Discrimination between Dementia Groups and Healthy Elderlies Using Scalp-Recorded-EEG-Based Brain Functional Connectivity Networks

Objective: To establish a practical method for discriminating dementia groups and healthy elderlies, by using scalp-recorded electroencephalograms (EEGs). Methods: 16-ch EEGs were recorded during resting state for 39 dementia groups and 11 healthy elderlies. The connectivity between any two electrodes was estimated by synchronization likelihood (SL). The brain networks were constructed by normalized SL values. The present leave-one-out cross validation (LOOCV) required the Euclidean distance between any two subjects having 120-dimensional vectors concerned with the SL values for six frequency bands. In order to investigate factors which would affect the LOOCV results, principal component analysis (PCA) was applied to all the subjects. Results: The accuracy for the upper alpha yielded more than 80% and 70% in the dementia groups and the healthy elderlies, respectively. The LOOCV result could be explained in terms of brain networks such as executive control network (ECN) and default mode network (DMN) characterized by factor loadings of principal components. Conclusions: Dementia groups and healthy elderlies could be characterized by principal components of SL values between all the electrode pairs, even less connections, which revealed disruption and preservation of DMN and ECN. Significance: This study will provide a simple and practical method for discriminating dementia groups from healthy elderlies by scalp-recorded EEGs.


INTRODUCTION
Alzheimer's disease (AD) is the most common form of dementia in the world. 50 million people are suffering from dementia and over 60 percent of dementia cases are Alzheimer's disease. In addition, these patients are likely to reach about 152 million people by 2050 [1]. AD is an irreversible neurodegenerative disease characterized by progressive impairment of memory, and loss of cognitive functions that affect a person's ability to perform daily activities. The evolution of the disease frequently follows some stages and symptoms gradually worsen over a number of years [2].
One of the difficult problems of AD is diagnosis. As things stand at the moment, there is no single test way for AD. Physicians are using several methods and tools to make a diagnosis, which included medical and family history, cognitive tests and physical and neurologic examinations, and brain imaging [3]. Also, several days or weeks are needed to complete the required tests and for the physician to interpret the results and make a diagnosis [3]. Therefore, AD diagnosis using easy and inexpensive techniques will provide better care to patients.
Current theories of AD postulate that in the brain networks the decline arises from alterations in functional integration of distributed brain systems or from structural disconnection between regions because of white matter damage. Such brain networks during resting states have been known as executive control network (ECN) [4], default mode network (DMN) [5] and salience network (SN) [6]. The ECN is a brain network responsible for high-level cognitive functions, notably the control of attention and working memory. The DMN is a large-scale network of brain areas that form an integrated system for self-related cognitive activity, including autobiographical, self-monitoring and social functions and the SN is a brain network involved in the orientation of attention to the most homeostatically relevant (salient) of ongoing intrapersonal and extrapersonal events [7].
From the point of view of cognitive functions and tests, Alzheimer's dementia has been known to be classified into the following five stages at least: preclinical stage, the second stage (Mild Cognitive Impairment (MCI)), mild stage (MMSE (Mini Mental Status Examination) > 20), moderate stage (MMSE between 10 and 20) and severe stage [2]. In particular, an early diagnosis of Alzheimer's disease in MCI and mild AD stages has become very important.

EEG Measurement
The present subjects consist of 39 dementias and 11 healthy elderlies, Table 1 shows those subjects information. EEG measurements were performed at Teikyo University School of Medicine, through a Nihon Kohden EEG-1224 for the subjects. The device was equipped with 16 Ag/AgCl electrodes (a Nihon Kohden H503A) were attached at Fp1, Fp2, F3, F4, C3, C4, P3, P4, O1, O2, F7, F8, T3, T4, T5, and T6 on the basis of the International 10 -20 System (Figure 1). The sampling rate was set to be 500 Hz. The filter setting was high pass filter (=120 Hz). All the subjects were instructed to lie on their back in the resting state with their closed eyes for 5 minutes at least. The study protocol illustrated in Figure 2, including all EEG data analyses, was approved by The Ethics Committee for Human Subject Researches, Faculty of Computer Science and Systems Engineering, Kyushu Institute of Technology. All EEG data was checked in the EEG lab (provided by Swartz Center for Computational Neuroscience) and deleted at least 1 minute from the starting time and the EEG data after 1 minute were used for the data analyses as use stable EEG data.

Synchronization Likelihood (SL)
After the EEG measurement, SL was calculated between any two electrodes. The SL is a measure of synchronization between two times series that is sensitive to linear and non-linear independencies. The basic principle of the SL is to divide each time series into a series of "pattern" (roughly, brief pieces of time series containing a few cycles of the dominant frequency) and to search for a recurrence of these patterns.  Figure 4 [19] shows the SL between two channels in terms of state vectors and critical distances. The reference vector of channel A is denoted X A,i (thick line square) here chosen to have embedding dimension m = 3 samples (small ticks) and lag L = 2 samples (dots). The reference vector is compared with state vectors (squares) X A,j (j = ±1, 2 … n) within a window of W2. State vectors starting at times j in the time interval outside the window W1 and within the window W2 (windows centered at time i) are compared with the reference vector. The time series is indicated with a solid horizontal line and the time intervals are indicated with a dashed line. The vectors X A,j , which are closer to the reference vector X A,i than the critical distance, r A ( Figure 4) are represented in white. Whereas the vectors that are not within the critical distance are represented in grey, and termed recurrences are represented with white squares. Similarly to channel A, a reference vector X B,i is compared with all state vectors X B,j (j = 1, 2 … n). If the vectors are closer to X B,i than r B then they are represented in white, otherwise in grey. The SL value is the number of simultaneous recurrences in channels A and B divided by the total number of recurrences within channels. In this situation, the SL value is 0.5. These procedures which convert the SL values between the 16 electrodes into the adjacency matrix are illustrated in Figure 2. The Lab_SL2 which is the Matlab script for calculating the SL was used in this study.

Brain Network Construction
SL values show strength of connectivity of each of the two electrodes ( Figure 4) [19]. For each electrode pair, averages of SL values in the healthy controls were calculated, and then SL values in the AD patients were divided by the healthy averages. Thus, from the brain network of the healthy group, that of the AD group was constructed, as shown in Figure 5.

Brain Network Modularization
The graph structure of the brain network was represented by the nodes and edges that correspond to the electrode positions and the SL values, respectively, where the present network was undirected and unweighted (binary) in this research ( Figure 5). The brain network was divided into some community groups, which could predict any cognitive function. The network constructed by SL average values was divided into two graphs, so that one is lower than the healthy group and other higher than the healthy group ( Figure 6). Moreover, the optimal community structure of a graph was found by maximizing the modularity measure over all possible partitions [20]. Figure 6. Modularization of brain network using graph theory.

Leave-One-Out Cross Validation (LOOCV)
LOOCV uses a single test data from the original samples as the validation data, and the remaining data as the training data ( Figure 2). Firstly, we picked one test data, and calculated "AD and healthy averages" for the remaining data. The "AD and healthy averages" are defined to be averages across subjects in each group for each electrode pair.
For one test data, 120 (=16 × 15/2)-dimensional Euclidean distance between the subject and "the dementia or healthy average" was calculated. If the Euclidean distance in the dementia group is smaller than that in the healthy group, the test data is determined to be from "dementia", otherwise from "healthy". This procedure was repeated for all the test data.

Principal Component Analysis (PCA)
In order to investigate factors (brain networks) which could affect the above LOOCV results, principal component analysis (PCA) is applied to all the subjects in terms of all the electrode pairs ( Figure 2). Figure 7 shows the dementia group networks for each frequency band compared with the healthy elderly controls. The SL values are averaged for all the time-series data in the dementia group and the healthy elderly group. Figure 7 also visualizes whether the SL average value between the nodes is higher or lower than the healthy control value. In all the frequency bands except for delta, the connections between Fp1-Fp2 in the dementia group are weaker than the elderly control group. In theta and gamma bands, the connectivity of the dementia groups is lower than that of the elderly controls.

Brain Network Construction
From non-overlapping community detection, nodes consisting of the same community could have high functional relevance. Figure 8 and Figure 9 show that the alpha band network of dementia groups is distributed in the whole of the brain, indicating that SL values in dementia group are higher than those in elderly controls. Moreover, the gamma band network of dementia groups is separated between the left and right sides of the brain. In the theta band, the connectivity in the dementia groups is almost completely lower than that in the elderly controls. J. Biomedical Science and Engineering    Table 2 shows the accuracy rate for "dementia" and "healthy". In the dementia group, three bands (lower alpha, upper alpha and beta) show the high accuracy, and also in the healthy group, two bands (theta and upper alpha) also show the high rate. So, the upper alpha band was applied to PCA. Figure 10 shows plots of all the subjects by the first two principal components (PC1 and PC2) in the upper alpha band. Table 3 depicts the cumulative proportion of the PCs. It follows that PC1 and PC2 explain only 56% of the SL value variation. In Figure 10, orange dots represent healthy controls, and blue dots represent dementia groups. This figure shows that the dementia groups and healthy groups might be separated (as mentioned in Discussion). To find which components affected the PCA results, factor loadings were calculated for all the electrode pairs ( Figure 11). Figure 11 also depicts three lines indicating main axes of factor loading variation in PC1 and PC2 by inspection. These lines are represented by PC1 factor loading values with larger than 0.85, PC2 factor loading values with larger than 0.4 and those with less than −0.4. And, Figures 12-14 show brain networks which were characterized by the three constraints.

DISCUSSION
The frontal cortex helps mediate the working memory that is used for temporary storage and manipulation of information and involved in many higher cognitive functions [21]. Therefore, well-known symptoms of AD are related with functions of the frontal cortex [22]. Because our results (Figure 7) indicated low connectivity in the frontal cortex, the brain networks might reveal dysfunction of the frontal cortex. Figure 8 and Figure 9 suggested that the networks of the AD group might have some characteristics so that the network of AD patients could distinguish from that of the healthy elderly controls.      The present LOOCV result yielded over 80% accuracy in the upper alpha band, which is the same as accuracy in classification tasks comparing AD patients and aged-matched healthy controls [23][24][25][26][27][28]. In order to investigate factors which could affect the present accuracy, PCA was applied to SL values in terms of any two electrodes. Figure 10 characterized each subject in terms of the first two principal components. Visual inspection of this figure roughly suggests that the dementia groups could be characterized only by the PC1 and the healthy controls by a combination of the PC1 and the PC2. Actually, the coefficients of correlation were 0.1233 and −0.6188 for the dementia groups and the healthy controls, respectively ( Figure 10). Moreover, Figures 12-14 show brain networks determined by factor loadings of the two PCs (PC1 and PC2), which were defined to be the PC1 factor loadings of more than 0.85, the PC2 factor loading of less than −0.4 and the PC2 factor loading of larger than 0.4, respectively, with reference to Figure  11.
Generally, brain networks during resting state can be defined on the basis of structural connectivity or functional interdependence from some large scale ones such as DMN, ECN and SN. The ECN is characterized by the dorsal prefronto-parietal network mainly involving the lateral prefrontal cortex (LPC) and the posterior parietal cortex (PPC) [21,29]. The DMN contains the medial prefrontal cortex (MPC), the posterior cingulate cortex (PCC), the inferior parietal lobe (IPL), the lateral temporal cortex (LTC) and the hippocampal formation (HF) [30], each of which organizes a different functional area. The two networks during resting states do not always conflict, sometimes cooperate between them [31] and affect each other. In particular, it has been reported that the synchronization of the fast alpha reflects the DMN function and is responsible for top-down processing [32]. Figure 12 seems to reveal the connection of DMN. The PCC, an occipital-core area of DMN, corresponds to the P3-P4-T5-T6, and the MPFC to the Fp1-Fp2-F3-F4 in the present experiment. Because, in this study, the EEGs were recorded during resting state with closed eyes, the brain networks such as DMN and ECN are likely to be formed.
In contrast, Figure 13 seems to reveal the brain network with the connection of ECN according to the PC2 factor loadings. The DMN is predominant in the absence of any external tasks, while the ECN is a resting-state-task-related network [7,[33][34][35][36][37]. Moreover, it has been well known that the DMN and the ECN have negative correlation (e. g., [36,[38][39][40][41][42][43][44]). This could be a reason why it is difficult to divide into dementia group and healthy one in the PC2. Additionally, Figure 14 shows occipitally dominant networks in the upper alpha band, which is supported by alpha activity in the occipital cortex (e.g., [45]).
Finally, dementia groups and healthy elderlies could be characterized by principal components of SL values between all the electrode pairs, revealing disruption and preservation of DMN and ECN. LOOCV using much less between-electrode connections yielded the same accuracy (85% and 73% for dementia groups and healthy elderlies, respectively) as Table 1. This reduction was executed by a model by AIC (Akaike information criterion) in a stepwise algorithm (e.g., [46]). The resultant reduction is shown in Figure 15. Thus, this study will provide an easy and practical method for discriminating dementia groups from healthy elderlies by scalp-recorded EEGs. J. Biomedical Science and Engineering

CONCLUSION
We obtained brain functional connectivity networks (BFCNs) for dementia groups including AD and MCI and elderly controls using scalp-recorded EEGs. The BFCNs were constructed from connectivity strength described by SL values at each electrode pair. Principal components of the SL values characterized the subjects in terms of disruption and preservation of default mode network (DMN) and executive control network (ECN) for the dementia groups and the elderly controls, respectively. Thus, this study will provide an easy and practical method for discriminating dementia groups from healthy elderlies using scalp-recorded EEGs.