitude, especially in N2 and P3 components which provided relatively satisfied sensitivity and specificity in diagnosing MCI as well as AD (5). When combining with emotional materials, Asaumi et al. (18) administrated emotion-loaded visual ERPs on elderly people and found prolonged P3 latency and decreased amplitude in AD compared to healthy controls and MCI under both positive and negative emotions. One study detected neural activities under specific emotions in AD and showed that declined activations were observed in left insula/frontal operculum when processing happy facial expression, while left medial prefrontal cortex when dealing with sadness (28). Furthermore, the decreased frontal with pronounced temporal activations were reported in MCI and AD regarding P3 response (29). Facial expression recognition deficits which primarily focus on the early ERP components such as P1, N170, and VPP have been fully investigated in AD (e.g., 30, 31). However, clear pictures of cerebral attentional function in MCI and AD under external emotional stimuli, that is, stimuli used to elicit emotions through external procedures (e.g., pictures, film clips, 32), remain poorly understood and need to be further investigated.

 

Methods

Participants

The expected total sample size (n = 158) was calculated by the following settings: effect size = 0.25, α = 0.05, power (1-β) = 0.8, and group = 3 using F test in G*Power (version: 3.1.9.7). Ultimately, 150 participants were recruited from the psychiatric clinics and communities in Zhejiang, China. 51 healthy volunteers (Controls, 24 males and 27 females; age range: 58-82 years, mean ± S.D.: 69.25 ± 6.69 years); 52 MCI (19 males and 33 females; age range: 60-82 years, mean ± S.D.: 70.33 ± 6.57 years); and 47 AD (15 males and 32 females; age range: 59-81 years, mean ± S.D.: 71.87 ± 5.44 years) patients. Through a semi-structured clinical interview, all participants were confirmed to have no other confounding factors including cerebrovascular disease, head injury, Parkinson’s disease, personality disorder, schizophrenia or substance abuse. By an experienced psychiatrist (MT), MCI patients were diagnosed based on Peterson criteria (33) with the score of Clinical Dementia Rating (CDR, 34) as 0.5, while AD patients according to National Institute of Aging-Alzheimer’s Association (NIA-AA, 35) with CDR scores as 1 ~ 2. There were no significant differences among the three groups regarding gender (χ2 = 2.52, df = 2, p = 0.284) or age (F (2, 147) = 2.14, mean square effect (MSE) = 84.36, p = 0.122). Significant differences were found as to educational level in the three groups when classified into lower (≤ 9 years of education) and higher level (> 9 years) (χ2 = 31.43, df = 2, p < 0.001), with Controls were more educated than both MCI and AD patients. The majority of MCI and AD patients in this study were diagnosed for the first time, only one participant in MCI group and two in AD group were with the duration of disease ranging from 1 to 3 years. When needed, two co-authors (CW and TX) were available to assist participants in filling out the questionnaires and completing the ERP tests. The study protocol was approved by the local ethics committee (No. 2021-KL-021-01) and all participants had provided their written informed consent before participating in this study (the informed consents of AD patients were signed by family members).

Questionnaires

All participants were asked to complete three self-assessment questionnaires, i.e., Cognitive Abilities Screening Instrument (CASI, 36), the Montreal Cognitive Assessment (MoCA, 37), and Functional Activities Questionary (FAQ, 38) in a quiet room. CASI is an instrument with 20 items assessing cognitive ability of elderly people, with nine domains namely Long-term memory, Short-term memory, Attention, Mental manipulation and concentration, Orientation, Abstraction and judgement, Language abilities, Visual construction, and Category fluency (36). CASI can be administrated within 15 ~ 20 minutes with a total score between 0 ~ 100, where higher scores indicate better cognitive capabilities. The convergent and discriminative validities of CASI have been confirmed (39) and it showed relatively satisfied sensitivity and specificity in Chinese populations (40). All the participants were instructed to answer the 11 items of MoCA battery to measure cognitive abilities related to Visuospatial/ Executive functioning, Naming, Memory, Attention, Language, Abstraction, Delayed recall, and Orientation (37). As the most commonly used questionnaire measuring cognitive dysfunction, MoCA was identified to be superior to Mini-Mental State Examination in detecting MCI (41). MoCA showed high sensitivity and specificity and the areas under the curves were 0.937 and 0.908 when detecting MCI and dementia, respectively (37, 42). FAQ was used to assess daily functional activities; it consists of 10 items including managing simple finances, complex finances, shopping, pursuing hobbies, simple cooking, complex cooking, following current events, using the telephone and other forms of communication, following a schedule, and maintaining mobility (38). Four scale points (0, 1, 2, 3) of each item are corresponding to increasing tendencies of dependent on assistance for an activity. Its sensitivity in differentiating dementia with a cut-off score ≥ 6 was 94.1% in Chinese rural residents (43) and when combining with other clinical tests, FAQ strongly predicted the conversion from MCI to AD (44).

ERP designs and recordings

After completing the above-mentioned questionnaires, participants were led to a dimly lit room and seated at 100 cm in front of a computer screen. The visual oddball ERPs paradigm under external emotional stimuli was originated from and modified according to previous research (45). Former study has proposed a series of pictures from International Affective Picture System (IAPS, 46) for the utilization in neurophysiological processing (47). Referred to this study, the authors selected the most presentative picture in each emotional domain which also considered the original valence and arousal ratings illustrated in the IAPS manual (46). The three scenes of distinct emotions, namely Neutral (picture code: 5390), Happiness (picture code: 2040), and Sadness (picture code: 2205), were presented by E-prime 3.0 (Psychology Software Tools, Pittsburgh, USA). In each emotional scene, a color picture was horizontally presented, sustaining about 19.8◦ × 13.5◦ of visual angles (Figure 1).

Participants were instructed to respond to a circle picture (target stimulus) as quickly as possible by pressing a button with their right thumb, and no reaction was needed to the square picture (standard stimulus) or emotional scene (either A: Neutral, B: Happiness, or C: Sadness). The three successive sessions (Neutral, Happiness and Sadness) were randomly displayed to each participant with a two-minute interval between adjacent sessions.

 

Three successive sessions (Neutral, Happiness or Sadness) with a two-minute interval between adjacent sessions were randomly displayed to each participant. Within each session, a fixation cross in the middle of a black background presented in the computer screen for 3000 ms, following by 144 ERP trials, with an inter-trial interval of 1200 ~ 1500 ms. Within each ERP trial, there was an external emotional stimulus of either Neutral, Happiness or Sadness (1024 ×768 pixels, lasting for 1800 ms) followed by an interval of 400 ~ 500 ms; then either a standard (960 ×720 pixels, 500 ms, a square of 40 mm × 40 mm) or target (960 ×720 pixels, 500 ms, a circle of 40 mm in diameter) stimulus appeared in the middle of the black background screen. The standard stimuli were delivered 108 times (75%) and the target ones 36 times (25%) in a randomized order (Figure 1). Participants were instructed to respond to the target stimuli actively by pressing a button with their right thumb as soon as possible, and no reaction was needed to the standard stimuli or emotional scenes. The long presentation time of external emotional stimuli in our paradigm was designed based on the following reasons. Even the timing of emotional processing is still a matter of debate (48), the late positive potential which occurs between 300 and 1000 ms after stimulus onset indicates extensive emotion-related processing mechanisms (49). However, AD patients showed significant emotional decoding and processing deficits, such as in identification and discrimination (8). On the other hand, Bourgin et al. (21) argued that AD was still able to process emotional information in low attentional load conditions (e.g. with long presentation time or fixation). Therefore, we set a long presentation time which might allow more engagement and processing of the emotional stimuli for our patient groups.
EEG signals were recorded with 32 channel elastic electrocap (g.Nautilus Research, g.tec, Austria) according to the 10-20 International System. Taking the right mastoid as reference electrode, and left mastoid as ground electrode, the impedance of each electrode was maintained below 10 kΩ with a sampling rate of 500 Hz. EEG signals were analyzed offline with EEGLAB toolobox (https://sccn.ucsd.edu/eeglab) running in Matlab 2021a (The MathWorks, Inc., Massachusetts, USA), using a band-pass of 0.1 ~ 30 Hz. The sampling epoch was 200 ms pre-stimulus and 800 ms post-stimulus for each stimulus (i.e., emotional, standard, or target one). Eye blink and muscle artifacts were identified and removed using the Independent Component Analysis (ICA) in EEGLAB. Thereafter, any epoch in which the EEG signal exceeded ± 100 μv was excluded from further analysis.
Electrodes in frontal, central and parietal sites were thought to be highly related to emotional processing, such as facial emotions (50). Take the distribution of both hemispheres into consideration, nine electrodes from frontal, central and parietal sites, i.e., F3, Fz, F4, C3, Cz, C4, P3, Pz, and P4 were selected, and ERP morphology in these electrodes determined by target stimuli were analyzed in terms of peak latency and baseline-to-peak amplitude (Figure 2A). Latency ranges of potentials were 80 ~ 230 ms for N1, 160 ~ 320 ms for P2, 200 ~ 400 ms for N2, 330 ~ 580 ms for P3. Moreover, the reaction times and response accuracies with regard to target stimuli were recorded.

Notes: a, p < 0.05 at AD vs. Controls in N2 or P3 latency; b, p < 0.05 at AD vs. MCI in N2 or P3 latency; C, p < 0.05 at MCI vs. Controls in P3 latency; *, p < 0.05 at AD vs. Controls in P3 amplitude; #, p < 0.05 at MCI vs. Controls in P3 amplitude

 

Statistical Analyses

One-way ANOVA was applied to the scale scores of CASI, MoCA and FAQ as well as reaction times and response accuracies in the three groups of participants. The latencies and amplitudes of ERP components were analyzed by two-way ANOVA, i.e., group (3) × electrode (9). Whenever a significant main effect was detected, the Bonferroni test was employed as a post-hoc comparison. Significant differences with p < 0.05 at no less than three coaxial electrodes (i.e., frontal: F3, Fz, F4, central: C3, Cz, C4, posterior: P3, Pz, P4 in lateral axis; left: F3, C3, P3, midline: Fz, Cz, Pz, right: F4, C4, P4 in sagittal axis) were required as the meaningful between-group differences. Relationships between ERP components and questionnaire scores were examined by the Pearson correlation test, and only significant correlations with p < 0.01 at no less than three coaxial electrodes were considered as stable and meaningful.
The respective 3D sources were reconstructed based on data obtained at the 32 electrodes, in order to observe the varied activations of cerebral regions corresponding to the significant differences in target stimuli under specific external emotional stimuli in the three groups. sLORETA (v20220427, https://www.uzh.ch/keyinst/loreta) was employed to determine the significant differences (corrected p < 0.05) of source localization between Controls, MCI, and AD, using log-F-ratio statistic with sLORETA-built-in voxel-wise randomization tests (5000 permutations) based on statistical nonparametric mapping.

 

Results

Concurrent cognitive function and behavioral results

The CASI scores were significantly different among the three groups of participants (F (2, 147) = 237.31, MSE = 16730.21, p < 0.001), with AD scored significantly lower than Controls (p < 0.001, 95% confidence interval (CI) = -40.79 ~ -32.57) and MCI (p < 0.001, 95% CI = -27.20 ~ -19.01), and MCI scored significantly lower than Controls (p < 0.001, 95% CI = -17.58 ~ -9.57). The MoCA (F (2, 147) = 361.39, MSE = 2462.33, p < 0.001) and FAQ (F (2, 147) = 95.65, MSE = 1212.56, p < 0.001) scores were also significantly different in the three groups, with AD scored significantly lower than Controls (p < 0.001, 95% CI = -15.41 ~ -12.85) and MCI (p < 0.001, 95% CI = -9.70 ~ -7.16), and MCI scored significantly lower than Controls (p < 0.001, 95% CI = -6.95 ~ -4.46) in MoCA, as well as AD scored significantly higher than Controls (p < 0.001, 95% CI = 7.61 ~ 11.09) and MCI (p < 0.001, 95% CI = 6.04 ~ 9.51) in FAQ (Table 1).

Note: a, p < 0.05 at AD or MCI vs. Controls, b, p < 0.05 at AD vs. MCI; CASI, Cognitive Abilities Screening Instrument; MoCA, The Montreal Cognitive Assessment; FAQ, Functional Activities Questionary.

 

Significant differences in reaction times (Neutral: F (2, 132) = 13.45, MSE = 153769.35, p < 0.001; Happiness: F (2, 133) = 20.03, MSE = 221283.25, p < 0.001; Sadness: F (2, 134) = 16.11, MSE = 247189.42, p < 0.001) and response accuracies (Neutral: F (2, 132) = 5.99, MSE = 423.03, p = 0.003; Happiness: F (2, 133) = 6.89, MSE = 499.09, p = 0.001; Sadness: F (2, 134) = 11.21, MSE = 983.59, p < 0.001) were found. Post-hoc comparisons revealed that AD reacted significantly slower than both Controls (Neutral: p < 0.001, 95% CI = 62.66 ~ 174.22; Happiness: p < 0.001, 95% CI = 86.18 ~ 194.42; Sadness: p < 0.001, 95% CI = 79.70 ~ 206.63) and MCI (Neutral: p = 0.004, 95% CI = 20.38 ~ 131.40; Happiness: p < 0.001, 95% CI = 33.90 ~ 142.14; Sadness: p < 0.001, 95% CI = 46.38 ~ 173.93), and showed significantly decreased accuracies compared to Controls (Neutral: p = 0.006, 95% CI = -10.11 ~ -1.35; Happiness: p = 0.002, 95% CI = -10.74 ~ -1.98; Sadness: p < 0.001, 95% CI = -13.82 ~ -4.22) and MCI (Neutral: p = 0.014, 95% CI = -9.56 ~ -0.83; Happiness: p = 0.015, 95% CI = -9.56 ~ -0.79; Sadness: p = 0.002, 95% CI = -11.80 ~ -2.15) (Table 1).

ERP components

The ERP components N1, P2, N2, P3 under the three external emotions were examined in three groups of participants. Only data showing significant between-group differences were presented, the remaining data are available in the supplementary materials. N1 amplitudes under Sadness (group effect, F (2, 134) = 3.23, MSE = 106.42, p = 0.043, partial η2 =0.05; electrode effect, F (8, 1072) = 19.72, MSE = 62.77, p < 0.001, partial η2 =0.13; group × electrode effect, F (16, 1072) = 1.96, MSE = 6.24, p = 0.013, partial η2 =0.03) were statistically different among the three groups. However, post-hoc comparisons did not find any meaningfully differences between groups. For detailed data in latencies and amplitudes of N1 and P2 components, please see Supplement Table I and II, respectively.
There were significant differences on N2 latencies under Neutral (group effect, F (2, 132) = 8.27, MSE = 77735.57, p < 0.001, partial η2 =0.11; electrode effect, F (8, 1056) = 1.99, MSE = 1239.42, p = 0.045, partial η2 =0.02; group × electrode effect, F (16, 1056) = 0.46, MSE = 284.84, p = 0.966, partial η2 =0.01). Post-hoc comparisons revealed that in AD, N2 latencies at all nine electrodes were significantly prolonged compared to Controls (p = 0.000 ~ 0.032), and at frontal electrodes were significantly delayed compared to MCI (p = 0.004 ~ 0.039). There were significant differences on N2 latencies under Happiness (group effect, F (2, 133) = 8.66, MSE = 89725.27, p < 0.001, partial η2 =0.12; electrode effect, F (8, 1064) = 1.35, MSE = 676.47, p = 0.216, partial η2 =0.01; group × electrode effect, F (16, 1064) = 1.00, MSE = 501.16, p = 0.456, partial η2 =0.02). In AD, N2 latencies at all nine electrodes were significantly longer than Controls (p = 0.000 ~ 0.017). There were also significant differences on N2 latencies under Sadness (group effect, F (2, 134) = 9.49, MSE = 97840.27, p < 0.001, partial η2 =0.12; electrode effect, F (8, 1072) = 1.54, MSE = 820.89, p = 0.140, partial η2 =0.01; group × electrode effect, F (16, 1072) = 1.00, MSE = 533.30, p = 0.456, partial η2 =0.02). In AD, N2 latencies at all nine electrodes were significantly prolonged compared to Controls (p = 0.000 ~ 0.012), and at middle as well as parietal electrodes were significantly increased compared to MCI (p = 0.001 ~ 0.021) (Table 2). For detailed data in N2 amplitudes, please see Supplement Table III.
There were significant differences on P3 latencies under Neutral (group effect, F (2, 132) = 9.90, MSE = 165008.02, p < 0.001, partial η2 =0.13; electrode effect, F (8, 1056) = 9.62, MSE = 7701.63, p < 0.001, partial η2 =0.07; group × electrode effect, F (16, 1056) = 0.88, MSE = 704.97, p = 0.592, partial η2 =0.01). Post-hoc comparisons found that in AD, P3 latencies at all nine electrodes were significantly delayed compared to Controls (p = 0.000 ~ 0.010), and at right electrodes were significantly longer than in MCI (p = 0.005 ~ 0.021). There were significant differences on P3 latencies under Happiness (group effect, F (2, 133) = 15.90, MSE = 227290.02, p < 0.001, partial η2 =0.19; electrode effect, F (8, 1064) = 2.44, MSE = 1488.08, p = 0.013, partial η2 =0.02; group × electrode effect, F (16, 1064) = 2.07, MSE = 1261.57, p = 0.008, partial η2 =0.03). In AD, P3 latencies at all nine electrodes were significantly prolonged compared to Controls (p = 0.000 ~ 0.005), at frontal and central electrodes were significantly elongated compared to MCI (p = 0.007 ~ 0.022), and in MCI, P3 latencies at frontal electrodes were significantly longer than in Controls (p = 0.005 ~ 0.020). There were also significant differences on P3 latencies under Sadness (group effect, F (2, 134) = 8.09, MSE = 138399.79, p < 0.001, partial η2 =0.11; electrode effect, F (8, 1072) = 4.68, MSE = 4612.89, p < 0.001, partial η2 =0.03; group × electrode effect, F (16, 1072) = 2.02, MSE = 1993.02, p = 0.010, partial η2 =0.03). In AD, P3 latencies at frontal and parietal electrodes were significantly prolonged compared to Controls (p = 0.000 ~ 0.020), and at parietal electrodes were significantly delayed compared to MCI (p = 0.004 ~ 0.022) (Table 3).

Notes: a, p < 0.05 at AD or MCI vs. Controls; b, p < 0.05 at AD vs. MCI.

Notes: a, p < 0.05 at AD or MCI vs. Controls; b, p < 0.05 at AD vs. MCI.

 

The P3 amplitudes under Happiness (group effect, F (2, 133) = 3.23, MSE = 750.08, p = 0.043, partial η2 =0.05; electrode effect, F (8, 1064) = 42.87, MSE = 271.46, p < 0.001, partial η2 =0.24; group × electrode effect, F (16, 1064) = 1.90, MSE = 12.06, p = 0.017, partial η2 =0.03) in the three groups were statistically different. Post-hoc comparisons showed that in AD, P3 amplitudes at right electrodes were significantly decreased compared to Controls (p = 0.004 ~ 0.039). The P3 amplitudes under Sadness (group effect, F (2, 134) = 3.64, MSE = 824.22, p = 0.029, partial η2 =0.05; electrode effect, F (8, 1072) = 60.02, MSE = 403.72, p < 0.001, partial η2 =0.31; group × electrode effect, F (16, 1072) = 1.46, MSE = 9.84, p = 0.106, partial η2 =0.02) were also significantly different: in AD, P3 amplitudes at parietal electrodes were significantly declined compared to MCI (p = 0.010 ~ 0.013) (Table 4). Taking an example, under Happiness, the averages of ERP morphology at the nine electrodes in Controls, MCI and AD groups were shown in Figure 2B, and under Happiness, the averaged scalp topographies of P3 component in the three groups were presented in Figure 3A. For under Neutral and Sadness, the averages of ERP morphology, please see Supplement Figure I and II, respectively. Likewise, for under Neutral and Sadness, the averaged scalp topographies of P3 component, please see Supplement Figure III.

Notes: a, p < 0.05 at AD or MCI vs. Controls; b, p < 0.05 at AD vs. MCI.

Notes: all the significant differences between groups were marked in yellow (colorbar as 1), and the red cross hairs indicated the peak intensity.

 

Source reconstructions

After the significant differences on N2 and P3 components were observed under the three external emotions, we located the possible differentiated neural sources for these components by performing 3D source reconstruction between groups during N2 (200 ~ 400 ms) and P3 (330 ~ 580 ms) time windows, respectively. During N2 time window, under Neutral, in AD, the activation of right superior temporal gyrus was significantly attenuated compared to Controls (the maximum voxel value, the same below); under Happiness, in MCI, the activation of right inferior frontal gyrus was significantly decreased compared to Controls; and under Sadness, in AD, the activation of right superior frontal gyrus was significantly reduced compared to MCI. During P3 time window, under Happiness and Sadness, when AD compared to MCI, the weakened cortical activations were significantly located in right fusiform gyrus and right middle occipital gyrus, respectively (Table 5). As an example, under Happiness, the maximum difference of source localization during P3 time window between AD and MCI was displayed in Figure 3B. For the maximum difference of source localization under other significant comparisons between groups, please see Supplement Figure IV.

Notes: Under Happiness, during N2 time window, the hypoactivation of right inferior frontal gyrus might be one early sign for detecting MCI. Under both Happiness and Sadness, during P3 time window, the abnormal activation of occipital lobe showed critical role in distinguishing MCI and AD.

 

Relationships between ERPs and concurrent cognitive states

In Controls, under Neutral, P2 amplitudes (n = 51, r = -0.39 ~ -0.45, p = 0.001 ~ 0.006) and N2 amplitudes (r = -0.42 ~ -0.46, p = 0.001 ~ 0.003) at parietal electrodes were negatively correlated with MoCA. In AD, under Happiness, N1 latencies at frontal and central electrodes were negatively correlated with CASI (n = 47, r = -0.47 ~ -0.54, p = 0.000 ~ 0.002), and positively with FAQ (r = 0.40 ~ 0.49, p = 0.001 ~ 0.009).

 

Discussion

As stated by recent data on ERPs research (e.g., 45, 51), several limitations would temper the interpretation of the current results. First, some medications might influence cognitive function as well as brain activity, unfortunately, we failed to record the medication of our participants. Second, other external emotions such as fear, surprise or anger which might also display emotional effect on the attentional processing in MCI and AD should be included in further investigation. Third, we failed to match the educational levels of our participants and did not investigate the gender differences of attentional mechanisms under different external emotion stimuli in MCI and AD. Fourth, even source localization with less than 32 electrodes also provides valuable insight concerning the underlying sources (52), the 32-channel used in the current study may lead to decreased spatial resolution and accuracy of source reconstruction. Fifth, our participants were only recruited form one province in China, whether the current results can be generalized to other regions of China or other countries need further verification. Nevertheless, we have demonstrated the visual attentional deficits under external emotional stimuli in both MCI and AD, and highlighted some specific variations which can serve as early signs for detecting MCI, as shown below.
The distinguished CASI and MoCA scores among the three groups were in accordance with former literature revealing that CASI and MoCA function as sensitive tools for detecting MCI and AD (40, 42). Moreover, our data on AD patients showed lower FAQ scores and response accuracies, as well as longer reaction times than those found in Controls and MCI. It is well identified that AD patients suffered severe decline in daily life activities which can be reflected by scales assessing the corresponding daily behavior abilities, such as FAQ (44). The declined response accuracies and prolonged reaction times in AD compared to Controls and MCI were also consistent with previous studies showing that the slowness of reaction time was correlated to poor cognitive function (53).
In the present study, under all three external emotions, in AD, N2 latencies at all nine electrodes were significantly extended compared to Controls; under Neutral, in AD, N2 latencies at frontal electrodes were significantly prolonged compared to MCI; and under Sadness, in AD, N2 latencies at middle as well as parietal electrodes were significantly increased compared to MCI. N2 latency refers to the sensitivity of cognitive processes to target or deviant stimulus (25), and embodies in the top-down attentional performance which indexes the following cognitive processing of previous encoding information together with P3 component (54). Under all three external emotions, in AD, the longer N2 latencies than in Controls conveyed the general decline of voluntary attention, which were consistent with other results previously reported (55, 56). Similarly, under Neutral and Sadness, in AD, the delayed N2 latencies compared to MCI were also in line with previous studies (57).
In P3 component, under Neutral, in AD, the P3 latencies at all nine electrodes were significantly longer than in Controls, and at right electrodes were significantly delayed compared to MCI. Under Happiness, in AD, P3 latencies at all nine electrodes were significantly prolonged compared to Controls, at frontal and central electrodes were significantly increased compared to MCI, and in MCI, P3 latencies at frontal electrodes were significantly longer than in Controls. Under Sadness, in AD, P3 latencies at frontal and parietal electrodes were significantly delayed compared to Controls, and at parietal electrodes were significantly extended compared to MCI. P3 component involves with the allocation of central top-down attentional resources and voluntary processing in working memory (26), thus extended P3 latency is related to disordered information processing and deteriorated cognitive function (29). Similar to previous literature (e.g., 18, 29), our current study reported the elongated P3 latencies in AD compared to both Controls and MCI under all three external emotions. Moreover, studies also displayed delayed P3 latencies in MCI compared to healthy controls (58, 59), which supported our finding that under Happiness, in MCI, P3 latencies were significantly longer than in Controls. The emotional effect of Happiness here might be explained by the following findings: i) AD patients showed preserved capacity to decode positive emotions but diminished ability to negative ones (10); ii) as the transitional stage between normal aging and AD, MCI suffered from similar deficits in emotion recognition and processing (60); iii) emotional stimuli would bias the resource deployment of attention, which could lead to the insufficient attention to subsequent target stimuli (22). Altogether, the preserved decoding to Happiness might affect the attention resources allocated to target stimuli, which induces under Happiness, in MCI, the prolonged P3 latencies compared to Controls.
P3 amplitude represents the amount of attention resource allocated to the target stimuli, where the attenuated amplitude is thought to be associated with declined intensity of voluntary cognitive processing (26). We found that under Happiness, in AD, the P3 amplitudes at right electrodes were significantly diminished compared to Controls, whereas under Sadness, in AD, the P3 amplitudes at parietal electrodes were significantly decreased compared to MCI. The current results demonstrated the diminished attention allocation in AD compared to Controls and MCI, in accordance with former literature (18). Moreover, Papadaniil et al. (29) argued that P3 latency, which conveys the speed of cognitive processing, was more affected than amplitude reflecting the intensity of attention resource allocation in AD. Indeed, our results showed that alterations in P3 latencies were more pronounced than amplitudes. To sum up, the above results of ERP N2 and P3 components in the three groups illustrated the impaired voluntary attention in both MCI and AD, and particularly emphasized that under Happiness, the alternations of P3 latency might serve as an early sign for detecting MCI, as shown in Table 6. Although we did not detect the emotional processing in MCI and AD directly, our results supported that emotional stimuli could capture more attentional resource than neutral ones and influence the attention allocation to subsequent target stimuli (17, 22).

Notes: ↑, prolongation in latency; ↓, diminishment in amplitude; -, no significant difference was found, where under Happiness, P3 latency might serve as one early sign for detecting MCI.

 

During N2 time window under Neutral, in AD, cerebral activation of right superior temporal gyrus was significantly attenuated compared to Controls. Under Happiness, in MCI, the activation of right inferior frontal gyrus was significantly decreased compared to Controls and under Sadness, in AD, the activation of right superior frontal gyrus was significantly diminished compared to MCI. Alves et al. (61) argued that emotional processing is dominant by the right hemisphere and highlighted the important role of the prefrontal cortex in emotional processing. Inferior frontal gyrus is a part of ventral attention network which is right lateralized and involved with stimulus-driven orienting (62). Its function on emotional processing has been emphasized as well (63). The superior frontal gyrus which is the key region of the prefrontal cortex serves broad domains such as cognitive control and execution within working memory (64), and plays a crucial role in the network connections when differentiating positive and negative emotions (65). Superior temporal gyrus, along with superior frontal gyrus and inferior temporal gyrus (mainly in right hemisphere) has been identified as brain regions significantly affected in AD patients (66). The above-mentioned studies supported our findings that during N2 time window, the right frontal and temporal lobes were primarily altered when comparing the source localization between Controls, MCI and AD, which indicates that under Happiness, the abnormal activation of right inferior frontal gyrus is another early sign for detecting MCI.
During P3 time window, under Happiness and Sadness, in AD, the activations of right fusiform gyrus and right middle occipital gyrus were significantly decreased compared to MCI, respectively. The occipital cortex, the visual information processing center, has been proven to play a crucial role in communicating with many other cortical areas precepting facial emotions (67). For instance, the involvement of right fusiform gyrus in processing facial stimuli has been well-documented (68). As well, it has been demonstrated the role of occipital regions in top-down attentional network, in which attentional signals are transient in occipital cortex then sustained in frontal and parietal regions (15). Considering its effect in AD, Babiloni et al. (69) reported that along pathologic aging, AD neurodegeneration in occipital lobe was correlated with the amplitude of resting-state alpha rhythms from occipital sources. Therefore, the above findings contributed to the understanding of our results, which suggested that the occipital areas influenced the cognitive processing of central resource allocation and voluntary attention in AD, and might play a critical role in discriminating MCI and AD.
In Controls, under Neutral, the significant negative correlations between MoCA scores and P2 as well as N2 amplitudes can be explained by the following results: i) larger amplitudes were regarded to represent extra stimulus processes which might acquire more attentional resources (70); ii) larger P2 and N2 amplitudes have been reported in old adults whose cognitive abilities were declined compared to young adults (70, 71), which helped to illustrate the negative correlations between cognitive function and the amplitudes of those ERP component. In AD, under Happiness, N1 latencies were significantly negatively associated with CASI but positively with FAQ scores. N1 involves with primary processing of incoming information (24), and the prolonged N1 latency which indicates the slowness of cognitive processing is in accordance with the characteristic of AD manifesting in deteriorated cognitive functions and impaired daily activities that can be assessed by CASI and FAQ, respectively.
We found that under all three external emotions, in AD, both N2 and P3 latencies were significantly prolonged compared to Controls and MCI, and under Happiness, in MCI, P3 latencies were significantly prolonged compared to Controls. Meanwhile, under Happiness, in AD, P3 amplitudes were significantly diminished compared to Controls, whereas under Sadness, in AD, P3 amplitudes were significantly decreased compared to MCI. Those results demonstrated that the voluntary attention was impaired in both MCI and AD, and under Happiness, the function of P3 latency in detecting MCI was particularly illustrated which can serve as an early sign for MCI. Furthermore, during N2 time window, abnormal activation of the cerebral areas demonstrated that frontal and temporal regions were significantly attenuated in our patient groups, in which under Happiness, the alterations of right inferior frontal gyrus might be another early sign for detecting MCI. During P3 time window, under both Happiness and Sadness, hypoactivation of occipital cortex were found when AD compared to MCI, reflecting its important role in differentiate MCI and AD. Thus, our study highlighted different cerebral attentional processing deficits under external emotional stimuli and its potential values for both clinical early diagnosing MCI and AD. Furthermore, the findings in the current study provide hints for the further interventions such as emotional therapy and non-invasive brain stimulation in cognitive decline.

 

Acknowledgements: The study was supported by the grants from the National Key Research and Development Program of China under No. 2022YFE0199300 (Dr. M. Tao), the National Science Foundation of China under No. 62076083 (Dr. H. Zeng), the GOING-FWD Consortium funded by the GENDER-NET Plus ERA-NET Initiative (Ref. Number: GNP-78) and “La Caixa” Foundation (ID 100010434) with code LCF/PR/DE18/52010001 (Dr. MT. Herrero). The authors appreciate Prof. Wei Wang (Norwegian University of Science and Technology) for his support on the ERP paradigm.

Author Contributions: MT and MTH conceived the study, CW, WY, TX, AGC, and EFV contributed to the study design, CW, WY, TX, HZ, FX, and FC collected and analyzed the data, and CW, MTH, and MT drafted the paper. All authors read and approved the final manuscript.

Authors’ Declarations: Regarding research work described in the paper, each one of our co-authors, CW, WY, TX, HZ, AGC, EFV, FX, FC, MTH, and MT, declares that there is no conflict of interest, and conforms to the Helsinki Declaration concerning human rights and informed consent, and follows correct procedures concerning treatment of humans in research. The study was approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang Chinese Medical University (No. 2021-KL-021-01).

 

SUPPLEMENTARY MATERIAL

 

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