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 NEURAL
ENGINEERING
TECHNIQUES FOR
AUTISM SPECTRUM
DISORDER
VOLUME 1: IMAGING AND SIGNAL ANALYSIS

Edited by

Ayman S. El-Baz
Bioengineering Department, University of Louisville, Louisville, KY, United States

Jasjit S. Suri
AtheroPoint, Roseville, CA, United States

 
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With love and affection to my mother and father, whose loving spirit
sustains me still
Ayman S. El-Baz

To my late loving parents, immediate family, and children

Jasjit S. Suri
 Contributors
Francisco Alcantud-Marín Universitat de València,
València, Spain
Marah AlHalabi Abu Dhabi University, Abu Dhabi,
United Arab Emirates
Mohamed T. Ali Bioengineering Department, Uni-
versity of Louisville, Louisville, KY, United States
Yurena Alonso-Esteban Universitat de València,
València, Spain
Muhammad Awais Bin Altaf Lahore University of
Management Sciences, Lahore, Pakistan
Sandra Amador Department of Computer Science
and Technology, University of Alicante, Alicante,
Spain
Rushil Anirudh Lawrence Livermore National
Laboratory (LLNL), Livermore, CA, United States
Abdul Rehman Aslam Lahore University of Man-
agement Sciences, Lahore, Pakistan
Oresti Baños Department of Computer Architec-
ture and Technology, Granada, Spain
Pura Ballester Department of Clinical Pharmacol-
ogy, Pediatrics and Organic Chemistry, Miguel
Hernandez University, Elche, Spain
Gregory Barnes Neurology Department, Univer-
sity of Louisville, Louisville, KY, United States
Sevgi Bayari Department of Physics Engineering,
Hacettepe University, Ankara, Turkey
Charles M. Borduin Department of Psychological
Sciences, University of Missouri, Columbia, MO,
United States
Cynthia E. Brown Department of Psychology, Stony
Brook University, Stony Brook, NY, United States
Lianhua Chi La Trobe University, Melbourne, VIC,
Australia
Lauryn Dooley Cellular Neurobiology and Neuro-
Nanotechnology Laboratory, Department of Bio-
logical Sciences, University of Limerick, Limerick,
Ireland
xiii
Ayman S. El-Baz Bioengineering Department, Uni-
versity of Louisville, Louisville, KY, United States
Yaser ElNakieb Bioengineering Department, Uni-
versity of Louisville, Louisville, KY, United States
Taban Eslami School of Computing and Informa-
tion Sciences, Florida International University
(FIU), Miami, FL, United States
Rui Fausto Department of Chemistry, University of
Coimbra, CQC, Coimbra, Portugal
Luay Fraiwan Abu Dhabi University, Abu Dhabi,
United Arab Emirates
Mohammed Ghazal Abu Dhabi University, Abu
Dhabi, United Arab Emirates
David Gil Department of Computer Science and
Technology, University of Alicante, Alicante, Spain
Andreas M. Grabrucker Cellular Neurobiology
and Neuro-Nanotechnology Laboratory, Depart-
ment of Biological Sciences, University of Limerick,
Limerick; Bernal Institute, University of Limerick,
Limerick; Health Research Institute (HRI), Univer-
sity of Limerick, Limerick, Ireland
Reem Haweel Bioengineering Department, Univer-
sity of Louisville, Louisville, KY, United States
Biwei Huang Carnegie Mellon University,
Pittsburgh, PA, United States
Gulce Ogruc Ildiz Department of Physics, Faculty
of Sciences and Letters, Istanbul Kultur University,
Istanbul, Turkey; Department of Chemistry, Uni-
versity of Coimbra, CQC, Coimbra, Portugal
Muhammad Nazrul Islam Department of Comput-
er Science and Engineering, Military Institute of Sci-
ence and Technology (MIST), Dhaka, Bangladesh
Ashraf Khalil Abu Dhabi University, Abu Dhabi,
United Arab Emirates
Nabila Shahnaz Khan Department of Computer
Science, University of Central Florida, Orlando, FL,
United States
xiv Contributors
Adel Khelifi Abu Dhabi University, Abu Dhabi,
United Arab Emirates
Li Li Harvard University, Cambridge, MA, United
States
Ali Mahmoud Bioengineering Department, Uni-
versity of Louisville, Louisville, KY, United States
Javier Medina Department of Computer Science,
University of Jaen, Jaen, Spain
Sakib Mostafa Division of Biomedical Engineering,
University of Saskatchewan, Saskatoon, SK, Canada
Kazi Shahrukh Omar Department of Computer
Science and Engineering, Uttara University, Dhaka,
Bangladesh
Ana M. Peiró Clinical Pharmacology Unit, Alicante
General University Hospital, Alicante, Spain
Jesús Peral Department of Software and Comput-
ing Systems, University of Alicante, Alicante, Spain
Aurora Polo Department of Computer Science, Uni-
versity of Jaen, Jaen, Spain
Lauren B. Quetsch Department of Psychological
Sciences, University of Arkansas, Fayetteville, AR,
United States
Joseph S. Raiker School of Computing and Infor-
mation Sciences, Florida International University
(FIU), Miami, FL, United States
Sayna Rotbei Department of Information Technol-
ogy, Mehralborz University, Tehran, Iran
Fahad Saeed School of Computing and Information
Sciences, Florida International University (FIU),
Miami, FL, United States
Ann Katrin Sauer Cellular Neurobiology and Neuro-
Nanotechnology Laboratory, Department of Bio-
logical Sciences, University of Limerick, Limerick,
Ireland
 
Ahmed Shalaby Bioengineering Department,
University of Louisville, Louisville, KY, United
States
Ahmed Soliman Bioengineering Department, Uni-
versity of Louisville, Louisville, KY, United States
Jasjit S. Suri AtheroPoint, Roseville, CA, United
States
Andrew Switala Bioengineering Department, Uni-
versity of Louisville, Louisville, KY, United States
Jayaraman J. Thiagarajan Lawrence Livermore Na-
tional Laboratory (LLNL), Livermore, CA, United
States
Mirac Baris Usta Department of Child and Ado-
lescent Psychiatry, Ondokuz Mayis University,
Samsun, Turkey
Aoife Vaughan Cellular Neurobiology and Neuro-
Nanotechnology Laboratory, Department of Bio-
logical Sciences, University of Limerick, Limerick,
Ireland
Haishuai Wang Fairfield University, Fairfield, CT,
United States
Fang-Xiang Wu Division of Biomedical Engineer-
ing; Department of Computer Science; Depart-
ment of Mechanical Engineering, University of
Saskatchewan, Saskatoon, SK, Canada
Nese Yorguner Department of Psychiatry, Marmara
University, Pendik Training and Research Hospital,
Istanbul, Turkey
Hong Yang The University of Sydney, Sydney,
NSW, Australia
Jawad Yousaf Abu Dhabi University, Abu Dhabi,
United Arab Emirates
Ziping Zhao Tianjin Normal University, Tianjin,
China
 Biography of the editors
Ayman S. El-Baz is a Distinguished Profes-
sor, University Scholar, and Chair of the Bioen-
gineering Department at the University of Lou-
isville, Kentucky. Dr. El-Baz earned his BSc and
MSc degrees in electrical engineering in 1997
and 2001, respectively. He earned his PhD in
electrical engineering from the University of
Louisville in 2006. In 2009, Dr. El-Baz was named
a Coulter Fellow for his contributions to the field
of biomedical translational research. Dr. El-Baz
has 17 years of hands-on experience in the fields
of bio-imaging modeling and non-invasive com-
puter-assisted diagnosis systems. He has au-
thored or coauthored more than 500 technical
articles (145 journals, 27 books, 78 book chap-
ters, 225 refereed-conference papers, 172 ab-
stracts, and 30 US patents and Disclosures).
xv
Jasjit S. Suri is an innovator, scientist, vision-
ary, industrialist, and an internationally known
world leader in biomedical engineering. Dr. Suri
has spent over 25 years in the field of biomedi-
cal engineering/devices and its management.
He received his PhD from the University of
Washington, Seattle and his Business Manage-
ment Sciences degree from Weatherhead, Case
Western Reserve University, Cleveland, Ohio.
Dr. Suri was crowned with President’s Gold
medal in 1980 and made Fellow of the American
Institute of Medical and Biological Engineering
for his outstanding contributions. In 2018, he
was awarded the Marquis Life Time Achieve-
ment Award for his outstanding contributions
and dedication to medical imaging and its
management.
 Acknowledgments

The completion of this book could not have
been possible without the participation and as-
sistance of so many people whose names may
not all be enumerated. Their contributions are
sincerely appreciated and gratefully acknowl-
edged. However, the editors would like to
express their deep appreciation and indebted-
ness particularly to Dr. Ali H. Mahmoud and
Ahmed Sharafeldeen for their endless support.
Ayman S. El-Baz
Jasjit S. Suri

xvii
 C H A P T E R

1
Prediction of outcome in children
with autism spectrum disorders
Mirac Baris Usta*
Department of Child and Adolescent Psychiatry, Ondokuz Mayis University,
Samsun, Turkey
*Corresponding author

1 Introduction who had a diagnosis of ASD after expert clini-

Autism spectrum disorder (ASD) is an um-
brella term for neurodevelopmental disabili-
ties that affect social and communication skills,
and in recent years, the trend toward escalating
prevalence is seen [1]. In children with ASD,
outcome prediction is a vital component of
planning behavioral interventions, treatment,
and also prognosis in clinical settings. In par-
ticular, adult outcome studies of ASD were done
in the early 1960s in literature [2,3], but the pro-
portion of research focused on the outcome is
very small compared to etiology, genetics, and
treatment studies. Children with ASD are a very
complex and heterogenic group, so researchers
need to reach large-scale patient group data to
explain the nature of ASD across life span. Also,
researchers need this data to support children
with autism to accomplish the best possible out-
come.
At present, the trajectory of development
and prognosis for a baby or toddler diagnosed
with ASD typically cannot be anticipated at the
time of diagnosis [4]. But most of the children
cian examination and valid methods at less than
3-year old have maintained their diagnosis [5].
It is challenging to recognize and diagnose mild
symptoms of ASD in babies and toddlers, par-
ticularly if they have average or excellent in-
telligence and cognitive skills [6]. Also, across
developmental stages, ASD symptoms tend
to decrease, possibly due to maturation and/
or medical/educational intervention [7]. Many
studies showed that children with ASD show
significant decreases in social and behavioral
symptoms severities [8–11].
Heterogeneity adds another difficulty to un-
derstanding outcomes in ASD. Comorbid condi-
tions are widespread in children with ASD and
have a significant impact on prognosis. Medical
conditions such as sleep disorders, epilepsy, at-
tention deficit and hyperactivity disorder, and
also irritability problems like self-injury or food
refusal have a high impact on functioning of chil-
dren and families [12,13]. Also, diagnostic defini-
tions of ASD are shifted. Lastly, in 2013 DSM 5
[14], and recently, children with ASD with aver-
age Intelligence quotient (IQ) and adaptive skills

Neural Engineering Techniques for Autism Spectrum Disorder

http://dx.doi.org/10.1016/B978-0-12-822822-7.00001-6
1 Copyright © 2021 Elsevier Inc. All rights reserved.
2 1. Prediction of outcome in children with autism spectrum disorders
in addition to less-severe symptom presenta-
tions are growing. Most of these studies have
focused on direct observation strategies and
intelligence testing, and better IQ scores and
the least-severe symptoms presentations are the
essential aspects for prognosis. In recent years,
the rising of the big data for health records and
big clinical databases has provided researchers
to use state-of-the-art techniques like machine
learning to understand and evaluate this com-
plex disorder outcome more precisely [15]. Also
results of the laboratory research, including elec-
troencephalography (EEG), eye tracking, facial
tracking, and functional magnetic resonance
imaging (MRI) studies, have been giving hope
for future research and practice [16–18]. These
techniques possibly will be superior to observa-
tional methods in the future, and they will make
it possible to evaluate toddlers and even babies,
which is vital for starting only known treatment
strategies, very early intervention, and behav-
ioral therapies [19].
Recently machine learning methods, such as
support vector machines, decision trees, and
neural networks, are used to derive accurate di-
agnosis predictive models from ASD datasets.
These methods are mostly automated, which
normally require minimal researcher involve-
ment during preprocessing and also in the data
process. Researchers use software packages for
these methods, for example, R [20], Weka [21],
RapidMiner [22], Knime [23], and MATLAB
toolbox [24]. In this research, the machine learn-
ing process is doing the predictive task, and re-
searchers are trying to build a classifier to pre-
dict cases of ASD or neurotypical for toddlers.
These classifiers are usually composed of a la-
beled dataset and evaluated on independent test
instances to measure its sensitivity and specific-
ity in predicting the diagnosis.
This chapter concerns the outcome of chil-
dren and babies with ASD in later life, focusing
on new biomedical research and also state-of-
the-art techniques that are multidisciplinary be-
tween engineering and clinical research. Major
 
trends and challenges of this research and meth-
ods for children with ASD in laboratory, clinical,
and real-life settings will be discussed.
2 Screening data studies
It has recommended screening all children for
autism symptoms with a combination of autism-
specific screening and developmental tests and
questionnaires at the age of 18 and 24 months
[25]. Toddlers with ASD may be identified at this
age; early interventions possibly make the out-
come better [26]. Clinicians are using electronic
health records and valid screening tools to com-
plete the administration and scoring. Also, re-
sults of screening tests are not diagnostic; they
help one to identify a child at risk and to choose
those who require additional evaluation. Most
of the screening tests are parent-completed ques-
tionnaires, and the worldwide most commonly
used tool is the modified checklist for autism in
toddlers (M-CHAT) [27]. It is used for screening
children between 16 and 30 months of age in pri-
mary care settings. Toddlers who have three to
seven items positive for ASD after the clinician
clarifying questions have 47% risk of ASD diag-
nosis, and a 95% chance of being diagnosed with
other developmental delays or disorders would
need intervention [28]. Very early screening may
not truly describe many children with milder au-
tism symptoms; therefore surveillance remains a
necessity [29]. In the literature, researchers ex-
amine the utility of automated strategies, which
may ease accessibility or shorten screening pro-
cedures. Ben-Sasson et al. [30] used a machine
learning algorithm to predict ASD risk with a
combination of the parent’s text and a single
screening question. Achenie et al. [31] used the
data of M-CHAT validation study, including so-
cioeconomic data and M-CHAT items of 16.168
toddlers and families, prediction ASD diagnosis
with feedforward neural networks result that
yielded correct classification (ASD or not ASD)
at a rate of 99.72%. Al Farsi et al. [32] presented
 3 Diagnostic test data studies
fuzzy cognitive maps (FCM), in which algo-
rithms modify the answers of each question to
three options, reduced the complexity of and
increased the expressivity of the M-CHAT. Also
Abbas et al. [33] used clinical and video data of
162 children at ASD risk, presented a chained
tree of machine learning algorithms, one of
which operates on the basis of a parental ques-
tionnaire and the other of which operates on
home cell phone videos that can outperform the
M-CHAT’s classification rate. Machine learning
classification of ASD risk has advantages over
classical methods on calculating individual risk
rates; moreover, with a real-time support system
they may help clinicians, teachers, and other
professionals who do screening for ASD.
3 Diagnostic test data studies
The most used clinical diagnostic methods
are Autism Diagnostic Interview [34] and Au-
tism Diagnostic Observation Schedule—Re-
vised (ADOS–R) [35], which have shown accept-
able accuracy and validity in numerous trials. It
is also self-reported or parent-based methods
such as autism-spectrum quotient [36] and so-
cial communication questionnaire [37]. These
instruments are mostly used for diagnosis by
experienced clinicians and require substantial
time to apply patients. The majority of these
instruments have mathematical summation for-
mulas made by hand by the clinician. Research-
ers have recently started to investigate this data
to improve the diagnostic process of ASD. The
primary aim of these studies is to improve diag-
nostic accuracy, provide computer-assisted deci-
sion-making and also quick access to health-care
services for patients. Machine learning methods
seem to be a good solution to these diagnostic
challenges; however, some biases and overfit-
ting issues may initially appear.
Wall et al. [38] tried to shorten the direct ob-
servation-based coding of the ADOS to provide
a shorter and computer-assisted version of this
 
3
structured method while maintaining validity.
Authors have shown that the algorithm they
have used performs with outstanding sensitiv-
ity, specificity, and accuracy in differentiating
patients with autism from neurotypicals. The
classifier used by authors consisted of eight
questions performed with >99% accuracy. Duda
et al. [39] showed an observation-based classi-
fier, which uses a decision tree algorithm, that
represented a 72% reduction in length from the
ADOS while retaining >97% statistical accura-
cy. Pratap and Kanimozhiselvi used childhood
autism rating scale [40] data, which is another
direct observation tool, to measure Naive Bayes
and artificial neural network algorithms on the
classification problem of ASD, and results have
shown that when models are integrated with
unsupervised learning methods, the accuracy of
classification of ASD cases improves [41]. These
classification results appear very promising, but
they come with some shortcomings. First, the
reliability of direct observation studies was only
established in the clinical environment, while
clinicians were administering all tasks. Second,
autism and normally developed children were
used in classification, ignoring the autism spec-
trum that is subtlest, more heterogeneous cat-
egory. There is need for more studies to show
clinical validation and feasibility of this method
to be used as a tool for ASD diagnosis.
These studies suggest that internet platforms
for fast measurement of autism risk, for ex-
ample, mobilized approaches, will help one to
shorten screening and diagnostic processes for
clinicians. The application of machine learning
diagnostic processes requires an understanding
of both clinical and computational content do-
mains. The researcher must consider the prop-
erties and sources of the data that must be un-
biased and not overstated. Ignoring heterogenic
autism context and focusing on only data pro-
cessing may produce misleading results. Future
research must consider algorithms for children
with subtle ASD symptoms and may add other
neurodevelopmental classifiers (IQ, language
4 1. Prediction of outcome in children with autism spectrum disorders
levels, and gender). It will be necessary to get
large databases that include enough numbers
of children who vary on these classifiers. More-
over, engineers and data scientists need to col-
laborate with clinicians for a validation of these
algorithms. Still, machine learning algorithms
have a significant potential to improve certain
aspects of ASD diagnostic instrument design by
dimension reducing vast behavioral informa-
tion and multiple aggregating instruments.
4 EEG and ERP data studies
The electroencephalogram (EEG) is a tool
that assesses the electrical activity of the brain
from electrodes placed on the scalp surface. The
signals are obtained from various brain regions
and used for the evaluation of the brain’s electri-
cal activity. The event-related potential (ERP), a
specific type of EEG, indicates transformations
of the electrical activity of the brain due to the
occurrence of a specific event. They are using in
autism developmental studies extensively.
EEG and ERP are noninvasive neurophysi-
ological tools for investigating infants’ brain
activities and have also recently been used to
understand mechanisms underlying atypical
development. In long term, they may be used as
biomarkers of autism and may point “red flags,”
in which infant needs very early interventions.
In addition, EEG/ERP tools are more noninva-
sive and straightforward to be used in clinical
settings, which make them easy to practice for
the study of brain development and behavior in
infants.
EEG and ERP have different frequencies of
wavebands, and its computational analysis is
performed on these varying bandwidths. EEG
waves are classified as delta (0.5–4 Hz), theta
(4–8 Hz), alpha (8–13 Hz), beta (13–35 Hz), and
gamma (>35 Hz) waves. Grossi et al. [42] used
EEG patterns to classify ASD patients and they
did 15 ASD and 10 neurotypical test subjects
resting EEG with 19 electrodes, closed and open
 
eyes. EEG data was analyzed in three phases:
in the first phase “Squashing,” signals trans-
lated into vectors. Multiscale ranked organizing
maps and multiscale entropy were used to clas-
sify different algorithms. Dataset randomly di-
vided training and test set and noise elimination
performed only on the training set. In the final
phase, authors used multiple validation proto-
cols and did leave-one-out cross-validation for
algorithms. Naive Bayes, random forest, logis-
tic regression, sequential minimal optimization,
kNN algorithms were used for classification,
and at the end of the process, logistic regression
and naive Bayes had 100% accuracy with all the
classification models.
Bosl et al. [43] used multiclass support ma-
chines to differentiate high-risk and neurotypi-
cal infants’ EEG data. A total of 49 infants were
there with one of their relatives to confirm ASD
diagnoses performed by a psychiatrist, whereas
the other 39 infants had no risk of ASD. Data was
collected from each subject in five different ses-
sions between 6 and 24 months. Raw EEG sig-
nals were processed using modified MSE. High,
mean, and low modified multiscale entropy for
each curve was calculated to create a feature set
of 192 values. This algorithm classified healthy
and high-risk infants after the age of 9 months
with 90% accuracy.
Jayarathna et al. [44] used EEG data to pre-
dict human-pointed ADOS-2 diagnostic test re-
sults. They analyzed 24 adolescents with ASD
and 22 neurotypical subjects while watching
joint-attention movies, during the ADOS-2 test
with human and baseline rest EEG. They used
32 electrodes for each subject. The authors used
statistical and entropy values to extract features
from EEG data. Researchers used entropy and
statistical values, including standard deviation,
mean, and combined mean on the data for the
feature analysis. For joint attention, they used
principle component analysis and random for-
est for classifying autism traits. Both algorithms
yielded as high as 90% accuracy to separate ASD
and non-ASD groups.
 6 MRI data studies
ERP is commonly used to investigate audi-
tory perception in infants because they do not
require direct attention or clear behavioral re-
sponse. Ravan et al. [45] used three age groups
(6 months, 12 months, and adult) ERP data for
classification. The authors used the SVM and
FCM methods after preprocessing and found
these classification performances of algorithms
above 94% at differentiating subjects’ ages. Stahl
et al. [46] used discrimination methods and ma-
chine learning for infant ERP data. A total of 36
infants’ data were used for the classification of
atypical neurodevelopment, and in each ses-
sion, a static fixation stimulus was presented
followed by a color image of a female face, with
either direct gaze or averted gaze from the in-
fant. Support vector machines and regularized
discriminant function analysis were able to clas-
sify infants with ASD risk and control infants
with using sixfold cross-validation with 64%
and 61% accuracies.
ERP and EEG data with machine learning
methods show potential in clinical research as
an effective instrument for the classification
high risk of ASD and the prediction of outcome.
Another advantage of EEG is its ability to be ap-
plied to natural and ecological tests, also clini-
cal settings in valid contexts, that will allow one
to obtain data from multiple participants (e.g.,
mother–infant dyads) simultaneously. In the fu-
ture, we need to assess the relationship between
caregivers with an infant to understand the
complex nature of social behavior and also the
risk of ASD in the very first months of life.
5 Eye-tracking data studies
ASD is rarely diagnosed with current di-
agnostic systems before the age of 2 years and
visual attention to the face, eye contact, which
starts as early as 5 months [47]. Eye tracking has
become a valuable tool for investigating very
young infants’ behavior over the last decade and
may use for early diagnosis in ASD. The previ-
 
5
ous work on this field has failed to find evidence
of eye tracking, gaze differences in infants at risk
of ASD or in infants who received an ASD diag-
nosis in toddlerhood. Improving machine learn-
ing methods may help one to increase prediction
accuracy rates.
Liu et al. [48] used eye-tracking dataset of
48 neurotypical, 39 ASD, and 22 children with
intellectual disability. The authors used a bag
of words algorithm for the area of interest, eye
movements, eye coordinates data, after that, the
SVM model with RBF kernel trained with pre-
processed data. As a result, they reached around
87% accuracy. Jiang et al. [49] used data from 19
neurotypical controls and 20 adults with ASD in
a free-viewing task. The authors used a database
that contains many natural scenes. Eye-tracking
data was processed by the authors for further
analysis. Cluster Fix was used for fixations and
saccades deducted from raw data. After this, the
authors computed fixation maps to classify two
groups. In the last part of the study, the authors
trained with the SVM model used leave-one-out
cross-validation for performance assessment.
This model showed real promise for eye track-
ing in ASD with 92% accuracy to classify ASD
and a neurotypical group.
Eye-tracking studies may benefit from state-
of-the-art machine learning methods to offer a
more accurate diagnosis. Free image viewing,
face recognition, and gaze studies contain the
data-driven approach of automatically learned
traits of ASD. The gaze is the essential part of
psychiatry examination for children with ASD,
and experimental studies show promising per-
formance and so in future eye tracking may be a
core tool for machine learning in ASD.
6 MRI data studies
MRI studies are the most used noninvasive
methods for investigating brain morphology.
In ASD, increased cerebellar hemisphere and
total brain volume are the most replicated
6 1. Prediction of outcome in children with autism spectrum disorders
abnormalities in conventional MRI. Also fronto–
temporo-parietal cortex, limbic system, and cer-
ebellum network abnormalities may underlie
the pathophysiology of ASD, which can be in-
vestigated with a special type of MRI, diffusion
tensor imaging. Subsequent reports suggested
that brain overgrowth and network abnormali-
ties appear during very early childhood [50], and
machine learning methods may help one to in-
vestigate this extensive data of high-risk infants.
Hazlett et al. [51] used data of 106 high-risk
ASD infants and 42 low-risk infants to investi-
gate the predictive value of brain volume. The
authors showed that the overgrowth of the corti-
cal areas between 6 and 12 months predicts ASD
at the age of 24 months in infants. Social deficit
and repetitive behaviors are also linked with the
emergence of the brain’s overgrowth. They used
a deep learning algorithm with a value of 81%
specificity and sensitivity of 88% to classify ASD
patients. The machine learning analysis was
based on a three-stage deep learning network
using unweighted and unbiased data. Ecker
et al. [52] investigated MRI data for classifying
20 ASD and 20 neurotypical adults and used a
set of five morphometric parameters to reveal
spatially distributed patterns of discriminating
regions. The authors used the SVM method for
the spatially distributed pattern of regions with
maximal weights and algorithm classified ASD
group with 90% sensitivity and 80% specificity.
7 Conclusions
The prediction studies presented in this chap-
ter are mostly preliminary and require more
data and replication across different children
with ASD. We need more observational data
about ASD to predict the outcome and arrange
treatment options until data-gathering technol-
ogy arrives. In the near future, all screening
methods, biological investigations, and treat-
ment strategies will be using machine learning
technology for toddlers and children.
 
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 C H A P T E R

2
Autism spectrum disorder and
sleep: pharmacology management
Pura Ballester a and Ana M. Peiró b,*
a
Department of Clinical Pharmacology, Pediatrics and Organic Chemistry, Miguel
Hernandez University, Elche, Spain; bClinical Pharmacology Unit, Alicante General
University Hospital, Alicante, Spain
*Corresponding author

1 Autism spectrum disorder medications, although scarce data about long-

Autism spectrum disorder (ASD) is a men-
tal disorder of the neurodevelopmental system.
They are characterized by restricted interest
and stereotyped repetitive behaviors, patterns
of behavior, and difficulties with social com-
munication and interaction. Unfortunately,
ASD diagnosis is progressively increased from
1/2500 to 1/68 in last three decades and, usu-
ally, it is accompanied by other comorbidities,
such as sleep problems [e.g., insomnia or circa-
dian rhythm sleep–wake disorders (CRSWDs)]
and intellectual disability (ID) [1]. Its approach
is to use to combine education, supportive care,
and behavioral therapy, together with drug
prescription to target most frequent related
conditions as depression, anxiety, hyperactiv-
ity, and obsessive–compulsive behaviors. Thus
ASD subjects, especially with certain patholo-
gies or multimorbidity, are usually exposed
to polypharmacy or potentially inappropriate
drug use effectiveness and even worst, about
safety profile exist.
1.1 Autism and intellectual disability
prevalence
ID is a lifelong manifestation that impacts
significantly on individuals’ health and fam-
ily quality of life. Furthermore, when ID coex-
ists with ASD, it uses to be underestimated and
consequently not taking account for early inter-
ventions and the support that individuals need.
Factors affecting prevalence and its underesti-
mation in neurocognitive diseases include its
own difficulty to determinate with usual ques-
tionnaires. Also, in research, criteria used to
identify ID can vary and are not matched with
age group or sociodemographic status of the
population. Even more, prevalence of ID varies
according to the definition and the cutoff scores
of diagnostic tools [2].

Neural Engineering Techniques for Autism Spectrum Disorder

http://dx.doi.org/10.1016/B978-0-12-822822-7.00002-8
9 Copyright © 2021 Elsevier Inc. All rights reserved.
10 2. Autism spectrum disorder and sleep: pharmacology management
1.2 Potential drug targets in autism
Currently any medication has been proven
effective in treating core characteristics of ID or
autism even less, there is any cure. Psychotropic
medications are frequently prescribed to treat
comorbid symptoms, in across all ages, despite
the little evidence related to their efficacy.
These comorbid conditions surrounding
the ASD may result from several interactions
between genetic (variations in the number of
copies or in chromosomal sequences) and envi-
ronmental (related to food, metabolites, and
drug exposure) factors. There are also other
autism risk factors, such as hypovitaminosis D,
previously identified in other studies [3]. Data
indicate that vitamin D is a novel and promising
treatment that can ameliorate the core ASD man-
ifestations in children [4,5]. Also, γ-aminobutyric
acid (GABA) is a neurotransmitter that pro-
motes the excitatory/inhibitory shift [6]. There
is a lack of GABA regulation in patients with
ASD. In ASD children, bumetanide improves
clinical outcomes through changing GABAer-
gic responses from excitation to inhibition [7].
Recently, this result has been confirmed in adult
population, and bumetanide has proved to
be effective for the clinical symptoms of ASD,
through the GABAergic signaling pathway [8].
This chapter aimed to summarize current evi-
dence on effectiveness and safety profile of phar-
macological interventions for the most frequent
symptoms and disorders associated to autism,
with a special focus on sleep problems and to
ID. To this day, clinicians should use pharmaco-
therapy with caution, carefully weighing risks
and benefits, and as a part of a comprehensive
personalized approach.
2 Sleep comorbid conditions in ASD
ASD has prevalent cooccurring medical
conditions, including a wide range that goes
from sleep problems, gastrointestinal disorders
 
(constipation or feeding difficulties), attention
deficit/hyperactivity disorders, epilepsy, anxi-
ety, or disruptive behaviors. All those conditions
add complexity to the ASD diagnose and dis-
turb the finding of an appropriate treatment and
intervention [9]. For example, recent studies sug-
gest that up to 8 from 10 ASD children or adoles-
cents have any difficulty falling and/or staying
asleep at night [10]. These issues make it harder
for them to concentrate, decreasing their capac-
ity to function, and lead to poor behavior. Fami-
lies that have an autistic member who struggles
with sleep often report higher stress levels [11].
2.1 Classification
Sleep problems are any condition that affects,
disrupts, or involves sleep and have nocturnal/
diurnal manifestations. Thus this is a condition
that frequently affects one’s ability to get enough
quantity or appropriate quality of sleep [12].
They can be classified following International
Classification of Sleep Disorders-Third Edition
(ICSD-3) criteria (Table 2.1).
2.1.1 Insomnia
This disorder is a “persistent difficulty with
sleep initiation, duration, consolidation or qual-
ity that occurs despite adequate opportunity
and circumstances for sleep and results in some
form of daytime impairment” [13].
2.1.2 Circadian rhythm sleep–wake
disorders (CRSWDs)
Circadian system regulates endogenous
rhythms (as the sleep–wake cycle) in most organ
systems, which are synchronized, with a recur-
ring periodicity of approximately 24 hours, by
the central pacemaker in the suprachiasmatic
nucleus and light/dark cycle [14].
In mammals the circadian clock network
controls circadian rhythms and coordinates the
expression of a variety of genes, helping the
organism to respond in advance and face to
environmental changes. Circadian clock genes
 2 Sleep comorbid conditions in ASD
TABLE 2.1 Sleep disorders summarized according to the International Classification of Sleep Disorders Third Edition
(ICSD-3) criteria.
Main family Types
Insomnia (216)
Intrinsic circadian rhythm • Delayed sleep–wake phase
sleep–wake disorders disorder (DSWPD)
(CRSWDs) • Advanced sleep–wake phase
disorder (ASWPD)
• Non-24-hour sleep–wake rhythm
disorder (N24SWD)
• Irregular sleep–wake rhythm
disorder (ISWRD)
REM (rapid eye movement) • Sleep walking
and NREM (non-REM) • Teeth grinding
sleep phase disorders • Absence of the muscle paralysis
could participate in sleep problems, psychiatric
symptoms related to brain development timing,
interfere in neuroendocrine or body tempera-
ture rhythms. That may impair how the indi-
vidual integrates his/her internal and external
rhythms [15].
CRSWDs arise when the circadian system
and sleep–wake cycle become desynchronized.
This category of disorders includes conditions,
in which sleep timing is out of alignment with
social, work, and sleep normal patterns across
the 24-hour day. These circadian disorders are
characterized by the inability to sleep at wished
times, difficulties initiating and/or keeping
sleep, and early awakening and impairments in
daytime functioning. They require symptoms to
be present for almost 3 months and confirmed
with 14 days of actigraphy [13]. ICSD-3 catego-
rizes seven different disorders; however, the
most important for autism are those with the
circadian phase shifted to an earlier time (phase
advance), or later time (phase delay) [16,17].
2.2 Prevalence
Most of the literature related to sleep prob-
lems in ASD is developed in children, as sleep is
 
11
Characteristics
Difficulty with sleep initiation, duration,
consolidation, or quality
• Difficulty with falling asleep and with
waking at the times imposed, but sleep
quality is typically reported as normal
• Difficulty staying awake during evening
hours and wake time is undesirably early
• Failure in entraining to the 24-hour light–
dark cycle and clock times
• Lacks a clear circadian pattern of sleep/
wake behavior
Episodes of arousal due to the absence of the
normal physiologic muscle paralysis
important in the early stages of life. Sleep prob-
lems prevalence in this population (50%–86%)
is significant higher compared to age-matched
typically developing children (9%–50%) and,
even more, with non-ASD developmental dis-
abilities children [10,18–20]. This would fur-
ther support the possible specific and currently
unknown relationship of ASD and, at the same
time, a sleep problem.
Moving toward the literature describing the
adulthood, there is scarce research data from
adults on the spectrum, even less, when ID is
present. Nevertheless, ASD is a lifelong condi-
tion, and recent research proved a continuance
of sleeping difficulties.
First study was conducted in 1993 which was
a three–case study published by Simblett and
Wilson, and they described for a participant:
“sleep disturbance with early morning wak-
ing” [21]. Recent studies have displayed a 41%
of sleep problems in a longitudinal follow-up
study with a sample of 92 cognitively able autis-
tic participants [22], and 45% of autistic adults
with severe ID had sleep problems according to
the results of the DASH II questionnaire [23].
Insomnia symptoms [longer sleep latency,
poor sleep efficiency (SE), shorter night sleep]
12 2. Autism spectrum disorder and sleep: pharmacology management
[24–32] and advanced or delayed CRSWD
[31,33,34] have been described regardless the
cognitive ability.
2.3 Diagnosis
All children with ASD should be screened
for insomnia with sleep questionnaire annually,
together with any medical condition (pain, aller-
gies, reflux, epilepsy, and dental issues between
others) that may be contributing to any sleep
problem and refer to appropriate subspecial-
ist. This is relevant because ASD population
need to be assessed for sleep disturbance before
any appropriate treatment is initiated. In fact, a
2-week sleep log can be used to compute sleep
parameters, or diagnose sleep problems and
prove the efficacy of any pharmacological inter-
vention considered, that should be starred with
melatonin. Other studies have spotted signifi-
cant differences in sleep architecture using sub-
jective measures (e.g., questionnaires) [35], but
as our adults with ASD and ID are nonverbal,
most questionnaires are not validated for them.
Recently, actigraphy has been very useful. This
portable device stores information related to a
week of rest/activity transitions, which is use-
ful to assist in the diagnosis in various sleep dis-
orders, including insomnia or circadian rhythm
disorders. Ambulatory circadian monitoring
(ACM) sleep parameters, for 5–7 consecutive
nights with the same actigraph, can give a vari-
ous and objectively information about sleep
parameters and circadian sleep–wake rhythm
indexes [36].
2.3.1 Sleep parameters
ACM can give information about several
sleep parameters analyzed. Here we point out (1)
total sleep time (TST), as the number of minutes
defined as sleep between night sleep onset and
sleep offset; (2) time in bed (TIB), as the num-
ber of minutes in bed at night until sleep offset;
(3) sleep onset latency (SoL) as the time until
night sleep onset; (4) number of awakenings
 
(number awake) as the number of wake up dur-
ing TIB; (5) waking after sleep onset (WASO) as
the minutes of wake up during the TST inter-
val; and (6) SE percentage calculated as [(TST/
TIB) × 100]. Sleep parameters were calculated
from ACM recordings, and sleep/wake diaries
filled by caregivers were used as a backup for
these results.
2.3.2 Circadian sleep–wake rhythm
indexes
CRSWDs were calculated from ACM record-
ings as previously described [37]. These indexes
serve to characterize the status of the circadian
clock and also the rest-activity cycle [38,39]. Rel-
ative amplitude (where higher values indicate
better circadian rhythmicity that is a greater dif-
ference between wake and sleep status values),
interdaily stability (higher values indicate stron-
ger circadian rhythm because values are similar
across days), and intraday variability (higher
values indicate weaker circadian rhythm due
to high variability within each day) are mea-
sured. Also, other parameters are calculated: M
(5, 10) and L (5, 10) indicate consecutive 5- and
10-hour periods of maximum (M-onset) and
least activity (L-onset); these phase markers are
presented as a mean value in an hour basis and
accompanied by a value (V). Finally, circadian
function index can assess the status for circa-
dian rhythmicity.
3 Pharmacological treatment of sleep
comorbid conditions in ASD
Given the involvement of neurotransmitters
and hormones in the regulation of the sleep–
wake cycle, showed at Table 2.2, and the evi-
dences of their dysregulation in at least some
individuals with autism, pharmacological treat-
ments may be useful in treating their insomnia
symptoms and CRSWDs.
However, there are no efficacious treatments
or practice guidelines for sleep problems in
 3 Pharmacological treatment of sleep comorbid conditions in ASD
TABLE 2.2 Brain areas and molecules in charge of sleep/wake transition and maintenance in ASD and its use in
sleep problems treatment.
Sleep
Neurotransmitter Mechanism of action
GABA Neuronal inhibition
Melatonin Soporific and chronobiotic
effects
Adenosine Mostly inhibitory
neuromodulator of
excitatory neurons
(ADORA1 and 2 receptors),
sometimes inhibitory
neurons
Melanin REM sleep and NREM sleep
concentrating
hormone
Wake
Serotonin High serotoninergic activity
promotes wakefulness and
inactivity REM sleep
Dopamine Initiate and maintain
wakefulness, and production
and modulation of REM
sleep is also modulated by
dopaminergic pathways
Acetylcholine Generates the brain-activated
states of wakefulness and
REM sleep
Glutamate Main excitatory
neurotransmitter
Orexin system Two excitatory peptides that
play a role in wakefulness
13
Brain areas ASD
Suprachiasmatic Reduced in cortical areas, decreased
nucleus, cortical areas, expression of receptors and
hypothalamus, and aberrant function of glutamic acid
pineal gland decarboxylase
Pineal gland Not normal increase during the night
and elevated levels during the day
Cortical cholinergic areas Negatively correlated with process S
and polymorphisms in the receptor
ADORA2
The brainstem, the In mice models of ASD the gene that
sublaterodorsal, dorsal produces this hormone is upregulated
raphe nucleus, and in the medial preoptic nucleus
locus coeruleus nuclei
Raphe nuclei of the Alteration its activity in the dorsal
brainstem raphe nucleus and interaction with
the amygdala. Increased whole-blood
serotonin levels in children with ASD
and unaffected relatives. Also, higher
levels of the intermediate metabolism
of the transformation of serotonin
into melatonin, altered serotonin
synthesis, variation in its transport,
and degradation
Ventral tegmental area Disruptive gene encoding the DAD2
and pineal gland receptors that may confer risk for
ASD and dysfunction of the brainstem
dopaminergic pathways
Pontine reticular Decreased concentrations of a precursor
formation, cerebral of acetylcholine and were correlated
cortex to limbic with the severity of autism
structures, and
hypothalamus
Cortex and thalamus Increased in plasma and aberrant
functioning that affects REM
Amygdala Reduced inputs in the amygdala
 
14 2. Autism spectrum disorder and sleep: pharmacology management
adolescents and adults on the autism spectrum
[40]. Therefore behavioral therapy is usually the
first option for poor sleep, with pharmacologi-
cal therapies when needed to help patients func-
tion in their activities [41,42]. But, there are only
two drugs: aripiprazole [43,44] and risperidone
[45,46] that have US Food and Drug Administra-
tion approval for their use in ASD, to treat irri-
tability and disruptive behavioral symptoms,
respectively.
Thus there is a diverse range of off-label
pharmacotherapeutics options and combined
prescriptions that may induce polypharmacy
(understood as four or more active prescrip-
tions during at least 6 months) in this popula-
tion without clear evidence of effectiveness. The
off-label use of some drugs to treat sleep prob-
lems could increase the risk of developing side
effects. Those that are concerning include meta-
bolic disturbances, weight gain, extrapyrami-
dal symptoms, and hyperprolactinemia, which
should be kept in mind when prescribing anti-
psychotics [47].
Even more, most failures of pharmacological
treatments may be due to the lack of matching
treatment to the underlying cause of the sleep
problem.
3.1 Melatonin receptor agonists
Nowadays, most promising molecules are
melatonin receptor agonist drugs. As mentioned
earlier, melatonin can be one of the inceptions
of ASD sleep problems in relation to its levels
and/or peak times. Pineal gland releases mela-
tonin in a cyclical, daily pattern with low signal
during the day and increased at night [48]. And,
melatonin circadian rhythm is a phase marker
of the sleep–wake transition, and the evening
rise in melatonin marks circadian rhythmicity
(dim light melatonin onset) [49]. In fact, lower
urinary 6-sulphatoxymelatonin [50] and plasma
melatonin [51] levels have been found in ASD
individuals in some studies, indicating some
abnormalities in this pathway.
 
3.1.1 Melatonin
Melatonin is the first pharmacological step
for sleep problems in autism with minimal
adverse events [52]. It has been demonstrated
effective for (1) reducing insomnia symptoms as
SoL [53–55], increasing SE [55], reducing num-
ber of awakenings [56], increasing TST [54,57],
and also improving CRSWD [57,58]. A reduc-
tion of wakes after sleep onset (WASO) may be
achieved using prolonged release forms that
have already proved safety in a trial up to 2
years [59]; (2) improving CRSWD through sleep
phase improvement [10,60].
However, data are based in scarce studies
either young adults [61], adults [62] or even less,
in children [63]. Thus there is a lack of clinical
studies to test the effectiveness of pharmacologi-
cal treatments for sleep problems, generally in
adults with ASD, particularly in autistic adults
with ID.
3.1.2 Melatonin combined with behavioral
interventions
Melatonin, together with behavioral inter-
ventions (e.g., functional analysis of the prob-
lem or stimulus control) [64] and sleep hygiene
(reducing naps, increasing morning physical
activity, and modulating the light intensity
received), has been used to treat sleep prob-
lems in ASD [65]. However, outcomes from
clinical trials with melatonin vary consider-
ably depending on the age range studied [66],
the diagnostic measures employed [67–69], the
length of the study [70,71], the different doses
used [58,63,70], and improved sleep outcomes
after treatment [72].
3.1.3 Agomelatine
Agomelatine (Valdoxan) was first reported in
1992, acting as an agonist for melatonin MT1 and
MT2 receptors and as an antagonist on serotonin
5HT2c receptors. The most exciting behavior of
agomelatine is its procircadian effect, acceler-
ating the restoration of circadian rhythms. The
binding affinity of agomelatine for MT1 and
 3 Pharmacological treatment of sleep comorbid conditions in ASD
MT2 is as strong as melatonin, but its half-life
is longer. And also that antidepressant efficacy
could be stronger due to melatonin secretion
through monoaminergic mechanisms [73,74].
AGOTEA study is the largest sample of autis-
tic adults with ID enrolled in a randomized
clinical trial, where an objective tool as ACM
assesses the effectiveness of a pharmacological
treatment for sleep problems [30]. There is only
a clinical trial that has a bigger sample size than
this with 27 participants. However, the sample
contained different mental pathologies, so there
were no conclusions about sleep improvement
only in autistic participants [61].
3.1.4 Agomelatine long-term use
In autism, there is no evidence about long-
term side effects of agomelatine [75]. A large
clinical trial (n = 711, 8-week treatment) reported
that seven individuals suffered an elevation of
transaminase levels (six recovered normal values
without leaving the trial). In spite of AGOTEA
sample already consuming a median of five
ongoing medications, the safety was acceptable,
with only 4% of prevalence of adverse event. In
contrast, agomelatine was effective increasing
TST. This was coherent with earlier publications
for melatonin in the younger ones [57,58].
3.1.5 Agomelatine use for CRSWD
The phase correction of peripheral tempera-
ture, a marker of circadian activity following
agomelatine [76], specifically when a phase
advancement is present, indicates an improve-
ment of CRSWD [77]. Furthermore, the phase
correction seen in AGOTEA study temperature
rhythm was described earlier in an open-label
study in an elderly sample and using a larger
dose of agomelatine [78]. The previous was also
described in a study with a range of doses of
agomelatine [79].
It is important to schedule its administration
and also to measure pharmacokinetic param-
eters when using a chronobiotic therapy. To
 
15
advance a rhythm the intake must occur mul-
tiple hours prior bedtime. On the other hand, at
the time of a phase advancement some experts
have advised for a low dose of melatonin [80],
but several authors pointed the need for further
studies in the field of the circadian regulation
[80–82]. The chronobiotic results obtained for
agomelatine are consistent with what has been
described using a sleep screening questionnaire
[83] to assess CRSWD.
It is unknown if our results can be extended to
adults with ASD and no ID, or to children with
ASD with sleep problems, whether agomelatine
may also improve other situations such as the
daytime sleepiness, shorter SoL, or increased
night waking also found in individuals with ASD.
3.1.6 Agomelatine combinations with other
therapy comorbidities
Apart from melatonin, donepezil, an acetyl-
cholinesterase inhibitor, has been studied in an
open-label study, tested by polysomnography, in
children [84]. An increase in TST and rapid eye
movement (REM) sleep values was obtained.
Additionally, risperidone, used for autistic
symptoms, has subsequently improved partici-
pants’ sleep rhythm [85,86]. Sleep improvements
shown here are also consistent with results for
agomelatine studies in patients with depres-
sion [87,88]. The increase in TST after active
treatment, seen in ACM recordings, has been
described in adults with major depressive dis-
order using PSG [87–89]. In an open-label study
[90], similar increase in TST, and also increased
SE and non-REM stage 3 were found with the
same dose as used in our study.
The following TST increment has been
reported in studies in participants with mood
disorders or anxiety that used subjective sleep
measures [91,92], and a reduction in insomnia
symptoms has been observed after agomelatine
treatment [93]. Nevertheless, some authors have
described no effects on sleep after agomelatine
treatment [94,95].
16 2. Autism spectrum disorder and sleep: pharmacology management
3.2 Other psychotropic drugs
Apart from the ones mentioned earlier, some
drugs that prompt sleep (neuroleptics, antide-
pressants, or stimulants) are recommended to
children, adolescents, and adults on the spec-
trum [96–100]. Although none comes with sleep
problems, drug side effects on sleep function are
very extensive. Sedative effects that psychotro-
pic medications used for ASD mental health and
behavioral issues [101] or anticonvulsants for
epilepsy could promote sleep but to date, no one
has tested this hypothesis. Longitudinal studies
proved that there is an increase in prescriptions
of psychotropic medication across the time from
31% in children to 45% in adults with autism
[96]. Also, recent studies reported an increment
of psychotropic prescriptions up to the 73%,
in young autistic adults with ages from 18 to
21 years [98]. The abovementioned experience
occurs even though there is limited evidence
of pharmacological effectiveness derived from
clinical trials in the ASD population.
3.2.1 Antipsychotics (risperidone and
quetiapine)
Risperidone and quetiapine, both neurolep-
tics, and selective serotonin reuptake inhibitors,
are used to control some behavioral symptoms
in autism, but their effects on sleep have been
also described [102,103]. An open-label study
in a small number of children on the spectrum
showed that donepezil, an inhibitor of ACh
degradation by acetyl cholinesterase enzyme,
was effective in increasing REM sleep per-
centage during nighttime [104]. Clonidine, an
ACh agonist, for attentional deficits [105], mir-
tazapine for depressive disorders [106,107],
or gabapentin for epilepsy [107] in autism are
under research. Some authors suggest that
clonazepam, a GABA agonist, could be a good
approach to increasing REM sleep [108], with-
out a clear conclusion.
Risperidone remains unlicensed for use in
ASD children, in the United Kingdom, but it is
 
approved for the treatment of persistent aggres-
sion in conduct disorder in children of subav-
erage intellectual functioning. Thus although
when sleep problems are present as autistic
comorbid conditions we could choose those
treatments that also aid sleep [109], this can-
not be a general recommendation based on evi-
dence. Further attention should be paid to the
metabolic phenotypes and possible drug–drug
interactions, because this could predispose ASD
individuals to side effects that derive from the
treatment of different comorbidities with off-
label pharmacological use [110], as hasten clear-
ance of melatonin when it is combined with
anticonvulsants [111].
3.2.2 Drug–drug interaction potential side
effects
Clinicians should be careful not to potenti-
ate adverse events taking into account that sub-
jects may be genetically predisposed P450 slow
metabolizers [112], and as melatonin is metabo-
lized by the mentioned via, and together with
drugs used for mood disorders, there is a con-
cern that these antiepileptic drugs may hasten
the clearance of melatonin [111].
4 Conclusions
Due to the different causes and features of
problematic sleep in ASD, future research into
the efficacy of sleep interventions may point to
phenotypic subclassifications rather than a wide
analysis, including the whole autistic spectrum
together [113]. The definition of sleep status by
specific subtype will help one to gather better
longitudinal data about responses to specific
treatments providing a better individualized
therapy. Even more, the use of ambulatory and
objective methods to study sleep disorders,
as actigraphy, could help for future research
because it is critical to disentangle the relation-
ship between measures of sleep captured by
reports and sleep objective tools. Additional
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Another random document with
no related content on Scribd:
Pflicht gegen Eure Hoheit gehalten, Sie über den Fall aufzuklären
und Ihnen die Kenntniß von meiner Schuldlosigkeit zu verschaffen.
So empfindlich mich auch die Ungnade des Fürsten getroffen, würde
mir doch diejenige meines theuern Prinzen noch vielfach
schmerzlicher sein, da ich dieselbe überdies nicht zu verdienen
glaube.«
»So reden Sie, reden Sie!« fiel der Prinz ungeduldig ein.
»Der Fürst, mein Prinz, hat mich, ohne Beweise für meine Schuld
zu besitzen, lediglich nach seinem Belieben verurtheilt.«
»Boisière hat ihm doch aber mitgetheilt —« wandte der Prinz ein.
»Und der Chevalier sprach die Wahrheit —« fiel Mühlfels mit
Nachdruck ein.
»Wie soll ich das verstehen?«
»Sie werden mich verstehen, mein Prinz, wenn ich Ihnen
bekenne, daß ich die Prinzessin nicht compromittiren wollte.« —
»Was sagen Sie?« rief der Prinz überrascht aus.
»Mißdeuten Sie meine Worte nicht, mein gnädiger Prinz. Wenn
mir die Prinzessin auch ein besonderes Wohlwollen schenkte, das
mich zu beglückenden Hoffnungen berechtigte, so trifft sie dennoch
nur in sofern ein Vorwurf, indem sie mich dadurch zu demselben
verleitete. Ob diese Hoffnungen jemals erfüllt worden wären, wage
ich nicht zu bestimmen, obwol ihr Interesse für mich eine solche
Annahme nicht gerade abweist.«
»Und dem ist wirklich so?« fragte der Prinz erregt und blickte
Mühlfels an.
»Ich schwöre es, mein Prinz!« »Warum verschwiegen Sie das
dem Fürsten?« —
»Weil, wie ich schon früher bemerkte, ich es für meine Pflicht
erachtete, die Prinzessin nicht bloszustellen.« —
»Sie thaten nicht recht daran, und ich gestehe Ihnen, es würde
mich gerade in diesem Augenblick gefreut haben, hätten Sie dem
Fürsten die Schwäche der Prinzessin enthüllt, die er noch immer für
tugendhaft hält. Doch, er soll das von mir erfahren; ich spreche ihn
morgen und will ihm Ihr Bekenntniß mittheilen. Wagte Sidonie sich
über Mariane zu beschweren, so bietet mir dies ein erwünschtes
Mittel, sie in dem rechten Licht zu zeigen. Ich sage Ihnen, Ihre
Mittheilung kommt mir sehr gelegen.« —
»Und wollen Hoheit so gnädig sein, mir zu verzeihen, wenn ich
das Entgegenkommen der Prinzessin annahm?« fragte Mühlfels
demüthig.
»Ach, lassen Sie die Bagatelle!« fiel der Prinz geringschätzig ein.
»Ich würde die Prinzessin in keiner Weise in ihren Passionen
belästigt haben, hätte sie mich nicht durch die Anklage beim Fürsten
heraus gefordert. Ich will doch sehen, wer mehr bei dem Fürsten gilt,
s i e oder i c h. Die Tugend an sich ist lächerlich; die geheuchelte
jedoch mehr als das. Sie sollen nicht fort, Mühlfels; Sie sollen und
müssen bleiben; denn ich bedarf Ihrer gerade jetzt am nöthigsten.
Die Prinzessin soll sich in ihren Erwartungen arg getäuscht sehen.
Wie konnte sie es wagen, unter solchen Umständen meinen Freund
anzuklagen und mich seiner zu berauben, lediglich um sich den
guten Schein zu retten. Ich merke, sie hat dabei auf Ihre
Gutmüthigkeit gerechnet; es soll ihr jedoch nichts helfen. Ihre gute
Absicht muß von dem Fürsten anerkannt werden; ich werde dafür
sorgen. Im Uebrigen, Mühlfels, bleiben wir die alten Freunde. — Ich
hoffe, auch die Angelegenheit mit Marianen wird sich nach Wunsch
erledigen lassen. Ich habe keine Lust, der Prinzessin zu weichen; ich
ahne, was sie verlangt; aber wahrlich, Sie soll ihren Willen nicht
haben!«
In solcher Weise sprach der Prinz, und wir erkennen daraus, wie
leicht seine Abneigung gegen die Prinzessin ihn verleitete, den
Einflüsterungen seines Günstlings Gehör zu schenken. Ueberdies
kam ihm, wie wir erfahren haben, Mühlfels’ Geständniß sehr
gelegen, da er dasselbe in seinem eigenen Interesse benutzen
konnte. Ob dasselbe begründet war, ob ihn der Baron absichtlich
täuschte, wie es der Fall war, um der Ungnade des Fürsten zu
entgehen, fiel ihm nicht ein zu untersuchen. Eben so wenig sah er
sich veranlaßt, zu überlegen, daß bei dem fleckenlosen Charakter
der Prinzessin die Aussage des Barons wenig Glauben verdiente.
An sittliche Tugend glaubte er nicht, jedoch an die Schwäche und
Sittenlosigkeit der Frauen, und dieser Glaube behielt auch in diesem
Fall um so mehr die Oberhand, da er die Prinzessin schuldig wissen
w o l l t e.
Mühlfels mußte ihm den Abend über Gesellschaft leisten, und er
fand dabei hinreichende Gelegenheit, die bekannten
Angelegenheiten vielfach zu besprechen und sich durch seinen
Günstling in seinen Vorsätzen noch mehr befestigen zu lassen.
Mit den besten Hoffnungen erfüllt, schied der Baron von ihm, in
hohem Grade beglückt, daß sein kühnes Mittel so gute Wirkungen
ausgeübt hatte. Er freute sich, auf den glücklichen Gedanken
gerathen zu sein, sich als das Opfer zu bezeichnen, das er der Ehre
der Prinzessin gebracht hatte. Die sowol von dem Prinzen als dem
Fürsten gehegten Vorurtheile kamen ihm dabei sehr zu statten, denn
sie ließen ihn hoffen, daß man seinen Worten Glauben schenken
würde. Und den Prinzen zu überzeugen, war ihm bereits gelungen.
Ueberdies hatte er dem Fürsten ähnliche Andeutungen gemacht und
ebenso gegen Boisière nichts Bestimmtes ausgesprochen; wenn er
nun die Kühnheit besaß, dem Gemahl der Prinzessin selbst deren
Schwächen und seine dadurch erregten Hoffnungen zu gestehen, so
lag in diesem bedeutsamen Umstande ein gewichtiger Beweis für
seine Schuldlosigkeit, indem zugleich alle Schuld auf Sidonie zurück
fiel. Gelang ihm das Letztere, so war er auch von der Zurücknahme
des fürstlichen Befehls überzeugt.
Wie gewöhnlich vertraute er seine Besorgnisse und Hoffnungen
seiner Mutter an, die nicht wenig überrascht war, den lieben Sohn in
einer so übeln Lage zu wissen. Sie stimmte jedoch seinen
Voraussetzungen bei und tröstete sich mit ihm in der Gewißheit von
dem großen Einfluß des Prinzen auf den Fürsten.
Sie sollten bald erfahren, wie sehr sie sich in dieser Beziehung
täuschten.
Der Prinz begab sich an dem nächsten Tage zu dem Fürsten, um
die bekannten Angelegenheiten zu besprechen, und unterließ nicht,
das Interesse seines Günstlings mit aller Wärme zu vertreten.
 Mit großer Aufmerksamkeit hörte ihn der Fürst an und schritt,
nachdem der Prinz seine Mittheilung geendet hatte, einigemal
schweigend und gedankenvoll durch das Gemach.
»Und Du glaubst den Worten des Barons?« fragte er, indem er vor
dem Prinzen stehen blieb und ihn fragend anschaute.
»Ich habe keinen Grund zum Gegentheil, und kenne den Baron
überdies zu genau, um an der Wahrheit seiner Mittheilung zu
zweifeln.« —
»Du hegst eine natürliche Vorliebe für ihn, da er Dein besonderes
Vertrauen besitzt; diese Vorliebe täuscht Dich jedoch dieses Mal und
Du übersiehst, daß die Prinzessin, fühlte sie sich schuldig, anders
gehandelt haben würde. Ich sage Dir, ein solch’ stolzes, freies
Wesen, wie sie, zeigt keine Schuldige, und der Baron hat das
Aeußerste gewagt, um sich von der Strafe zu befreien. Ich kenne die
Menschen genügend, um nicht zu wissen, daß ein Mann, wie der
Baron, in einem Fall, in welchem seine Ehre auf dem Spiel steht,
sich nicht in solcher Weise opfert. Das ist lediglich ein Kunstgriff von
ihm, der ihm jedoch nichts helfen soll. Ihn verleitete seine Eitelkeit zu
der Täuschung; ich bin davon durchaus überzeugt. Er wollte sich mir
gefällig zeigen, um Nutzen daraus zu schöpfen. Ich gebe zu, daß
ihm die Prinzessin ein gewisses Wohlwollen schenkte; das ist jedoch
nichts Besonderes. Sollte er darin eine Berechtigung zu so
bedeutsamen Hoffnungen gefunden haben, so ist das seine Schuld,
und darum muß er büßen. Ich wie Du sind es der Prinzessin
schuldig, und so soll die Sache ihren Gang haben.« —
Der Prinz wurde durch diesen festen Bescheid seines Oheims in
hohem Grade verstimmt und bemühte sich auf das äußerste, den
Baron von der Strafe zu befreien; indessen vergebens. Der Fürst
beharrte auf seinem Entschluß und schnitt seine weiteren
Bemühungen mit dem Bemerken ab, daß eine viel wichtigere
Veranlassung ihn bestimmt habe, den Prinzen zu sich bitten zu
lassen, und er daher des Barons Sache als abgethan betrachte.
Alsdann fragte er ihn, durch welche Umstände Mariane veranlaßt
worden sei, sich in das Schauspiel zu drängen.
 Der Prinz fand es für gut, dem Fürsten das Nähere darüber zu
verschweigen, indem er seinen Liebling durch die demselben
beiwohnende Unerfahrenheit zu entschuldigen bedacht war und
zugleich die Versicherung aussprach, nicht die geringste Kenntniß
von dem Besuch gehabt zu haben.
Auch jetzt hörte ihn der Fürst ruhig und aufmerksam an und
entgegnete alsdann mit Strenge:
»Nicht das M ä d c h e n, sondern S i e trifft die Schuld, wenn so
etwas geschehen konnte; daß es geschah, ist ein Zeichen, wie
wenig Respect das Mädchen für Sie hat. So weit durften Sie es
jedoch nicht kommen lassen. Wir haben Ihre Liaisons, sobald sich
dieselben in den erforderlichen Grenzen hielten, schweigend
geduldet; wir finden uns jedoch nach dem Erfahrenen veranlaßt, Sie
dem Einfluß dieses jedenfalls sehr listigen Mädchens zu entziehen,
vor Allem jedoch der Prinzessin für die erfahrene Scene dadurch
eine Genugthuung zu verschaffen; und so befehlen wir Ihnen, das
Mädchen sofort zum Verlassen der Stadt zu veranlassen. Ich weiß,
daß die Prinzessin nichts Geringeres erwartet, und eine solche
Forderung kann nur billig genannt werden. Ueberdies bin ich das
auch mir und dem Hofe schuldig. Sie werden sich also mit dem
Mädchen arrangiren. Uebrigens dürfte diese niedrige Person zu
einer Liaison mit einem Prinzen sehr wenig geeignet sein; Sie tragen
daher selbst die Schuld, wenn man darüber spottet und Ihren guten
Geschmack in Zweifel zieht. Des Mädchens freches Eindringen in
die gute Gesellschaft hat nun den schlagendsten Beweis geliefert,
daß der Spott nur gerecht war, und so werden Sie wissen, was Sie
zu thun haben.« —
Der Fürst schwieg und trat an das Fenster, durch welches er auf
den Garten blickte.
Bebend vor zorniger Erregung, die des Oheims Strenge und
Beschluß in ihm erzeugt hatte, und zu einer Erwiderung unfähig,
stand der Prinz da. Schon durch die verweigerte Gnade hinsichts
des Barons erbittert, steigerte die Bestimmung über Mariane seinen
Zorn in hohem Grade. Derselbe drohte ihn zu übermannen und er
beherrschte ihn nur mühsam.
 »Und ist das Ihr unumstößlicher Beschluß?!« preßte er endlich
hervor.
»Er ist es,« fiel der Fürst ruhig ein und fügte dann mit Nachdruck
hinzu: »Ich denke, Prinz, Sie sind sich das selbst schuldig, wenn Sie
nicht der Lächerlichkeit verfallen sollen.«
»Wer wagte das zu behaupten?!« fuhr der Prinz auf.
»Ich, Ihr F ü r s t!« fiel dieser in gebietendem Ton ein.
»Sie können mir den Umgang mit dem Mädchen nicht
verwehren!« rief der Prinz in hellem Zorn und mühsam Athem
holend.
»Nicht?« fragte der Fürst ironisch und fuhr mit strenger Kälte fort:
»Hören Sie, Prinz Albert, was Ihnen Ihr Fürst sagt: ist das Mädchen
nicht innerhalb vierundzwanzig Stunden aus dem Bereich der Stadt,
so werde ich es durch Polizeibeamte hinausbringen lassen, und
damit Sie nicht etwa aus zu großer Liebe für die Dirne verleitet
werden, sie etwa als ihr =Cavalier servante= zu begleiten, werden
Sie bis auf Weiteres Ihr Palais nicht verlassen. Und dabei bleibt’s!«
Mit diesen Worten begab sich der Fürst in das Nebengemach und
ließ den Neffen in der furchtbarsten Erregung zurück. Sein Auge
flammte, und ehe der Fürst noch die Thür schloß, zertrümmerte er
den Stuhl, auf den er sich so lange gestützt hatte, mit einem
raschen, mächtigen Stoß. Alsdann taumelte er aus dem Gemach
und warf sich in den auf ihn harrenden Wagen.
Es war tief in der Nacht; dennoch schimmerte in einem der
Zimmer der Villa Marianens Licht und verrieth, daß die Bewohner
derselben noch nicht die Ruhe gesucht hatten.
Dies war in der That der Fall; denn wenn auch die sämmtliche
Dienerschaft daselbst sich der Nachtruhe erfreute, saßen doch
Mariane und Madame Voisin beisammen und unterhielten sich in
leisem Ton mit einander.
Neben ihnen standen gepackte, offene Reisekoffer.
»Ich sage Ihnen, Fräulein, daß das Alles Ihr Besuch des
Schauspiels veranlaßt hat,« wiederholte Madame Voisin zum mehr
denn zehnten Mal.
»Sie irren sich. Wie könnte solche Kleinigkeit —« wandte Mariane
ein.
»Nun, Sie werden es ja bald erfahren. Ohne einen erheblichen
Grund konnte der Prinz nicht auf den Gedanken gerathen, Sie reisen
zu lassen. Ich wiederhole, das geschieht nicht mit seinem Willen,
sondern es steckt etwas dahinter, Sie werden es erleben. Lesen Sie
seinen Brief nur noch einmal durch.«
Mariane ergriff in Folge dieser Aufforderung einen neben ihr auf
dem Koffer liegenden Brief, den sie vor wenigen Stunden von dem
Prinzen erhalten hatte und worin er ihr anzeigte, daß besondere
Umstände ihn nöthigten, sie aus der Stadt für eine kurze Zeit zu
entfernen. Sie und Madame Voisin, die sie auf der Reise begleiten
würde, sollten sich dazu vorbereiten, jedoch nur mit den
nothwendigsten Sachen versehen. Mariane möge ihn in der Nacht
erwarten und würde alsdann alles Weitere von ihm erfahren. Sein
Besuch müßte der Dienerschaft durchaus verheimlicht werden und
sollten sie ganz besonders darauf bedacht sein.
»Nun, Fräulein, ist Ihnen jetzt die Sache klar?« fragte Madame
Voisin.
»Wir sollen eine kleine Reise machen, vielleicht nach meiner
Heimath, und das wäre schön; sonst finde ich nichts Besonderes in
den Worten,« meinte Mariane ziemlich ruhig.
»Dann habe ich nichts mehr zu sagen,« sprach Madame Voisin
und begann auf’s Neue zu packen; Mariane jedoch, von der
Voraussetzung erfüllt, eine Zeit lang in der Heimath verleben zu
dürfen, plauderte weiter.
»Wie werden sie meine Schmucksachen und schönen Kleider dort
bewundern! So etwas haben sie noch nicht gesehen. O, ich will
ihnen davon schenken, so viel es irgend geht; der Prinz kann ja für
Neues sorgen. Und der Wald ist auch grün und frisch, und ich kann
mich darin wie früher nach Belieben ergehen, und um so besser wird
es mir dann wieder hier gefallen, wenn ich zurückkomme. Wenn ich
nur meine Vögel und Affen auch mit mir nehmen dürfte.« —
 In solcher Weise schlug sich das Mädchen alle Sorgen und
Bedenklichkeiten aus dem Herzen, indem sie sehr bald Madame
Voisin nachahmte und allerlei, oft die überflüssigsten Dinge in den
Koffer packte, wobei sie zugleich und auch die Erstere ab und zu
aufhorchten, wenn sich der Nachtwind oder ein anderes Geräusch
draußen geltend machte.
Während sie sich also beschäftigten, bemerkte man zwei in
Mäntel gehüllte Männergestalten durch eine Hinterthür aus dem
Palais des Prinzen schleichen und sich vorsichtig an den Häusern
fortbewegen. Ihr Benehmen verrieth, daß sie nicht erkannt sein
wollten, und die herrschende Dunkelheit kam ihnen dabei sehr zu
statten. Auch war Mitternacht fast vorüber, die Straßen unbelebt und
überall herrschte Ruhe und Stille; ein weiterer günstiger Umstand für
ihre Absicht.
Ziemlich rasch und schweigend durchschritten sie mehre Straßen
und gelangten alsdann außerhalb der Stadt und auf den Landweg,
den sie verfolgten, bis sie Marianens Villa erreichten.
Sie traten durch die offene Pforte in den die letztere umgebenden
Garten ein und einer von ihnen begab sich an das erleuchtete
Fenster und klopfte leise an. Die Frauen fuhren erschreckt auf, und
Madame Voisin beeilte sich, die nach der Veranda führende Thür zu
öffnen, durch welche die Gäste dann leise und vorsichtig eintraten.
Es war der Prinz und Mühlfels.
»Schläft Alles?« fragte der Erstere leise.
Die Voisin bejahte, worauf sich der Prinz zu Marianen begab.
Diese empfing ihn mit einem leisen Freudenruf, und er schloß sie
innig in die Arme und küßte sie heftig.
»Und ich soll reisen, mein Prinz?« fragte sie.
»Ja, und es ist Deine Schuld, wenn ich Dich für einige Zeit
entbehren muß. Ich sagte es Dir voraus. Warum warst Du mir auch
ungehorsam!«
»O, sei nicht böse, mein Prinz; sei nicht böse und vergieb Deinem
thörichten Waldvogel!« flehte Mariane und schmiegte sich an ihn,
während Thränen ihren Augen entquollen.
Doch es bedurfte ihrer Bitte um Verzeihung nicht mehr; des
Prinzen Unmuth war längst verraucht; er liebte sie viel zu heftig, um
ihr nicht noch Uebleres nachzusehen. Seine Liebe zu ihr machte
sich überdies auch in dem Augenblick, in welchem er sich von ihr für
längere Zeit trennen sollte, nur noch in erhöhterem Maß geltend und
erfüllte ihn mit dem Verlangen, die letzten Stunden des
Zusammenseins so viel als möglich auszukosten.
»Ich habe Dir längst vergeben, mein süßer Vogel, und nun sei
wieder munter und weine nicht mehr,« beruhigte sie der Prinz.
»Ich werde also nach Hause reisen?« fragte sie, wieder beruhigt.
»Nein, mein Liebchen; nicht nach Hause, sondern nach der
prächtigsten Stadt der Städte, nach Paris!« —
»Nach Paris, der Wunderstadt?!« rief Mariane und schlug in
freudiger Ueberraschung die Hände in einander.
»Ja, dahin soll die Geliebte des Prinzen gehen und soll sich dort in
allen Dingen unterrichten lassen, die einer vornehmen Dame
ziemen. Denn wisse, Mariane, sobald ich zur Regierung komme,
sollst Du Gräfin werden, wie Du es willst, und dann wird man Dich
gern in den vornehmen Cirkeln dulden.« —
»O, das ist ein gescheidter Gedanke von meinem Prinzen!« rief
Mariane erfreut aus und umarmte und küßte ihn. »Nach Paris! Was
werde ich da Alles zu sehen bekommen! O,« fuhr sie eifrig fort, »ich
will fleißig sein und mich bemühen, Vielerlei zu lernen, und Du sollst
vor meiner Klugheit erstaunen, wenn ich zurück komme!«
»Das weiß ich und das werde ich,« fiel der Prinz lachend ein.
»Und übe das Singen fleißig; Du weißt, es macht mir Freude.«
»Alles, Alles werde ich thun, wie Du es befiehlst, mein süßer, guter
Prinz!« rief Mariane und fragte dann, diesen betrübt anblickend:
»Wirst Du aber auch nicht Deine Waldtaube vergessen und
bisweilen an sie denken?«
»Sei dessen sicher, mein Schatz; Du weißt, wie lieb ich Dich
habe.« —
 »Ja, ja, ich weiß es!« rief sie und schmiegte sich an ihn. Nach
einer kurzen Pause fragte sie: »Und meine Vögel und Affen, kann
ich sie mitnehmen?«
»Das geht nicht; übrigens kannst Du Dir dort so viel Du willst und
noch schönere kaufen.« —
»Dann ist es gut; doch mußt Du mir die Thierchen pflegen lassen,
damit ich sie bei meiner Rückkehr wieder finde.« —
»Es soll geschehen; und auch Deine Villa soll behütet werden und
ich will sie noch verschönern lassen.« —
Mariane war darüber sehr glücklich und dankte dem Prinzen mit
zärtlichen Worten und Liebkosungen, indem sie zugleich noch
allerlei Sorgen und Wünsche aussprach, die der Prinz zu
beschwichtigen sich bemühte.
In solchem Geplauder und Getändel ging ihnen die Zeit dahin,
während dessen Mühlfels mit Madame Voisin die ernsteren und
geschäftlichen Angelegenheiten der Reise und des Aufenthaltes in
Paris erörterte. Die Dame war eine Pariserin und also mit den
Verhältnissen daselbst genügend vertraut; sie eignete sich daher zur
Gesellschafterin des unerfahrenen Mädchens ganz vortrefflich.
Dieser Umstand hatte den Prinzen auf den Gedanken geleitet,
Mariane dorthin zu schicken.
Die Strenge seines Oheims hatte, wie wir erfahren haben, seinen
Zorn und Unmuth in dem höchsten Grade erregt, so daß er sich
sogar zu dem so groben Verstoß gegen die dem Fürsten schuldige
Rücksicht verleiten ließ.
In seinem Palais angelangt, brach sein Zorn in ganzer Stärke aus,
und seine Umgebung hatte darunter wie gewöhnlich nicht wenig zu
leiden.
Erst gegen Abend und als ihn Mühlfels besuchte, beruhigte er sich
wieder so weit, daß er einen Entschluß fassen konnte.
In diesen mischte sich jedoch zugleich das lebhafte Verlangen, da
er seines Oheims Befehl nachkommen mußte, der Entfernung
Marianens den übeln Schein der Ausweisung zu nehmen und
zugleich zu zeigen, wie weit entfernt er war, sie aufzugeben.
Und so brach er dem Befehl des Fürsten und der Forderung
Sidoniens die Spitze ab, indem er das Mädchen in der Absicht nach
Paris sandte, sie dort ausbilden zu lassen. Daß dies dem Fürsten
und Sidonien bald bekannt wurde, dafür wollte er sorgen. In solcher
Weise war er bemüht, sich Genugthuung für die seiner Ansicht nach
erfahrene Unbill zu verschaffen.
Er stattete Mariane zugleich so reich mit Mitteln aus, daß sie ein
glänzendes Haus in Paris machen konnte, und that dies nicht allein
aus Zuneigung zu ihr, sondern auch aus der früher bezeichneten
Absicht. Das Weitere haben wir bereits erfahren.
Das Morgengrauen mahnte ihn, zu scheiden, und er trennte sich
nach dem zärtlichsten Abschied von Marianen, — die reichlich
Thränen vergoß und ihn nicht von sich lassen wollte — nachdem er
ihre Abreise für den nächsten Tag bestimmt hatte. Dieselbe sollte
jedoch nicht etwa heimlich und auch nicht in der Dunkelheit
geschehen, sondern vielmehr am lichten Tage und während des
vollen Treibens in den Straßen, damit sie nicht den Anschein der
Verbannung oder ängstlicher Flucht gewann. So wollte er dem
Fürsten und seiner anspruchsvollen Gemahlin trotzen.
Und wie er es befohlen hatte, so geschah es.
Nachdem sich Mariane von ihren Thieren wiederholt in der
zärtlichsten Weise verabschiedet und ihr Lieblingsäffchen in ihrer
Reisetasche sorglich untergebracht hatte, da sie sich von demselben
nicht zu trennen vermochte, verließ sie, begünstigt von dem
schönsten Frühlingswetter, am Nachmittag die Villa und fuhr stolz
durch die Stadt, um auf die Straße nach Paris zu gelangen.
Hunderte neugieriger Augen gafften die Equipage an, allerlei
zweideutige Witze wurden laut, und manches spöttische Lächeln
folgte ihr, und ehe Mariane noch die Stadt verlassen hatte, durcheilte
dieselbe bereits das Gerücht von ihrer Abreise nach Paris.
So erreichte der Prinz seine Absicht und freute sich darüber nicht
wenig.
 Der Trennung von Marianen sollte am nächsten Tage diejenige
von Mühlfels folgen.
Es darf wol kaum bemerkt werden, wie tief der Letztere durch die
Fruchtlosigkeit der Bemühungen des Prinzen, ihm Gnade bei dem
Fürsten auszuwirken, gebeugt wurde. Aber mit seinem Kummer und
Zorn erwachte auch zugleich das lebhafte Verlangen in ihm, sich für
die ihm, wie er glaubte, von Sidonien zugefügte Schmach zu rächen.
Diese mußte er erdulden; ihre Gunst hatte er auf immer verscherzt;
so blieb ihm nur noch das Verlangen nach Rache.
Wie gelegen kam ihm nun die gemachte Entdeckung hinsichts
Sidoniens Neigung für den Grafen, und er war schlecht genug,
dieselbe in seiner Absicht zu benutzen. Von dem Prinzen
eingeladen, im traulichen Beisammensein den letzten Abend bei ihm
zu verbringen und ihm durch seine Gesellschaft den Schmerz über
Marianens Abreise zu beschwichtigen, hatte er sich bei demselben
zur Zeit eingefunden.
Es konnte nicht ausbleiben, daß im Lauf der Unterhaltung auch
sehr bald Mühlfels’ Angelegenheiten nochmals von ihnen
besprochen wurden, und so geschah es, daß der Baron bemerkte:
»Muß ich auch dem Machtgebot des Fürsten folgen, so bin ich
doch überzeugt, daß die Zeit nicht zu fern ist, in welcher er das an
mir verübte Unrecht erkennen und einsehen wird, daß ich schuldlos
leide.«
»Ich hoffe es, Mühlfels, und geschieht dies nicht, so trösten Sie
sich mit der Aussicht, daß ich dereinst die Fehler meines Oheims gut
zu machen wissen werde.« —
»O, ich weiß es, mein theurer Prinz, und Ihre Gnade ist mein
einziger Trost in meiner entehrenden Lage. Aber ich hoffe, es soll
mir gelingen, den Fürsten zu der Einsicht seines Unrechts zu
führen.« —
»Ich verstehe Sie nicht, Mühlfels,« bemerkte der Prinz und
schaute ihn fragend an.
»Das kann nicht anders sein, da ich Ihnen das Wichtigste in der
Angelegenheit mit der Prinzessin verschwiegen habe.« —
 »Wissen Sie noch mehr?« fragte der Prinz überrascht.
»Allerdings, und was ich Ihnen sagen kann, ist noch bedeutsamer,
als was Sie bereits von mir erfahren haben, und kennzeichnet die
Scheinheiligkeit Ihrer Gemahlin noch mehr, als ihre Verläugnung der
mir gewährten Gunstbezeigungen,« entgegnete Mühlfels mit
Nachdruck.
»Sie machen mich begierig darauf. Sprechen Sie!« fiel der Prinz
erregt ein.
»Vielleicht lag es in der Prinzessin Absicht, mich von hier zu
entfernen,« bemerkte Mühlfels.
»Was sollte sie dazu bestimmen?« —
»Das Bewußtsein, in mir einen Verräther ihrer Schwäche zu
finden.« —
»Das könnte sein!« fiel der Prinz ein.
»Verstehen Sie mich recht, mein Prinz, ich meine damit nicht den
Verrath der mir erzeigten Gunst, sondern die Liebe für einen
Andern.« —
»Sie hat also eine Liaison?« fragte der Prinz.
»Ich bin davon durchaus überzeugt,« entgegnete Mühlfels und
theilte ihm nun mit gut gewählten Worten seine Entdeckungen und
Vermuthungen hinsichts Sidoniens Neigung für den Grafen mit.
Der durch seine Mittheilung erzeugte Eindruck auf den Prinzen
war ein überraschend erwünschter, da dieser von Alledem keine
Ahnung hatte und das Vernommene daher eine um so tiefere
Wirkung auf ihn ausübte.
»Und warum erfahre ich das Alles erst jetzt?!« fragte der Prinz.
»Weil ich es bisher für besser erachtete, darüber zu schweigen.
Da die Prinzessin jedoch durch ihr übles Verhalten gegen mich sich
jeder auf sie zu nehmenden Rücksicht begeben hat, darf ich ihr auch
keine Schonung mehr angedeihen lassen.« —
 »Sie hätten mich und den Fürsten schon früher damit bekannt
machen sollen.«
»Das hätte zu keinem erwünschten Resultat geführt und mich
obenein in die Gefahr gesetzt, als Undankbarer und Ruhestörer
bezeichnet zu werden. Sie wissen, mein Prinz, ich war der
Prinzessin Rücksicht schuldig. Uebrigens erinnere ich Sie, daß
meine Mittheilung auch, da ich die erforderlichen Beweise dafür nicht
besitze, keine besondere Bedeutung gewinnen konnte. Meiner
Ansicht nach kommt es darauf an, die Rückkehr des Grafen
abzuwarten und ihn und die Prinzessin alsdann in der Stille zu
beobachten und sich also die nöthigen Beweise ihrer Schuld zu
verschaffen. Sie ahnen nicht, daß ihr Geheimniß verrathen ist, und
werden daher um so leichter in die ihnen gestellte Falle gehen, wenn
sie sich nicht vielleicht auch ohne eine solche verrathen.«
»Sie haben Recht, ganz Recht, und Ihre Entdeckung ist kostbar!«
rief der Prinz in großer Erregung, der das Vernommene mit
rachsüchtiger Begier aufgriff. »Könnte ich sie entlarven und der Welt
ihre Scheinheiligkeit offenbaren, ich würde mich für das Erfahrene
reich entschädigt fühlen. Denn ich vermag Ihnen nicht
auszudrücken, wie verhaßt mir Sidonie nach der letzten Geschichte
geworden ist. Läßt sich Ihre Entdeckung in meinem Sinne
ausbeuten?«
»Würde ich hier geblieben sein, hätte sich das wahrscheinlich
leicht machen lassen, besonders da der Graf jeden Tag eintreffen
kann; jetzt jedoch, so entfernt von hier, sehe ich dazu keine
Möglichkeit.«
»Ein fataler Umstand! Um so mehr werde ich bedacht sein, den
Fürsten zur Abkürzung Ihrer Verbannung zu bewegen. Sie sollen
nicht lange dort sein.«
»Hoheit würden mich dadurch sehr beglücken; denn eine
unverdiente Strafe erträgt sich schwer.«
»Ich werde dafür sorgen, daß Sie dort gut aufgenommen werden
und Ihnen der Commandant alle Freiheit gestattet. Ich gebe Ihnen
ein paar Worte an diesen mit.«
 »Tausend Dank, mein gnädigster Prinz. Doch nun gestatten Sie
mir, Ihnen noch meine Ansicht über die Behandlung der bewußten
Angelegenheit zu bezeichnen.«
»Reden Sie, Mühlfels; denn es ist mir lieb, zu erfahren, was Sie für
die Folge darin zu thun gedenken. Ich will die Sache bis zum
Aeußersten verfolgen, um die Befriedigung meiner Rache
vollkommen zu genießen.«
»Und ich denke, dies soll uns auch gelingen, besonders wenn mir
die Rückkehr bald gewährt wird. Bis dahin jedoch bitte ich Sie, mein
Prinz, von dem Vernommenen weder dem Fürsten, noch irgend
einem Andern das Geringste zu verrathen. Sie kennen die
Hofverhältnisse zu genau, um eine solche Vorsicht nicht zu billigen.
Ueberdies dürfte Ihre persönliche Einmischung vor der Hand auch
gefährlich werden. Sie sind zu hitzig und Ihre Erregung würde sich
um so rascher steigern, da Sie der Beleidigte sind. Dadurch könnte
die Angelegenheit leicht einen nichts weniger als erwünschten
Ausgang nehmen. Darum bitte ich, lediglich mir alles Weitere zu
überlassen, und überzeugt zu sein, daß ich alle Sorgfalt auf
Enthüllung dieser Sache anwenden werde.«
»Sie haben Recht und so soll es dabei bleiben, und um so mehr
werde ich mich bemühen, Ihnen die baldigste Rückkehr bei dem
Fürsten auszuwirken.«
Nachdem sie diese Angelegenheit noch weiter besprochen,
Mühlfels des Prinzen Empfehlung an den Commandanten
empfangen hatte, schied der Baron unter den gnädigsten
Freundschaftsbezeigungen von dem Prinzen, nicht wenig erfreut,
seinen finstern Racheplan in so vortrefflicher Weise zur Geltung
gebracht zu haben. Daß ihm derselbe gelingen würde, zweifelte er
nicht; jedenfalls verschaffte er ihm die so gewünschte baldige
Rückkehr, und das war ein großer Vortheil. Diese Hoffnung gewährte
ihm und seiner tief verletzten Mutter keinen kleinen Trost, als er in
der Frühe des nächsten Tages sich von ihr und der Residenz trennte
und, nur von einem Diener begleitet, die Reise nach der öden und
einsamen Garnison antrat. Es verstand sich von selbst, daß die
Baronin sofort um ihre Entlassung aus dem Dienst der Prinzessin
einkam, die ihr natürlich auch bewilligt wurde.
Mit besonderer Genugthuung sah der Fürst seine Befehle in
solcher Weise erfüllt, da man ihm die herausfordernde Weise
verschwieg, in welcher Mariane die Stadt verlassen hatte. Ein paar
Tage darauf ließ er dem Prinzen seine Freiheit ankündigen, und
dieser benutzte dieselbe sofort, sich nach der ersten Residenz zu
begeben, seine alten Freunde daselbst um sich zu versammeln und
mit ihnen in der früheren Weise zu leben und so den Schmerz über
den Verlust seiner Günstlinge zu vergessen.
Der Fürst ließ ihn vorläufig gewähren und that dies in der Absicht,
ihn bald mit um so größerer Strenge an seinen Aufenthalt zu binden
und dadurch zugleich zur Einsicht der Nothwendigkeit einer
Versöhnung mit ihm und Sidonien zu leiten. Dies geschah, und der
Prinz trug mit gesteigertem Unmuth den ihm auferlegten Zwang,
seine Gemahlin verwünschend, der er alle Schuld zu dem ihn
Betroffenen beilegte.
Sidonie vernahm mit Befriedigung die ihr von dem Fürsten
bereitete Genugthuung, dankte ihm persönlich dafür, und die Frage
der Trennung von dem Prinzen wurde nicht weiter berührt.
Trotzdem übersah sie die Gefahr nicht, welche sie dadurch für
sich herauf beschworen hatte; denn es konnte mit Sicherheit
erwartet werden, daß sich der Prinz und auch Mühlfels für das
Erlittene an ihr zu rächen bedacht sein würden. Um so erwünschter
war ihr daher des Fürsten Vorschlag, ein Bad zur Stärkung zu
gebrauchen, und bereitwillig ging sie darauf ein, da sie sich dadurch
zugleich dem leidigen Hofleben entziehen und in der gebotenen
Freiheit ergehen konnte. Wol nicht ohne Absicht traf sie die Wahl
eines Badeorts, der von des Grafen Besitzung nicht allzu fern lag
und diesem die Gelegenheit zu einem Besuch bot. Da ihr Arzt ihre
Wahl billigte, so erschien diese als dessen Bestimmung, und ihre
Vorliebe für den gewählten Ort wurde dadurch verhüllt.
Ungefähr drei Wochen nach den näher bezeichneten Vorfällen
reiste sie in Begleitung ihrer Tochter, Aureliens und einer nicht eben
großen Dienerschaft dahin ab.
 Sie hatte den Prinzen bis zu diesem Augenblick nicht gesprochen;
sie wurde durch ihre Abreise genöthigt, ihm Lebewohl zu sagen, und
sie that dies, wenngleich mit großer Ueberwindung.
Der Prinz, weit entfernt ihr freundlich entgegen zu kommen, zeigte
ihr vielmehr ein kaltes, verletzendes Verhalten, dem sie sich so
schnell als möglich zu entziehen suchte. Ihm war es angenehm, sie
nicht mehr in seiner Nähe zu wissen, und mit Ungeduld sah er der
Zeit entgegen, in welcher es ihm mit Mühlfels’ Hilfe gelingen sollte,
sich an ihr zu rächen.

Ende des zweiten Bandes.

Druck von G. Pätz in Naumburg a/S.
 Anmerkungen zur Transkription:

Die erste Zeile entspricht dem Original, die zweite Zeile enthält die Korrektur.

S. 40
Nein, Hoheit, eine Trauung scheut er;
Nein, Hoheit, eine Trennung scheut er;

S. 68
Gedanken und Erfindungen in ihrer zeugte
Gedanken und Erfindungen in ihr erzeugte
 *** END OF THE PROJECT GUTENBERG EBOOK PRINZESSIN
SIDONIE (BAND 2/3) ***

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