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  <front>
    <journal-meta />
    <article-meta>
      <title-group>
        <article-title>A software pipeline for pre-processing and mining EEG signals: application in neurology</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <string-name>(Discussion Paper)</string-name>
        </contrib>
        <contrib contrib-type="author">
          <string-name>Mario Cannataro</string-name>
          <email>cannataro@unicz.it</email>
          <xref ref-type="aff" rid="aff0">0</xref>
        </contrib>
        <contrib contrib-type="author">
          <string-name>Chiara Zucco</string-name>
          <email>zucco@unicz.it</email>
          <xref ref-type="aff" rid="aff0">0</xref>
        </contrib>
        <contrib contrib-type="author">
          <string-name>Barbara Calabrese</string-name>
          <email>calabreseb@unicz.it</email>
          <xref ref-type="aff" rid="aff0">0</xref>
        </contrib>
        <contrib contrib-type="author">
          <string-name>Miriam Sturniolo</string-name>
          <email>sturniolom@yahoo.it</email>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <string-name>Antonio Gambardella</string-name>
          <email>a.gambardella@unicz.it</email>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <contrib contrib-type="editor">
          <string-name>EEG, Psychogenic Non-Epileptic Seizures, Machine Learning, pre-processing</string-name>
        </contrib>
        <aff id="aff0">
          <label>0</label>
          <institution>Department of Medical and Surgical Sciences, University ”Magna Graecia”</institution>
          ,
          <addr-line>Catanzaro</addr-line>
        </aff>
        <aff id="aff1">
          <label>1</label>
          <institution>Mater Domini Polyclinic, University ”Magna Graecia”</institution>
          ,
          <addr-line>Catanzaro</addr-line>
        </aff>
      </contrib-group>
      <pub-date>
        <year>2021</year>
      </pub-date>
      <fpage>5</fpage>
      <lpage>9</lpage>
      <abstract>
        <p>Psychogenic non-epileptic seizures (PNES) resemble epileptic seizures, but they do not show the characteristic electrical discharges associated with epileptic seizures. Long term video monitoring combined with EEG recording is the gold standard in clinical practice, but this methodology is quite expensive and time-consuming. This paper presents a software pipeline to discriminate short-term interictal EEG from PNES and epileptic patients. The pipeline supports EEG signals pre-processing, features selection and classification. A first case study concerning the classification of 75 EEG (healthy, PNES and epileptic subjects) is under evaluation.</p>
      </abstract>
    </article-meta>
  </front>
  <body>
    <sec id="sec-1">
      <title>1. Introduction</title>
      <p>
        Psychogenic non-epileptic seizures (PNES) are sudden behavioural changes mimicking epileptic
seizures but without EEG ictal patterns, caused by psychic alterations [
        <xref ref-type="bibr" rid="ref1">1</xref>
        ], [
        <xref ref-type="bibr" rid="ref2">2</xref>
        ]. PNES have been
associated to a dysfunction in the processing of psychological or social distress, abuse during
childhood or severe traumatic events [
        <xref ref-type="bibr" rid="ref3">3</xref>
        ], [
        <xref ref-type="bibr" rid="ref4">4</xref>
        ]. In [
        <xref ref-type="bibr" rid="ref5">5</xref>
        ], the authors reported an aggravation of
the seizure frequency in PNES patients, a vulnerable group of people during this pandemic
COVID-19.
      </p>
      <p>
        Misdiagnosis with epilepsy may lead to treatments through antiepileptic drugs (AEDs) with
the risk of iatrogenic morbidity and elevated cost for the patient and Health Care Systems [
        <xref ref-type="bibr" rid="ref6">6</xref>
        ]. It
has been discovered that the correct diagnosis of PNES is usually delayed for an average of seven
years [
        <xref ref-type="bibr" rid="ref7">7</xref>
        ], with a profound impact on patients and caregivers quality of life. The gold standard
for PNES diagnosis is represented by the visual examination of seizures captured during
videoelectroencephalography (video-EEG), either spontaneously or provoked by intermittent photic
stimulation (IPS) suggestion techniques. These methods are time-consuming and ethically
nEvelop-O
disputable; thus, since the experts evaluate no definite criterion, visual analysis of EEG signals
is insuficient. The International League Against Epilepsy (ILAE), using a consensus review of
literature, evaluated fundamental diagnostic approaches, including detailed history and seizures
description, EEG, video-EEG, neurophysiology, neuroimaging, hypnosis, and neuro-humoral
monitoring [
        <xref ref-type="bibr" rid="ref6">6</xref>
        ].
      </p>
      <p>To the best of our knowledge, only a few studies have investigated semi-automatic or
automatic machine learning-based approaches for discrimination between epileptic and PNES
subjects by only considering EEG recordings. The current study is one of the few in which an
EEG dataset, without any correlated video-EEG PNES marker, has been analyzed to discriminate
PNES via EEG.</p>
      <p>Specifically, this paper proposes a novel and semi-automatic pipeline to discriminate PNES
subjects from epileptic subjects based on the extraction of spectral features and classification
through a Machine Learning-based approach. To design a software pipeline that allows
discrimination, we have implemented diferent classifiers, i.e. Support Vector Machine (SVM), Linear
Discriminant Analysis (LDA), Bayesian Network (BN). In this work, we have analyzed EEG
recordings of twenty-five PNES subjects, twenty-five healthy volunteer subjects and twenty-five
epileptic patients.</p>
      <p>The paper is organized as follows: Section 2 presents the background relative to EEG analysis
and classification, focusing on PNES discrimination; Section 3 describes experimental EEG
acquisitions. Section 4 presents and discusses the proposed software pipeline, highlighting the
features of software modules. Finally, Section 5 concludes the paper.</p>
    </sec>
    <sec id="sec-2">
      <title>2. Background on EEG analysis and classification</title>
      <p>The EEG signals are random and non-stationary and may contain valuable information about
the brain state with millisecond temporal resolution. However, it isn’t efortless to disentangle
information from these signals directly in the time domain by observing them. EEG spectrum
contains some characteristic waveforms that fall primarily within five frequency bands: delta
(1–-4 Hz), theta (4–-8 Hz), alpha (8-–13 Hz), beta (13-–30 Hz) and gamma (30–60 Hz). Many
eforts have been made for automatic and semi-automatic EEG processing by exploiting several
algorithms that operate in time, frequency, or the time-frequency domain. Among the time
domain (TD) features, Mean Absolute Value (MAV), Zero Crossings (ZC), Slope Sign Changes
(SSC) and Waveform Length (WL) are some examples. Fourier Transform (FT) and Power
Spectral Analysis (PSD) are the most common features extracted in the frequency domain.
The most used methods are Wavelet Transform (WT) and Hilbert - Huang Transform in the
time-frequency domain.</p>
      <p>
        There are many studies on EEG data analysis. The work [
        <xref ref-type="bibr" rid="ref8">8</xref>
        ] describes a new method to identify
seizures in EEG signals using feature extraction in time-frequency distributions (CFDs). In [
        <xref ref-type="bibr" rid="ref9">9</xref>
        ],
the authors analyze the diferences in power spectral density between healthy subjects and
schizophrenic patients in various frequency bands. Moreover, frequency and time-frequency
approaches have been applied for analysis of patients with brain damage [
        <xref ref-type="bibr" rid="ref10">10</xref>
        ], automatic
detection of epileptic seizures [
        <xref ref-type="bibr" rid="ref11">11</xref>
        ] and, also, early detection of mild cognitive impairment and
Alzheimer’s disease [
        <xref ref-type="bibr" rid="ref12">12</xref>
        ].
      </p>
      <p>
        Various data mining techniques such as Association Rule, classification, regression, and
clustering have been used in the literature. Support vector machine (SVM) is a machine learning
model used for classification, and regression analysis [
        <xref ref-type="bibr" rid="ref13">13</xref>
        ].
      </p>
      <p>
        Diferential diagnosis cannot rely only on clinical features of PNES because most of the signs
ift with epileptic seizures. Longer duration, gradual onset, asynchronous movement, closed eyes,
lateralized head movement contribute to a complex clinical pattern of PNES. These events are
involuntary and out of the patient’s conscious control. PNES patients mimic the diferent type
of epileptic seizures but no epileptic seizures electrophysiological patterns. Thus discrimination
would be useful to aid neurologist diagnosis and consequently assign the right pharmacological
treatment. The prevalence of PNES is high in selected populations: 5–-20% in outpatient epilepsy
populations [
        <xref ref-type="bibr" rid="ref14">14</xref>
        ], [
        <xref ref-type="bibr" rid="ref15">15</xref>
        ]. 10–-40 % of patients referred to tertiary epilepsy centers for medically
refractory seizures [
        <xref ref-type="bibr" rid="ref16">16</xref>
        ]. Making PNES diagnosis is soupy with medico-legal hazards, and it is
hard to prove [17].
      </p>
      <p>EEG recordings alone are not suficient to diagnose PNES: an ictal scalp EEG may show no
epileptic features during simple partial seizures or mesial frontal lobe seizures. The latter may
be easily mistaken for PNES. The diferentiation between non-epileptic seizures and healthy
subject can be dificult. Therefore, a good knowledge of the semiology of PNES is essential for
the early screening of patients for video-EEG monitoring (VEM) and correct interpretation of
the examination. PNES should also be diferentiated from physiological, non-epileptic events
such as syncope, cataplexy, migraine, paroxysmal movement disorders, breath-holding spells,
stable ictal heart rate [18].</p>
      <p>Additionally, VEM monitoring is highly time-consuming and labour intensive and therefore
is relatively expensive and limited in availability; thus, alternative diagnostic procedures are
necessary.</p>
      <p>Despite many eforts made, no bio-marker of PNES has yet been identified. In [ 19], the
authors sustain patients with PNES have a stable frequency of rhythmic movements, about
(5Hz), which produces a stable rhythmic artefact on the EEG with little variation or evolution.
Bolen et al. [20] have noted significantly more multifocal abnormalities in frontal, temporal,
parietal, occipital, cerebellar and brainstem brain regions PNES patients.</p>
      <p>Continuous wavelet transform is used in [21] to process CNT and PNES EEG signal.</p>
      <p>In [22], a machine learning (ML) pipeline for classifying EEG epochs of PNES and healthy
controls is introduced. This software pipeline consisted of a semi-automatic signal processing
technique and a supervised ML classifier to aid the discriminative clinical diagnosis of PNES.
Statistical features like the mean, standard deviation, kurtosis, and skewness were extracted from
a power spectral density (PSD) map split up into the five conventional EEG rhythms. Finally, we
evaluated three diferent supervised ML algorithms, namely, the Support Vector Machine (SVM),
Linear Discriminant Analysis (LDA), and Bayesian network (BN), to perform EEG classification
tasks for control vs PNES subjects. The algorithm’s performance was evaluated on a dataset of
20 EEG signals (10 PNES and 10 control), achieving an average accuracy above 90 %.</p>
    </sec>
    <sec id="sec-3">
      <title>3. EEG signals acquisition</title>
      <p>The data under evaluation were collected from the Operative Unit of Neurology, Mater Domini
Polyclinic, University of Catanzaro, Italy. In this study, we analyzed EEG recordings from 25
patients with PNES, 25 healthy patients referred to as CNT and 25 epileptic patients. PNES
diagnosis was made based on a typical episode recorded during video-EEG, with EEG showing
neither concomitant ictal activity nor post-ictal. Healthy controls did not sufer from any
neurological disorder and had a normal neurological examination. None of the subjects was
on chronic medication or had received any drug up to 24 hours before EEG acquisition. The
study was conducted following the Declaration of Helsinki and formally approved by the local
Medical Research Ethics Committee. Participants were comfortably seated in a semi-darkened
room and with open eyes. The technician kept the subject alert in order to prevent drowsiness.</p>
      <p>EEG recordings were conducted in poorly light-room using 19 Ag/AgCl surface electrodes
placed according to the International 10/20 System. Recordings were performed with a Xltek®
Brain Monitor EEG Amplifier with a sampling rate of 256 Hz; high-pass filter at 0.5 Hz and a
low-pass filter at 70 Hz, plus a 50 Hz notch filter. All of the EEG signals were recorded using a
montage with the following channels layout: Fp1, Fp2, F3, F4, C3, C4, P3, P4, O1, O2, F7, F8, T3,
T4, T5, T6, Fz, Cz and Pz, and reference in Pz.</p>
      <p>All the electrode-skin impedance has been kept below 5 KΩ. The EEG data were recorded in
a resting condition. Each participant was seated in a comfortable chair in an electrically and
acoustically shielded room. EEG artefacts were rejected through a semi-automatic procedure:
(i) first artefacts components were individuated through clinical (visual) inspection; (ii) all signal
segments afected by evident artifactual components are cut of from raw EEG data.</p>
    </sec>
    <sec id="sec-4">
      <title>4. EEG software pipeline</title>
      <p>The architecture of the proposed EEG software pipeline (written in Python language) presents
the following modules:
• Pre-processing: this module performs digital filtering and semi-automatic artefact
rejection;
• Features extraction: Power Spectral Density (PSD) function is evaluated for each channel
by using Welch’s method. From PSD functions, cumulative power coeficients in clinical
bands are calculated to build features vector to fed in input to the classifiers;
• Features selection: searches for the most significant features for classification;
• EEG classification: the framework implements diferent machine learning approaches,
such as Support Vector Machine, Bayesian Networks and Linear Discriminant Analysis
to discriminate PNES EEG from CNT EEG.</p>
      <p>The rest of the section details the features of each module.</p>
      <sec id="sec-4-1">
        <title>4.1. EEG Pre-processing</title>
        <p>In general, EEG signals are contaminated by environmental noise or even distorted by artefacts.
Removing noise is an important step in EEG signals processing. A correct data cleaning may
improve the signal to noise ratio and helps to disentangle the most informative features from
the signal. Even if diferent semi-automatic approaches have been proposed for EEG
preprocessing, in clinical practice, the rejection of artefacts is performed manually by trained
neurologists by discarding contaminated EEG epochs. Therefore, the pre-processing stage is
operator-dependent, tedious and time-consuming.</p>
        <p>In this study, each EEG recording was checked by a trained neurologist to marker noise and
artefact corrupted epoch. Subsequently, all EEG data were pre-processed using digital filtering
techniques. Specifically, we have used a Butterworth band-pass filter (0.1-70 Hz) and a notch
iflter (cut-of frequency 50 Hz) to reduce high-frequency artefacts and power-line interference.</p>
      </sec>
      <sec id="sec-4-2">
        <title>4.2. EEG Features Extraction</title>
        <p>After the pre-processing step, the next step in the EEG software pipeline is the features extraction
stage. As mentioned before, features extraction aims to extract relevant information contained
in the signals. One of the most used features extractor in EEG signals processing is the Power
Spectral Density (PSD) analysis. Diferent methods for PSD estimation have been reported in
the literature. We have chosen Welch’s method.</p>
        <p>Welch Spectrum Welch’s method is a well-known non-parametric method for PSD
estimation. Let be [],  = 0, · · ·,  − 1 are the samples from an EEG segment. To estimate the
Welch’s spectrum of this segment, three basic steps are applied:
• First, divide the original EEG time series into  sections (possibly overlapped  ) of equal
lengths  ;
⌊⌋ = ⌊ + ⌋
 = 0, …  − 1,
and  = 0, …  − 1
• Apply a window to each section and then calculate the periodogram on the windowed
sections (modified periodograms). The periodogram is defined as:
 ̃ () =
1 | −∑1 ()
 =0</p>
        <p>2
− 2</p>
        <p>| .
  ( ) =
1 −1</p>
        <p>∑   ( )
 =0
(1)
(2)
(3)
• Average the modified periodograms from the K sections in order to obtain an estimator
of the spectral density.</p>
        <p>Where   estimates the cross power spectral density of two discrete-time signals, x and y,
the Welch method eliminates the tradeof between spectral resolution and variance by allowing
the segments to overlap. If a high-frequency resolution is desired, one can only split the record
into a small number N of segments of length L. In system identification, the number of segments
K is typically 2,3, 6. Unfortunately, a small number of segments K implies a higher variance of
the estimated power spectrum. Therefore, it is worth looking into methods using overlapping
sub-records for reducing the variance as the main processing algorithm remains unchanged.
Our analysis uses a segment with 50% overlap for the first step and the Hamming window in
the second step.</p>
        <p>In this paper, power spectral density (PSD) of classical frequency bands from around 1 Hz to
70 Hz were used as features. Specifically, delta (1-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), beta
(13-30 Hz), gamma (30-70 Hz) bands have been considered.</p>
        <p>The main processing steps of our feature extraction approach are:
• Power Spectral Density (PSD) was estimated trough Welch method;
• from PSD matrix output, we selected five frequency sub-bands;
• for each band we computed cumulative power.</p>
        <p>All features extracted are arranged into a vector, known as a features vector.</p>
      </sec>
      <sec id="sec-4-3">
        <title>4.3. Features Selection and EEG Classification</title>
        <p>Features selection is useful in the presence of high-dimensional data as it reduces the space of
the features. This module is still under implementation. To discriminate CNT EEG from PNES
EEG, we have implemented three supervised Machine Learning algorithms. The classi ers used
in this paper are the SVM, LDA, and BNs.</p>
        <p>The SVM algorithm is based on the statistical learning theory. An SVM [23] constructs a
separating hyperplane or a set of hyperplanes in a high dimensional space. Intuitively, a good
separation is achieved by the hyperplane with the largest distance to the nearest training data
points of any class (so-called functional margin).</p>
        <p>Bayesian networks (BNs) [20], also known as belief networks, belong to probabilistic graphical
models (GMs). These structures are used to extract knowledge about an uncertain domain.
Each node in the graph represents a random variable, while the edges between the nodes
represent probabilistic dependencies among the corresponding random variables. The graph
dependencies are estimated by using known statistical and computational methods. Hence,
Bayesian Networks provide a simple definition of independence between any two distinct nodes.</p>
        <p>LDA classifier is one of the classification methods that finds an optimal linear transformation
that maximizes the class separability. LDA generates a linear combination of data sets that
allows the largest mean diferences between the desired classes. It works well when the feature
vector is multivariate normally distributed in each class group, and diferent groups have a
common covariance.</p>
      </sec>
    </sec>
    <sec id="sec-5">
      <title>5. Conclusions</title>
      <p>The main contribution of this paper is a comprehensive software pipeline written in Python
for the acquisition, pre-processing and classification of EEG signals. A first experimentation of
the pipeline in the classification of PNES vs epileptic subject is under evaluation by the clinical
team of the Neurology Unit of the University Magna Graecia of Catanzaro. The preliminary
results show that a features selection phase is necessary to improve the performance of the
classification.
[17] S. R. Benbadis, Nonepileptic behavioral disorders, 2013.
[18] C. Opherk, L. J. Hirsch, Ictal heart rate diferentiates epileptic from non-epileptic seizures,</p>
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