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\begin{document}

\title{Gamma network topology and pathological changes in drug-resistant
temporal lobe epilepsy with cognitive deficits}



\author[1]{Nan Lin}%
\author[1]{Qiang Lu}%
\author[2]{Xinshan Liu}%
\author[3]{Dingding Zhang}%
\author[1]{Wanchen Dou}%
\author[1]{Dachun Zhao}%
\author[1]{Weifang Gao}%
\author[1]{Zhe Zhang}%
\author[1]{Jia Li}%
\author[1]{Heyang Sun}%
\author[1]{Jianhua Chen}%
\author[1]{Xiangqin Zhou}%
\author[1]{Liri Jin}%
\author[1]{Yan Huang}%
\author[1]{Liwen Wu}%
\author[2]{Mengyang Wang}%
\author[1]{Qing Liu}%
\affil[1]{Peking Union Medical College Hospital}%
\affil[2]{Capital Medical University Sanbo Brain Hospital}%
\affil[3]{Chinese Academy of Medical Sciences \& Peking Union Medical College}%


\vspace{-1em}



  
  \date{May 17, 2024}


\begingroup
\let\center\flushleft
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\endgroup





\selectlanguage{english}
\begin{abstract}
Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy,
frequently accompanied with cognitive deficits. The present study aims
to investigate functional network alterations affected by cognitive
impairments in drug-resistant TLE. Patients with drug-resistant TLE were
divided into normal cognition (NC) and abnormal cognition (AC) groups
based on their primary medical history and completed the Wechsler
intelligence scale. Thirty-one patients in the NC group and 30 in the AC
group had mean intelligence quotients (IQ) of 107 (96-137) and 71
(60-85), respectively. Eighteen controls were enrolled in the study.
Graph theory analysis showed decreased alpha small world index (SWI) in
the AC group compared to that in the NC group and controls. Increased
SWI in the fast rhythm was observed in both TLE groups compared with
controls. But the gamma SWI in the AC group declined and was
significantly lower than in the NC group at 50--70 Hz. A lower IQ is
associated with a decreased SWI in alpha and 50-70Hz. Spectral analysis
revealed reduced alpha power and increased delta power in the TLE groups
compared to the controls. Immunofluorescence analysis revealed more
severe amyloid-\selectlanguage{greek}β \selectlanguage{english}(A\selectlanguage{greek}β\selectlanguage{english}) and phosphorylated Tau (p-Tau) loads in the
resected hippocampus of the AC group than that of NC group. Cognitive
deficits in drug-resistant TLE are associated with general EEG activity
slowing, loss of efficiency in gamma connectivity, and increased A\selectlanguage{greek}β \selectlanguage{english}and
p-Tau expression. These alterations are potential markers and
intervention targets for concomitant cognitive decline in drug-resistant
epilepsy.%
\end{abstract}%



\sloppy


Gamma network topology and pathological changes in drug-resistant
temporal lobe epilepsy with cognitive deficits

\textbf{Running title} : cognitive deficits affect EEG and pathology in
TLE

Nan Lin\textsuperscript{1}, Qiang Lu\textsuperscript{1}, Xinshan
Liu\textsuperscript{2}, Dingding Zhang\textsuperscript{3}, Wanchen
Dou\textsuperscript{4}, Dachun Zhao\textsuperscript{5}, Weifang
Gao\textsuperscript{1}, Zhe Zhang\textsuperscript{1}, Jia
Li\textsuperscript{1}, Heyang Sun\textsuperscript{1}, Jianhua
Chen\textsuperscript{1}, Xiangqin Zhou\textsuperscript{1}, Liri
Jin\textsuperscript{1}, Yan Huang\textsuperscript{1}, Liwen
Wu\textsuperscript{1}, Mengyang Wang\textsuperscript{2}, Qing
Liu\textsuperscript{1}

\textbf{Nan Lin and Qiang Lu contributed equally to this work.}

\textbf{Author affiliations:}

1 Department of Neurology, Peking Union Medical College Hospital,
Beijing 100730, China

2 Department of Neurology, SanBo Brain Hospital, Capital Medical
University, Beijing 100093, China

3 Medical Research Center, State Key laboratory of Complex Severe and
Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of
Medical Sciences and Peking Union Medical College, Beijing 100730, China

4 Department of Neurosurgery, Peking Union Medical College Hospital,
Beijing 100730, China

5 Department of pathology, Peking Union Medical College Hospital,
Beijing 100730, China

\textbf{Correspondence authors:}

Qing Liu

Department of Neurology, Peking Union Medical College Hospital, Beijing,
China.

Email: drliuqing@126.com.

Mengyang Wang

Department of Neurology, SanBo Brain Hospital, Capital Medical
University, Beijng, China.

Email: mengyangwang@ccmu.edu.cn.

\textbf{Data availability statement :}

The data that support the findings of this study are available from the
corresponding author (QL) upon reasonable request

\textbf{Acknowledgments}

\textbf{Funding:} This work was supported by the Chinese Academy of
Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS)
{[}Grant number: 2021-I2M-1--034, 2021-I2M-1--018, 2016-I2M-1--002{]},
the Fundamental Research Funds for the Central Universities {[}grant
number: 3332021011{]}, National Natural Science Foundation of China
{[}NSFC; grant numbers 81971293, 81788101{]}, National Key Research and
Development Program of China {[}Grant number: 2016YFC0905100{]},
Research Fund from CAAE {[}UCB-2018029, CU-A-2021-21{]}, the National
Key Research and Development Project {[}grant number: 2018YFC2000803{]},
and Hygiene and Health Development Scientific Research Fostering Plan of
Haidian District Beijing {[}HP2021-03-50801{]}.

\textbf{Conflict of interests:} None of the authors have potential
conflicts of interest to be disclosed.

Gamma network topology and pathological changes in drug-resistant
temporal lobe epilepsy with cognitive deficits

\textbf{Abstract}

Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy,
frequently accompanied with cognitive deficits. The present study aims
to investigate functional network alterations affected by cognitive
impairments in drug-resistant TLE. Patients with drug-resistant TLE were
divided into normal cognition (NC) and abnormal cognition (AC) groups
based on their primary medical history and completed the Wechsler
intelligence scale. Thirty-one patients in the NC group and 30 in the AC
group had mean intelligence quotients (IQ) of 107 (96-137) and 71
(60-85), respectively. Eighteen controls were enrolled in the study.
Graph theory analysis showed decreased alpha small world index (SWI) in
the AC group compared to that in the NC group and controls. Increased
SWI in the fast rhythm was observed in both TLE groups compared with
controls. But the gamma SWI in the AC group declined and was
significantly lower than in the NC group at 50--70 Hz. A lower IQ is
associated with a decreased SWI in alpha and 50-70Hz. Spectral analysis
revealed reduced alpha power and increased delta power in the TLE groups
compared to the controls. Immunofluorescence analysis revealed more
severe amyloid-\selectlanguage{greek}β \selectlanguage{english}(A\selectlanguage{greek}β\selectlanguage{english}) and phosphorylated Tau (p-Tau) loads in the
resected hippocampus of the AC group than that of NC group. Cognitive
deficits in drug-resistant TLE are associated with general EEG activity
slowing, loss of efficiency in gamma connectivity, and increased A\selectlanguage{greek}β \selectlanguage{english}and
p-Tau expression. These alterations are potential markers and
intervention targets for concomitant cognitive decline in drug-resistant
epilepsy.

\textbf{Keywords:} EEG; cognitive deficits; drug-resistant temporal lobe
epilepsy; graph theory; pathology.

\textbf{Acknowledgments}

\textbf{Funding:} This work was supported by the Chinese Academy of
Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS)
{[}Grant number: 2021-I2M-1--034, 2021-I2M-1--018, 2016-I2M-1--002{]},
the Fundamental Research Funds for the Central Universities {[}grant
number: 3332021011{]}, National Natural Science Foundation of China
{[}NSFC; grant numbers 81971293, 81788101{]}, National Key Research and
Development Program of China {[}Grant number: 2016YFC0905100{]},
Research Fund from CAAE {[}UCB-2018029, CU-A-2021-21{]}, the National
Key Research and Development Project {[}grant number: 2018YFC2000803{]},
and Hygiene and Health Development Scientific Research Fostering Plan of
Haidian District Beijing {[}HP2021-03-50801{]}.

\textbf{Conflict of interests:} None of the authors have potential
conflicts of interest to be disclosed.

\textbf{Introduction}

Epilepsy is a prevalent neurological disorder that affects approximately
50 million people worldwide (Meyer et al., 2010). Temporal lobe epilepsy
(TLE) is the most common form of localization-related epilepsy in
adults. Hippocampal onset accounts for at least 80\% of all temporal
lobe seizures (Tatum, 2012). The temporal lobe is involved in learning,
memory, and affective behavior (Gilliam et al., 2003). Damage to this
structure as a result of recurrent spontaneous seizures can result in
cognitive impairment (Helmstaedter, 2002), which has been frequently
described as a potential comorbidity of TLE (Meador, 2002).

Gamma activity (30--100 Hz) has been linked to memory access (Gruber \&
M\selectlanguage{ngerman}üller, 2005; Gruber et al., 2002; Herrmann et al., 2004; Kaiser et al.,
2003). Previous studies have reported suppressed synchronization of
gamma frequency in cognition disorders, such as Alzheimer's disease
(Politoff et al., 1996; Stam et al., 2002; Wang et al., 2020). Since
gamma alternation occurs early in disease progression, it may be
involved in the pathological processes of dementia. Modulation of the
gamma band is a promising intervention for cognitive improvement in
Alzheimer's disease (Park et al., 2020; Tian et al., 2021). Increased
gamma band power has been reported in idiopathic general epilepsy (Pegg
et al., 2020; Willoughby et al., 2003). However, EEG variations in gamma
frequency in patients with TLE with cognitive impairment remain poorly
understood.

We established a retrospective cohort of patients with drug-resistant
TLE with and without cognitive deficits. Using this cohort we evaluated
the characteristics of interictal resting-state EEG data in gamma
frequency and pathological changes in the resected hippocampus of the
patients. Spectral analysis, functional connectivity, and graph
theoretical analysis were used in the current study to quantify the
brain's functional system. We observed changes in small-world topology
in the gamma band, and elevated amyloid-\selectlanguage{greek}β \selectlanguage{english}(A\selectlanguage{greek}β\selectlanguage{english}) and phosphorated Tau
(p-Tau) deposition in TLE patients with cognitive dysfunction.

\textbf{Materials \& Methods}

\textbf{Patients}

The study population consisted of patients with drug-resistant TLE
treated between June 2012 and September 2021. The diagnosis of TLE was
made by experienced epilepsy specialists according to criteria from the
International League Against Epilepsy (ILAE) classification of
epilepsies and epileptic syndromes (Commission on Classification and
Terminology of the International League Against Epilepsy, 2017). All
patients underwent EEG recordings and brain magnetic resonance imaging
(MRI). Seizure origin was confirmed using EEG in all patients.
Drug-resistant epilepsy was defined as the failure of two tolerated and
appropriately chosen anti-seizure drug schedules (whether as
monotherapies or in combination) to achieve sustained seizure inhibition
(Kwan et al., 2010). The exclusion criteria were as follows: (1)
epileptiform discharges over other regions except the temporal lobe on
EEG; (2) concomitant seizures originating in non-temporal regions; (3)
brain MRI revealing obvious lesions in non-temporal areas, which may
influence seizure type or cognition; and (4) complications of other
neurological disorders that may influence seizure or cognition,
including tumor, trauma, stroke, mental retardation, neurodegenerative
disease, and inherited neurological diseases, such as tuberous
sclerosis.

Patients who met the following criteria were included in the abnormal
cognition (AC) group: (1) complaints of cognitive decline, which
interfered with daily routines and work performance; (2) declined
calculation ability (\textless{} four correct, subtract 7 from 100,
continued five times); and (3) impaired memory ability (\textless{} 2
points, recall the names of three objects learned earlier). The criteria
of normal cognition (NC) group were as follows: (1) no complaints of
cognitive dysfunction, qualified for job, and (2) normal calculation and
memory abilities. The Wechsler Intelligence Scale (WIS) was used in 30
patients in the AC group and 31 patients in the NC group. All patients
underwent video EEG monitoring using a 40-channel video-EEG monitoring
system (Nicolet, USA) at the hospital for over 24 h. We also enrolled 18
sex- and age-matched healthy controls (HC). Recording electrodes were
placed according to the international 10--20 system, densely in the
bilateral temporal regions based on the international 10--10 system,
with a sampling frequency of 512 Hz. The 40 electrodes included Fp1,
Fp2, F3, Fz, F4, F7, F8, C3, Cz, C4, T7, T8, P3, Pz, P4, P7, P8, O1, Oz,
O2, AF7, AF8, F9, F10, FC5, FC6, FT7, FT8, FT9, FT10, C5, C6, T9, T10,
CP5, CP6, TP7, TP8, TP9, TP10.

Hippocampal tissue was available from seven patients who underwent
surgery. There were four patients in the AC group and three in the NC
group. The mini-mental state examination (MMSE) was performed in these
patients for cognitive evaluation. Hippocampal sclerosis was observed in
all the pathology reports.

\textbf{EEG examination and data preprocessing}

Resting-state EEG data without excessive noise, muscle artifacts, or
epileptiform discharges were extracted and preprocessed using EEGLAB
(R13\_6\_5b) in MATLAB R2017b. An independent component analysis was
used for further artifact removal, particularly for muscle artifacts.
EEG data were resampled at 500 Hz and recomputed against the average
reference. A 50 Hz notch filter was applied to attenuate the
contamination from the alternating current. The bandpass filter was set
to 0.1--100 Hz. The EEG data were split into non-overlapping epochs of
two seconds. Each participant underwent 60--120 epochs.

\textbf{Source analysis and functional connectivity}

An EEG cortical source analysis was performed using exact low-resolution
electromagnetic tomography (eLORETA) software (Pascual-Marqui et al.,
2011; Vecchio et al., 2021) (publicly available
at\emph{http://www.uzh.ch/keyinst/NewLORETA/LORETA01. htm}). This is a
linear source imaging method used in resting-state EEG studies to
estimate the current source densities of EEG rhythms in different
frequency bands. Regions of interest (ROIs) were defined according to
the Brodmann areas: 41 ROIs (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 17, 18,
19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 34, 35, 36, 37, 38,
39, 40, 41, 42, 43, 44, 45, 46, 47, 48), for each hemisphere. A lagged
linear coherence between all pairs of the 82 ROIs was extracted by ``all
nearest voxels'' for seven frequency bands: delta (1--4 Hz), theta (4--8
Hz), alpha (8--12 Hz), beta (12--30 Hz), gamma 1 (30--50 Hz), gamma 2
(50--70 Hz), and gamma 3 (70--90 Hz).

\textbf{Graph theoretical analysis}

Graph theoretical analyses were performed by GRETNA (Wang et al., 2015)
in MATLAB R2017b. Graph theory is the study of graphs, which are
mathematical structures used to model pairwise relations between
objects. The graph is made up of nodes and edges. In the current study,
nodes represent ROIs, while edges represent functional connectivity,
which is the lagged linear coherence calculated using eLORETA, which was
used for graph theory in a previous study (Vecchio et al., 2021). The
small world index (SWI) calculated from graph theoretical analysis was
used for further analysis due to the association with cognition (Vecchio
et al., 2014; Zeng et al., 2015). A previous study reported that
increased hippocampal volume reflected increased small-world
characteristics in gamma frequency band of connectivity in Alzheimer's
disease (Vecchio et al., 2017). The study by Vecchio et al. reported
higher gamma small world characteristics during the resting state and
better performance in short-term memory (Vecchio et al., 2016). The
small world network combines high levels of local clustering among nodes
and short path length (Bullmore \& Sporns, 2009). SWI was defined as the
ratio of the normalized clustering coefficient (Cw) and the normalized
path length (Lw) (Rubinov \& Sporns, 2010; Vecchio et al., 2018). Brain
networks have a small world property (Bassett \& Bullmore, 2006). The
density threshold was set from 0.15 to 0.50, with a 0.05 interval. The
upper limit of the density threshold was defined by the size of the
connectivity matrix (82, 82) (Supplemental Method 1). SWI in 0.30--0.50
thresholds showed similar trends in each group (Supplemental Fig. 1). We
chose the data at a density threshold of 0.45 for further analyses.

\textbf{Frequency spectral analysis}

Frequency spectral analysis was performed using a fast Fourier transform
(1000-point) algorithm. The absolute power spectral density (PSD, dB,
10log10(V\textsuperscript{2}/Hz)) for each channel was calculated based
on the periodogram. Relative PSD (rPSD) was computed by normalizing the
total power over the entire frequency range. The absolute and relative
PSDs were averaged across channels within groups to measure the global
comparisons between groups in each frequency band. A group comparison of
the PSDs for each channel was also performed.

\textbf{Immunohistochemistry}

Formalin-fixed paraffin-embedded hippocampal tissue blocks were
sectioned at 5 mm thickness and subjected to fluorescence
immunohistochemistry. Tyramide signal amplification (TSA) was used for
double fluorescence immunostaining of the same tissue section (T\selectlanguage{ngerman}óth \&
Mezey, 2007). Double staining was used in combination with antibodies
against neuron-specific nuclear protein (NeuN; Cell Signaling
Technology, \#24307) and A\selectlanguage{greek}β \selectlanguage{english}peptide 1-42 (Abcam, ab201061), and a
combination of antibodies against microtubule association protein-2
(MAP2, MILLIPORE, \#1990899) and p-Tau (phosphor T231, Abcam, ab151559).
All samples were processed using standard protocols and solutions (T\selectlanguage{ngerman}óth
\& Mezey, 2007).

A\selectlanguage{greek}β \selectlanguage{english}and p-Tau depositions were quantified using an image analysis system
(AON-STUDIO, 2021) based on the contrast between the stained and
unstained regions. In each case, images were captured, and a threshold
optical density was obtained that differentiated positively stained
tissue from the background. Image analysis was performed while blinded
to the identity of each patient. Three regions (\selectlanguage{ngerman}×200) of the hippocampus
were randomly sampled from each patient. The final measurement was
obtained by dividing the area of the immune-positive plaques by the
total sampling area. Data from all sampled areas were used for group
comparisons. The significance of group differences was determined using
the Mann-Whitney U test.

\textbf{Statistics analyses}

The SWI and PSD data were normally distributed according to normality
Q-Q plots. An analysis of variance (ANOVA) was performed to assess group
differences in SWI and PSD, followed by post-hoc analyses with false
discovery rate (FDR) correction when overall significant effects were
observed. An independent t-test was used for AC and NC group comparisons
of SWI. Spearman's correlation test was used for the correlation
analysis between the SWI and cognition scales. Continuous non-normal
data were examined using the Kruskal-Wallis or Mann-Whitney U-test for
group comparisons. The chi-squared test was used for group comparisons
of categorical data. The level of significance was set at
\emph{p}\textless{} 0.05. Analyses of SWI and PSD were performed for
each frequency band. \emph{p} -values were FDR-corrected for multiple
comparisons. Group comparisons of functional connectivity were corrected
using network-based statistic (NBS) (Zalesky et al., 2010). Statistical
analyses were performed using IBM SPSS Statistics v22.

\textbf{Results}

WIS was performed in 61 patients with drug-resistant TLE (68.9\% were
male, median age 31, range 12--53). At the time of the EEG recordings,
the median disease course was 13 years (0.5--35 years). There were no
group differences in terms of age and sex between the TLE and HC groups
(Table 1). Forty-four patients presented with temporal lesions. Anterior
temporal lobectomy or lobotomy was performed on 50 patients. Pathology
reports were available for thirty-six patients, including focal cortex
dysplasia (n=28), hippocampal sclerosis (n=15), and tumors (n=3).
Radiofrequency thermocoagulation was performed in two patients, and
vagus nerve stimulation (VNS) was performed in one patient. Operations
were performed in more patients with cognitive impairment than in those
with normal cognition (\emph{p} = 0.005). The mean IQ and memory
quotient (MQ) in the NC group was 107 (range 93-137) and 101 (range
72-122), respectively. In the AC group, the mean IQ was 71 (50--85) and
the mean MQ was 64 (40--83).

\textbf{Graph theory analysis}

In the current study, TLE patients with WIS scores in the NC (\emph{n} =
31), AC (\emph{n} = 30), and HC (\emph{n} = 18) groups were included for
further analyses. The results of the graph theory are presented in Table
1 and Figure 1. SWI in the AC group tended to be increased in delta and
theta frequency but decreased in alpha frequency compared to that in the
NC group and controls. Group differences were significant for alpha
(\emph{p} \textsubscript{NC-AC}=0.006). Increased SWI in the fast rhythm
was observed in both TLE groups compared with controls. However, in the
gamma frequency, SWI in the AC group declined to the level of SWI in
controls. SWI in the AC group was significantly lower than that in the
NC group at 50--70 Hz (\emph{p} \textsubscript{NC-HC}=0.031,\emph{p}
\textsubscript{NC-AC}=0.031) after applying the FDR correction.

Spearman's correlations between the WIS and SWI were tested in each
frequency band (Supplemental Table 1). After applying a multiple test
correction, the results showed that SWI in alpha and 50--70 Hz was
positively correlated with IQ (alpha: \emph{r} = 0.434, \emph{P} =
0.003; 50--70 Hz: \emph{r} = 0.352, \emph{p} = 0.021) and MQ
(alpha:\emph{r} = 0.373, \emph{P} = 0.010; 50--70 Hz: \emph{r} =
0.412,\emph{p} = 0.007) (Figure 2). The results of Spearman's
correlation analysis of the SWI and cognition scores are summarized in
Supplemental Table 1.

Group comparisons of functional connectivity between all ROIs were
performed using EEG data from 40-channel EEG recordings. After applying
NBS, no significant differences were observed.

\textbf{Spectral analysis}

The cross-channel grand average of the global EEG, PSD, and rPSD was
calculated (Figure 3 A and B and Supplemental Table 2). After FDR
correction, absolute PSD in slow rhythms was significantly increased in
the TLE groups compared to controls (delta:\emph{p}
\textsubscript{HC-NC=}0.012,\emph{p} \textsubscript{HC-AC}=0.012;
theta:\emph{p} \textsubscript{HC-NC=}0.019,\emph{p}
\textsubscript{HC-AC}=0.012). Group differences in rPSD were also
detected for delta (\emph{p} \textsubscript{HC-NC}=0.003,\emph{p}
\textsubscript{HC-AC}=0.002) and alpha (\emph{p}
\textsubscript{HC-NC}=0.002,\emph{p}
\textsubscript{HC-AC}\textless{}0.001). The results revealed that the
general EEG activity slowed in drug-resistant TLE. No significant group
differences in the absolute and relative PSDs were observed for gamma.

Moreover, group comparisons of PSDs were performed in each channel
(Figure 3 C\&D and Supplemental Table 3 \& 4). As shown in Figure 3,
powers in slow rhythm in the TLE groups were significantly increased
mainly over the anterior regions, particularly the anterior and middle
temporal lobes, compared to controls. The absolute PSD in alpha showed
no difference in the group comparison. However, the relative PSD
revealed that the percentage of alpha power decreased in both TLE groups
over the entire head compared to controls. For gamma frequencies, the
rPSD over the central, frontal, and temporal lobes was lower in the TLE
groups than in the controls.

\textbf{Pathology in hippocampus of drug-resistant TLE}

Hippocampal tissues were available in seven patients with drug-resistant
TLE, four in the AC group, and three in the NC group. The mean disease
course was 13 years from seizure onset (5--23 years) in the NC group and
17 years (17--23 years) in the AC group. There were no significant
differences in disease course, sex, or age. All patients underwent MMSE
(Table 2). The mean MMSE score was 28 (28--29) in the AC group and 20
(17--23) in the NC group. Immunofluorescence revealed A\selectlanguage{greek}β \selectlanguage{english}and p-tau
deposits in both the NC and AC groups (Figure 4A and B). Three sampled
regions (\selectlanguage{ngerman}×200) were randomly selected from the hippocampus of each
patient. The percentage of each sampled area with positive A\selectlanguage{greek}β \selectlanguage{english}and p-Tau
immunofluorescence was calculated using a quantitative analysis (Table
2). The mean percentage of A\selectlanguage{greek}β \selectlanguage{english}in the sampled regions was 0.13\%
(0.03\%--0.26\%) in the NC group and 0.26\% (0.01\%--0.67\%) in the AC
group. The mean p-Tau load was 0.61\% (0.25\%--1.25\%) in the NC group
and 1.20\% (0.58\%--2.33\%) in the AC group. As shown in Table 2 and
Figure 4C, there was a significant difference in the severity of A\selectlanguage{greek}β \selectlanguage{english}and
p-Tau load between the NC and AC groups (A\selectlanguage{greek}β: \selectlanguage{english}\emph{p}
\textsubscript{NC-AC} = 0.034; p-Tau: \emph{p} \textsubscript{NC-AC} =
0.012).

\textbf{Discussion}

Graph theory has been proposed for detailed understanding of structural
connectivity between cortical areas (Sporns et al., 2005). In this
study, graph theory revealed that SWI in drug-resistant TLE increased
from beta frequency and had a markedly high level in gamma frequency. A
recent study also found that in patients with focal epilepsy, SWI tended
to increase in gamma frequency (30--45Hz) (Hatlestad-Hall et al., 2021).
Our study presented all the SWI trends from delta to gamma (30--90Hz) in
TLE patients. SWI is used to describe the balance between the local
connectedness and the global integration of a network. Small-world
organization is intermediate between random networks, short overall path
length associated with a low level of local clustering, regular networks
or lattices, and the high-level of clustering, which is accompanied by a
long path length (Vecchio et al., 2014). Hypersynchronous neuronal
activity associated with epilepsy could cause widespread functional
network alterations. The elevated beta and gamma SWI in drug-resistant
TLE may reflect increased post-synaptic activity of local neurons.
Increased neuronal activity changes the ionic environment of neurons and
leads to increased burst firing of neurons (Heinemann et al., 1986;
Jensen et al., 1994). Intensified gamma networks may be related with the
epileptic characteristics and cortical neuron excitation.

Interestingly, we showed that SWI increased at beta frequency in
patients with TLE and cognitive deficits and then markedly declined at
gamma frequencies. The change was significant at 50-70 Hz, compared to
that in patients with normal cognition. The correlation between
gamma-SWI and cognition has been demonstrated in previous studies
(Vecchio et al., 2017; Vecchio et al., 2016), that lower gamma SWI in AD
is associated with better short-term memory and a smaller hippocampal
volume. Graph analysis suggests less efficient interaction and
disconnection between brain regions in patients with Alzheimer's
disease, and gamma activity is closely correlated with cognitive
functions (Engel et al., 2001). Our study showed that gamma SWI could be
influenced by focal epilepsy, but a comparison between patients with
drug-resistant TLE to eliminate the influence of epilepsy revealed that
gamma SWI was positively correlated with cognition level, especially in
high gamma. Moreover, TLE patients with cognitive deficits may have
reduced efficiency of network communication in gamma bands in the
context of hypersynchronous neuronal activity. Additionally, the alpha
SWI in both TLE groups was not significantly different from that in the
healthy controls, may due to the small sample and multiple test
correction. However, alpha SWI in TLE showed a positive association with
IQ and MQ scores.

Spectral analyses revealed a reduction of spectral power in the alpha
band and increased power in the delta and theta bands in patients with
drug-resistant TLE, compared to healthy controls. Changes in patients
with cognitive impairment were more pronounced. This indicated that the
general EEG was slow in drug-resistant TLE. Increased delta power is
mainly localized over the anterior head, especially in the temporal
region. The results are corresponding to temporal lesions in TLE.
Decreased gamma power was detected in the temporal, central, and frontal
lobes; however, the average rPSD in the entire head was not
significantly different. Previous studies have suggested reduced
resting-state gamma power/synchronization in Alzheimer's disease (Koenig
et al., 2005; Ribary et al., 1991; Stam et al., 2002). The present study
revealed that interictal EEG without epileptiform discharges in TLE had
lower gamma power in the temporal and frontal regions. No group
differences of gamma power were detected between the TLE groups. But the
gamma-communicating functional network was influenced by cognitive
impairment in TLE.

Pathological changes were significant in epilepsy patients with
cognitive deficits, including A\selectlanguage{greek}β \selectlanguage{english}and p-Tau deposition in the resected
hippocampus. The current study showed that amyloid and p-Tau loads were
increased in TLE patients with cognitive deficits compared to patients
with normal cognition. Both A\selectlanguage{greek}β \selectlanguage{english}and p-Tau deposits have been documented
in drug-resistant TLE tissue (Gourmaud et al., 2020; Tai et al., 2016).
Increased A\selectlanguage{greek}β\selectlanguage{english}1--42 peptide and hyperphosphorylated Tau in the hippocampus
are associated with cognitive deficits and have been reported in
temporal lobe epilepsy (Gourmaud et al., 2020). A\selectlanguage{greek}β \selectlanguage{english}peptides play a key
role in Alzheimer's disease pathogenesis (Karran et al., 2011). The
findings of our and previous studies indicate that A\selectlanguage{greek}β \selectlanguage{english}and p-Tau deposits
may be correlated with impaired cognition in drug-resistant TLE. Gamma
frequency entrainment can attenuate amyloid load and improve cognition
in AD and wild-type animal models (Iaccarino et al., 2016; Park et al.,
2020; Tian et al., 2021). Considering these data, we propose that
alterations in gamma frequency may be a potential therapeutic target for
drug-resistant TLE with cognitive deficits.

\textbf{Limitations}

The present study had limitations. First, the WIS scores were lacking in
the control group, and would enable more robust conclusions from
comparisons between controls and drug-resistant TLE patients.
Nonetheless, a detailed medical history, especially concerning
neurological diseases, was reviewed for healthy controls. Additionally,
all controls passed the primary cognition test with calculation and
memory abilities. Second, a larger sample size for the pathological
analysis will further validate these data. Moreover, evaluating
pathological factors directly reflecting the cause of impaired
efficiency of brain connectivity, such as synapsis and myelination
status may lead to more robust conclusions.

\textbf{Conclusion}

Overall, we demonstrated that cognitive deficits in drug-resistant
temporal lobe epilepsy may lead to slowing of general EEG activity, loss
of efficiency in gamma band connectivity, and increased A\selectlanguage{greek}β \selectlanguage{english}and p-Tau
expression. The EEG and pathological changes in these patients indicated
that high frequency may be an evaluation marker and a potential
therapeutic target for cognitive dysfunction.

\textbf{Conflict of interests:} None of the authors have potential
conflicts of interest to be disclosed.

\textbf{Ethics statement:} The studies involving human participants were
reviewed and approved by The Ethics Committee of Peking Union Medical
College Hospital (No. JS3511). The patients/participants provided their
written informed consent to participate in this study.

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Table1. Demographic data, cognition scales and small world index across
gamma bands in drug-resistant temporal lobe epilepsy\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
HC (n=18)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
NC (n=31)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
AC (n=30)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
P\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age (mean, range)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
33(16-58)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
28(12-51)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
33(13-53)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{P}=0.116\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Sex (M:F)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10:8\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
22:9\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
20:10\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{P}=0.541\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Disease course /y (mean, range)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11.5(0.5-31)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
15.0(1-35)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{P}=0.113\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
IQ\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
107(93-137)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
71(50-85)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{P} \textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
MQ\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
101(72-122)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
64(40-83)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{P}\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
MRI temporal lesion\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
21(67.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
23(76.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{P}=0.570\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Operations\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
23(74.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
30(100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{P}=0.005\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Lobectomy/lobotomy\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
20(74.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
30(100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{P\textless{}}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Thermocoagulation\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2(6.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{P}=0.492\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
VNS\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1(3.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{P}=1.000\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Small world index\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
ANOVA (2, 76)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1-4Hz\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.971 (0.029)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.975 (0.026)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.978 (0.021)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
F=0.364, \emph{P}=0.696\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4-8Hz\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.985 (0.021)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.982 (0.030)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.990 (0.027)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
F=0.598, \emph{P}=0.645\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
8-12Hz\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.980 (0.016)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.985 (0.022)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.972 (0.015)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
F=6.248, \emph{P}=0.021 P\textsubscript{NC-AC}=0.006\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
12-30Hz\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.995 (0.021)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.012 (0.043)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.008 (0.035)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
F=1,468, \emph{P}=0.415\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
30-50Hz\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.002 (0.038)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.017 (0.042)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.010 (0.033)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
F=0.954, \emph{P}=0.546\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
50-70Hz\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.006 (0.032)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.031 (0.036)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.009 (0.032)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
F=4.543, \emph{P}=0.049 P\textsubscript{NC-HC}=0.031,
P\textsubscript{NC-AC}=0.031\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
70-90Hz\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.011 (0.043)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.031 (0.047)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.006 (0.033)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
F=2.992, \emph{P}=0.131\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

HC: healthy control; NC: normal cognition; AC: abnormal cognition

Table 2. Amyloid-\selectlanguage{greek}β \selectlanguage{english}and phosphorated-Tau load (percentage of sampled area
with positive immunohistochemistry) in hippocampus of drug-resistant
temporal lobe epilepsy.\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Age\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Sex\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
MMSE\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Amyloid-\selectlanguage{greek}β \selectlanguage{english}load (\%)\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
p-Tau load(\%)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
NC-case1\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
31\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
28\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.03 0.05 0.08\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.38 0.96 0.25\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
NC-case2\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
24\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
29\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.08 0.21 0.11\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.32 1.25 0.83\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
NC-case3\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
33\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
28\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.26 0.12 0.20\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.38 0.72 0.40\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
AC-case1\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
27\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
17\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.01 0.27 0.42\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
1.97 0.58 1.45\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
AC-case2\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
39\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
23\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.19 0.48 0.13\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.88 1.03 1.19\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
AC-case3\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
30\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
20\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.30 0.14 0.12\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.64 0.63 1.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
AC-case4\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
52\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
19\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.67 0.28 0.13\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
1.8 0.87 2.33\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{P}\textsubscript{NC-AC} = 0.629\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{P}\textsubscript{NC-AC} = 1.000\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{P}\textsubscript{NC-AC} = 0.057\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{P}\textsubscript{NC-AC} = 0.034\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{P}\textsubscript{NC-AC} = 0.012\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

NC: normal cognition; AC: abnormal cognition

\textbf{Figure legends}

\textbf{Figure 1.} \textbf{Small world index (SWI) trends in
drug-resistant TLE and control groups.} SWI in the AC group decreased in
alpha frequency compared to that in the NC group and controls. The SWI
increased in beta frequency in both TLE groups, then declined in gamma
frequency in AC group. TLE: temporal lobe epilepsy; NC: normal
cognition; AC: abnormal cognition.

\textbf{Figure 2.} \textbf{Association between cognitive scales and
small world index (SWI) by Spearman's correlations. (A-D)} SWI in alpha
and gamma frequency bands (50-70Hz) showed positive correlation with
intelligence quotient and memory quotient after FDR correction.

\textbf{Figure 3. Frequency spectral analysis in drug-resistant temporal
lobe epilepsy (TLE) patients. (A) \& (B)} Across-channel grand average
of Power spectral density (PSD) showed increased delta power and
decreased alpha power in drug-resistant TLE groups, compared to
controls. \textbf{(C) \& (D)} Increased delta power in TLE groups are
mainly over the anterior regions. For gamma frequencies, the relative
PSD over the central, frontal, and temporal areas was lower in the TLE
groups than in the controls.

\textbf{Figure 4.} \selectlanguage{greek}\textbf{Amyloid-β (Aβ) and phosphorated-Tau (p-Tau)
immunofluorescence in hippocampus of drug-resistant TLE.}\selectlanguage{english}
\textbf{(A)}Different A\selectlanguage{greek}β \selectlanguage{english}expression between NC and AC groups is
observed, with similar Neun expression. \textbf{(B)} The p-Tau
deposition is more severe in AC group, compared with NC group, while the
expression of MAP2 is similar in two groups. \textbf{(C)} Quantitative
analysis showed substantial differences between NC and AC groups in A\selectlanguage{greek}β
\selectlanguage{english}and p-Tau expression. NC: normal cognition; AC: abnormal cognition.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure1/figure1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure2/figure2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure3/Figure3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure4-new/figure4-new}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

