Rev. Neurosci.
2014; 25(6): 841850
Shreya Bhat, U. Rajendra Acharya, Hojjat Adeli*, G. Muralidhar Bairy and Amir Adeli
Autism: cause factors, early diagnosis and
therapies
Abstract: Autism spectrum disorder (ASD) is a complex
neurobiological disorder characterized by neuropsycholog-
ical and behavioral deficits. Cognitive impairment, lack of
social skills, and stereotyped behavior are the major autistic
symptoms, visible after a certain age. It is one of the fastest
growing disabilities. Its current prevalence rate in the U.S.
estimated by the Centers for Disease Control and Prevention
is 1 in 68 births. The genetic and physiological structure of
the brain is studied to determine the pathology of autism,
but diagnosis of autism at an early age is challenging due
to the existing phenotypic and etiological heterogeneity
among ASD individuals. Volumetric and neuroimaging
techniques are explored to elucidate the neuroanatomy of
the ASD brain. Nuroanatomical, neurochemical, and neu-
roimaging biomarkers can help in the early diagnosis and
treatment of ASD. This paper presents a review of the types
of autism, etiologies, early detection, and treatment of ASD.
Keywords: autism spectrum disorders; CHD8; GABA;
neural connectivity; virtual reality.
DOI 10.1515/revneuro-2014-0056
Received August 8, 2014; accepted August 11, 2014; previously pub-
lished online September 12, 2014
Introduction
The human brain is one of the most composite organs
of the body because of its complex genetic structure
*Corresponding author: Hojjat Adeli, Departments of Neuroscience,
Biomedical Engineering, Biomedical Informatics, Electrical and
Computer Engineering, The Ohio State University, 470 Hitchcock
Hall, 2070 Neil Avenue, Columbus, OH 43210, USA,
e-mail: adeli.1@osu.edu
Shreya Bhat and G. Muralidhar Bairy: Manipal Institute of
Technology, Department of Biomedical Engineering, Manipal,
Karnataka 576104, India
U. Rajendra Acharya: Department of Electronics and Computer
Engineering, Ngee Ann Polytechnic, Singapore 599489, Singapore;
and Faculty of Engineering, Department of Biomedical Engineering,
University of Malaya, 50603, Malaysia
Amir Adeli: Department of Neurology, The Ohio State University,
Columbus, OH 43210, USA
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and compound neural connectivity. A synaptic connec-
tion between neurons is termed as scale-free network as
it changes with development. The more information
collected by the brain, the more will be the synaptic
connections and its study becomes more complex. The
relationship between the functional brain wiring and cog-
nitive development enhances the understanding of neu-
rodevelopmental disorders (Bosl etal., 2011).
Autism is one of the psychological and heterogene-
ous developmental disorders due to the abnormal wiring
between the different brain regions (Figure 1) (Matson
et al., 2012). It is a neuropsychiatric syndrome, derived
from the Greek word autos, meaning an isolated self, in
which a person keeps himself/herself isolated from the
surrounding interactions. The Centers for Disease Control
and Prevention (CDC) estimated that the prevalence rate
of autism in 2006 was 1 in 110 children (Kotagal and
Broomall, 2012) and increased to 1 in 88 births by 2012
(CDC, 2012). Its current prevalence rate estimated by the
CDC is 1 in 68 births, or 14.7 children per 1000 (Falco,
2014). Around 1 in 175 children in Alabama and 1 in 45
children in New Jersey are identified as having an autism
spectrum disorder (ASD). It is more common in White chil-
dren compared with African-American or Hispanic chil-
dren, and boys are five times more prone to this disorder
compared with girls (Falco, 2014) because of mutations in
the X-chromosome patched-related (PTCHD1) gene. The
microdeletion of the PTCHD1 gene as shown in Figure 2A
is maternally inherited and is dominant in males as they
possess XY chromosomes whereas females have XX chro-
mosomes. The microdeletion of the PTCHD1 gene becomes
a recessive character in females (Noor etal., 2010). Around
5% of male ASD cases are due to the compound heterozy-
gous, rare inherited functional loss of homozygous, and
X-chromosome hemizygous mutations (Stein etal., 2013).
Autism is believed to affect various systems of the
body and appears to have numerous etiologies (Matson
etal., 2012). Clinical symptoms are observed in children
above 1.52years of age due to irregularity in the physical
and computational connectivity of neurons. It can mani-
fest in the form of disturbed sleep, depression, decreased
sleep duration, anxiety, and increased sleep onset delay
(Belmonte et al., 2004). The prevalence of sleep prob-
lems in autistic children is more when compared with
842S. Bhat etal.: Autism: cause factors, early diagnosis, and therapies

A
A

B
B

Figure 2Chromosomal variations.

(A) Microdeletion of the chromosome leading to neurodevelopmen-
tal disorder. (B) De novo copy number variation in ASDs.
Figure 1The brain wiring between different brain regions.
(A) Normal brain and (B) autistic brain.
range. Siblings of an affected individual have 218%
chances of being autistic (CDC, 2014).

those with developmental delay. Researchers portray

that aggression, hyperactivity, and stereotyped behaviors
are common in autistic males, whereas autistic females
show anxiety, depression, and greater intellectual
impairment (Jeste and Geschwind, 2014). Other features
are macrocephaly (Herbert, 2005), where the growth of
head circumference speeds up in the first 2 years fol-
lowed by deceleration in later childhood (Aylward etal.,
2002), repetitive behavior, developmental delay, cogni-
tive impairment (Happe etal., 2006; Yates and Couteur,
2013), and lack of communication and interactive skills
(Narain, 2006). Early behavioral characteristics observed
in infants are delay in babbling and improper sleep and
eating habits (DiCicco-Bloom et al., 2006). Ongoing
research indicates that in identical twins, if one child is
autistic, there is a 3695% chance for the other child to be
autistic, whereas in nonidentical twins, it is in the 030%
Different forms of autism
Autism is expanded to ASD representing a range of dis-
orders affecting an individuals communication, behav-
ior, and social interaction. Even though the three major
areas, communication, behavior, and social interaction,
are affected in autism, autistic individuals have enhanced
discrimination ability where they can observe minute var-
iations in feature and visual search tasks (Figure 3). This
unique characteristic acts as an anomaly in autistic indi-
viduals as they are biased to variations in the surrounding
(Brandwein etal., 2013). These variations, distracting the
normal population, help in stimulus information process-
ing (Elsabbagh et al., 2013). Around 10% of the autistic
population has special skills called savant skills. These

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 S. Bhat etal.: Autism: cause factors, early diagnosis, and therapies843

Figure 3Illustration of the enhanced discrimination ability among autistic individuals.

The response of a normal subject to the surrounding stimuli is also shown.

people are brilliant in mathematical calculations, possess
high memory power, and have extraordinary artistic and
musical abilities. For example, an autistic systems admin-
istrator named Gary McKinnon hacked most of the US
government computers in 2002 (Kushner, 2011) and dis-
covered multiple errors in their system. Table 1 describes
three major types of ASD. Table 2 presents autism catego-
rization according to the latest clinical research.
In addition to the three major types of autism
described in Table 1, there are several other less common
types, termed as pervasive developmental disorders:
regressive autistic spectrum disorder, where a child is
normal until 1824months and then regresses to autistic
symptoms; childhood disintegrative disorder, a rare dis-
order affecting social, motor, and language skills (NIMH,
2014); and Rett syndrome, where mutations are linked to
the X-chromosome and are generally seen in girls (Chah-
rour etal., 2008).
Seizure in epileptic patients hampers their neurologi-
cal function, which in turn affects the social functioning
of the brain (Mammone et al., 2012; Martis et al., 2013;
Hearld, 2014; Strzelecka, 2014). Around 25% of children
with autism develop seizures (Scassellati, 2005). Accord-
ing to Gabis et al. (2005), the frequency of epilepsy in

Table 1Different types of ASD (CDC, 2014).

Types Also termed as Clinical features Percentage affected

Autistic disorder Classic autism Impairment in interactive, 20% of the

cognitive, communication and population
language skills
Self-injurious and unusual
behavior
Aspergers syndrome High functioning Normal language and cognitive Majority of the
autism ability population
Unusual behavior, social
impairment
Pervasive developmental Atypical autism Challenges in social interaction Below 5%7% of
disordernot otherwise specified and communication the population

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844S. Bhat etal.: Autism: cause factors, early diagnosis, and therapies
Table 2Autism categorization according to the latest clinical
research (Venker etal., 2013).
Types Clinical features
Persistently Difficulty with daily living activities, self-
severe injurious behavior, severe cognitive disability
Persistently Impairment in social interaction and
moderate communication
Improving Improvement in development due to
behavioral therapies
Worsening Intensive and self-injurious behavior
autistic children is higher. Autistic girls have a higher
rate of epilepsy compared with boys, thus explaining the
cause of lower analyzing ability in autistic girls.
Factors causing autism
Various studies and experiment-based analyses have
attempted to provide probable causes of autism, summa-
rized in Figure 4.
The gene expression is varied due to copy number var-
iations or environmental toxins. Welburg (2011) reviewed
the role of genetic variants and copy number variations in
ASDs. Few cases of autism are due to de novo mutations
(Iossifov etal., 2012). The de novo genes are responsible
for neuron motility, axon guidance, and synaptic devel-
opment (Gilman etal., 2011). Studies reveal that de novo
copy number variations (structural changes) are more
common in autistic children compared with normal chil-
dren, as illustrated in Figure 2B (Levy etal., 2011; Sanders
et al., 2011). According to the latest research on genet-
ics, the mutation of CHD8 (chromodomain helicase DNA
binding protein 8) gene is linked to autism, resulting in
macrocephaly and wide set eyes (Bernier et al., 2014).
Figure 4Possible causes of ASD.
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Stereotyped behavior, impaired social interaction, and
weak synaptic transmission are associated with the irreg-
ular microglia-mediated synaptic pruning (Zhan et al.,
2014). The different types of brain cells are present in the
six distinct layers of cortex responsible for learning and
memory. Changes in genetic structure vary the formation
of cortex layers, leading to patches of disorganization in
the cortex (Hamilton, 2014).
Apart from genetic factors contributing to autism,
environmental factors including mercury, radiation, and
diesel exhaust have been implicated. Further, mater-
nal viral infections, valproic acid and thalidomide used
during pregnancy, and exposure to pesticides have been
reported to affect the central nervous system of the fetal
brain (CDC, 2014). Krakowiak et al. (2012) associated a
mothers metabolic conditions during pregnancy to ASD,
developmental delay, and cognitive impairment in the off-
spring. It has also been found that gestational maternal
hypothyroxinemia is linked to ASD (Roman etal., 2013).
Autism is a neurobiological abnormality affecting the
size of the corpus callosum (He etal., 2010), a collection
of nerve fibers connecting the two hemispheres (left and
right) of the brain and playing a major role in the trans-
mission of sensory, motor, and cognitive information.
Agenesis of the corpus callosum contributes to develop-
ing autism, depicted in Figure 5 (Paul etal., 2014). Zielin-
ski etal. (2014) reported increased cortical thinning in the
frontal lobe, parietal lobe, occipital lobe, and the entire
cortex of the ASD subjects.
Neuroimaging techniques have shown that children
suffering from ASD possess anomalous brain connectiv-
ity. The intrinsic wiring potential of a brain region cor-
responds to lower wiring costs associated with shorter
geodesic distances. The geodesic distances capture the
complex surface of the brain. It has been observed that
the brains intrinsic connectivity differs in ASD subjects
compared with normal subjects (Figure 6), and hence, the
wiring costs in autistic subjects are significantly reduced
(Ecker and Murphy, 2014). It has been found that func-
tional connectivity with other brain regions is decreased
within the frontal and temporal cortical regions of the
ASD brain (Tyszka et al., 2014). The transfer of informa-
tion is reduced due to less specialized autistic brain,
i.e., overconnectivity between neural assemblies (Misic
etal., 2014) and underconnectivity of the functional brain
regions (Mostofsky and Ewen, 2011; Just et al., 2012),
resulting in language impairment (Verly etal., 2013) and
reduced learning rate (Schipul etal., 2012).
Dinstein etal. (2011) reported weak interhemispheric
neural synchronization (Anderson et al., 2011) in tod-
dlers with autism. The disrupted neural synchronization
 S. Bhat etal.: Autism: cause factors, early diagnosis, and therapies845
A Observation Schedule (Lord etal., 2012).
B
Figure 5Corpus callosum: (A) normal and (B) autistic (agenesis of
the corpus callosum).
is evident in naturally sleeping autistic toddlers, and the
strength of cortical synchronization is negatively corre-
lated in autistic subjects, whereas it is positively corre-
lated in subjects with verbal ability. Atypical autonomic
processing resulting in low skin conductance (Eilam-
Stock et al., 2014) and decreased neuropsychological
functioning (Nair et al., 2013) results in ASD symptom
severity.
Early diagnosis
The diagnosis of autism is based on the standards
explained in Diagnostic and Statistical Manual of Mental
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Disorders, 5th edition (DSM, 2013) and Autism Diagnostic
Early diagnosis of autism helps to provide behavio-
ral therapies to the affected individuals. Toddlers with
developing autism concentrate more on the mouth region
of the face compared with the eye region (Rutishauser
etal., 2013; Shic etal., 2014) and have weak judgmental
ability. Hence, detection of gaze and position can help in
the diagnosis of autism (Lahiri etal., 2011; Guillon etal.,
2014). Bekele et al. (2013) used a virtual-reality-based
(Bohil etal., 2011; Carozza etal., 2014) facial expression
intervention system that monitors eye gaze and physi-
ological signals for ten ASD adolescents and ten typically
developing adolescents in emotion recognition tasks. The
differences between the ASD and typically developing
groups were determined using eye tracking indices and
performance data. Weigelt et al. (2012) found quantita-
tive difference in facial discrimination between autistic
and normal subjects as autistic subjects possess impaired
facial identity recognition and eye discrimination. Studies
reveal that the increased response to direct gaze triggering
unprompted mental state attributions is reduced in autis-
tic subjects, and they show increased response to averted
gaze than the direct gaze (Hagen etal., 2014).
Takarae et al. (2014) reported on the correlation of
neurons in visual motion processing using the functional
magnetic resonance imaging technique. The brain area
V5 responsible for visual perception and pursuit was con-
sidered. The ASD and the typically developing groups
were subjected to passive viewing of visual movement and
visual pursuit tracking. Passive viewing is related to static
images, and pursuit tracking, to moving images. They
reported increased V5 activation during passive viewing and
decreased V5 activation during visual pursuit in the autistic
subjects. The increased activation during passive viewing
implied connectivity alterations in the V5 area, followed by
reduced GABAergic tone (-amino butyric acid) and inhibi-
tory modulation. The study also suggested that high abnor-
malities at the network level are related to visual processing
in autism. The cortical response to the dynamic social stimuli
is disrupted in ASD adolescents, indicating disordered con-
nectivity between the different brain regions and the lateral
region of fusiform gyrus (Weisburg etal., 2014).
Chromosomal microarray analysis, exome sequenc-
ing (Yu et al., 2013), and genetic testing are appropriate
tools in the identification of de novo mutations and ASD
risk genes (Jeste and Geschwind, 2014). Keehn et al.
(2013) proposed a hypothesis that links abnormal atten-
tion networks including alerting, orienting, and executive
control network to autism. Autistic individuals lack com-
munication skills, speech perception (Kujala etal., 2013),
846S. Bhat etal.: Autism: cause factors, early diagnosis, and therapies
Intrinsic wiring of
the brain
Normal brain
Minimum distance between the two different points along the cortical surface
(Geodesic distance)
Shorter geodesic
distance
Normal behavior
Figure 6Intrinsic wiring of the normal and autistic brain.
and comprehension (Jones etal., 2014). The left temporal
cortex activity is responsible for social language compre-
hension in typically developing children, but it is reduced
in autistic children and the activity rate decreases with
age (Eyler etal., 2012). The early diagnosis of lateralized
abnormalities of temporal cortex processing can lead to
early neurodevelopmental pathology in autism.
Stevenson etal. (2014) reported on the link between
multisensory temporal function and speech processing in
ASD individuals. The ASD and typically developing par-
ticipants underwent three tasks: (a) an audiovisual sim-
ultaneity judgment task that includes single stimulus per
run, audio, and visual-leading stimuli, (b) a McGurk task
including audio only, visual only, and audiovisual presen-
tations, and (c) auditory and visual temporal-order judg-
ment tasks including run with auditory and visual stimuli.
The sensory representations are the building blocks of
higher order domain of speech perception. They observed
weak binding between the multisensory temporal func-
tion and audiovisual speech processing using the McBurk
effect that in turn causes communication impairment in
ASD individuals.
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Autistic brain
Significantly lower
geodesic distance due
to the abnormal
connectivity
Repetitive behavior
A recent development is automated electroencepha-
logram-based diagnosis (Adeli and Ghosh-Dastidar, 2010;
Cong et al., 2013; Kimiskidis et al., 2013; Herrera et al.,
2013) of ASD (Ahmadlou etal., 2010, 2012a,b) using three
different computational paradigms of signal processing
such as wavelets (Tao etal., 2012; Xiang and Liang, 2012;
Kodogiannis et al., 2013), neural networks (Graf et al.,
2012; Alexandridis, 2013; Celikoglu, 2013; Zhang and Ge,
2013), and nonlinear analysis (Acharya etal., 2012, 2013)
and chaos theory (Cen etal., 2013; Hsu, 2013). This is the
subject of another review article by the authors (Bhat
etal., 2014).
Therapies
Intervention methods can enhance social engagement
and reciprocity in autistic children. Infants and toddlers
at risk for ASD are introduced to learning therapies, and
parent-child interactions are enhanced to develop inter-
active and communicative skills in toddlers at high risk
 S. Bhat etal.: Autism: cause factors, early diagnosis, and therapies847

(Dawson, 2008). Multisensory speech integration ability
is enhanced when ASD children enter adolescence due to
plausible causes such as hormonal changes after puberty,
differential myelination patterns along the white matter
tracts, and potential increases in social interaction (Foxe
etal., 2013).
Rodriguez and Kern (2011) suggest that therapies
addressing neuroinflammation can be introduced to
control microglial activation and enhance neuronal con-
nection. The concentration of methionine, cystine, and
glutathione in ASD children is less, and oxidized glu-
tathione concentration is high. The lower concentration of
cystine in autistic children results in high oxidative stress.
Thus, zonisamide, an antiepileptic drug, can be admin-
istered that enhances the influx of cystine to reduce the
oxidative stress (Ghanizadeh, 2011).
Lai etal. (2012) reported that the left inferior frontal
gyrus in ASD subjects is highly activated during song stim-
ulation but not speech stimulation. Since musical abilities
are preserved due to increased neural connectivity and
sensitivity for song, musical therapies can be introduced
to improve verbal communication in the ASD population.
Few ASD individuals possess extraordinary cognitive
strengths in different domains such as problem solving,
art, music, and innovative skills.
Table 3Summary of psychological therapies in the treatment of
ASD.
Iuculano et al. (2014) studied the brain activity pat-
terns in the ASD and typically developing children while
solving complex numerical problems. ASD children show
different multivariate activation patterns in cortical regions
involved in perceptual skills and prove that they have better
problem-solving ability. This ability can act as a boon to the
autistic population and improve the quality of life.
A summary of the current psychological therapies
used in the treatment of ASD is presented in Table 3.
Conclusion
Autism is a neurodevelopmental disorder that cannot be
cured, but measures can be taken to convert this disabil-
ity to ability. Studies have revealed that alterations in the
chromosome structure due to environmental factors, vari-
ations in the neural connectivity, and different parts of the
brain converge to autistic symptoms. Atypical behavior in
children arises after 1824 months, but the identification
of phenotypic, behavioral, and neurophysiological risk
indices with the help of neuroimaging techniques can
determine the early signs of the disorder. Advances in sci-
entific understanding of ASDs help in the innovation of
several pharmacotherapies. The increase in parent-child
interactions, applied behavioral analysis, developmental
psychopathology, cognitive neuroscience, and neurobi-
ology has led to the development of effective treatments
after the early diagnosis of autistic symptoms.

Applied therapies Areas of improvement Authors

Neurofeedback training
and speech therapy
Enhancement in
cognitive skills
Karimi
etal., 2011
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