Rev. Neurosci. 2014; 25(6): 841–850

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 neuropsychological 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 neuroimaging 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 published 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: [email protected] 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

and compound neural connectivity. A synaptic connection 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 cognitive development enhances the understanding of neurodevelopmental disorders (Bosl et al., 2011). Autism is one of the psychological and heterogeneous 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 children compared with African-American or Hispanic children, 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 chromosomes. The microdeletion of the PTCHD1 gene becomes a recessive character in females (Noor et al., 2010). Around 5% of male ASD cases are due to the compound heterozygous, rare inherited functional loss of homozygous, and X-chromosome hemizygous mutations (Stein et al., 2013). Autism is believed to affect various systems of the body and appears to have numerous etiologies (Matson et al., 2012). Clinical symptoms are observed in children above 1.5–2 years of age due to irregularity in the physical and computational connectivity of neurons. It can manifest in the form of disturbed sleep, depression, decreased sleep duration, anxiety, and increased sleep onset delay (Belmonte et  al., 2004). The prevalence of sleep problems in autistic children is more when compared with

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842      S. Bhat et al.: Autism: cause factors, early diagnosis, and therapies

A

A

B B

Figure 2 Chromosomal variations. (A) Microdeletion of the chromosome leading to neurodevelopmental disorder. (B) De novo copy number variation in ASDs. Figure 1 The brain wiring between different brain regions. (A) Normal brain and (B) autistic brain.

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 followed by deceleration in later childhood (Aylward et al., 2002), repetitive behavior, developmental delay, cognitive impairment (Happe et al., 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 36–95% chance for the other child to be autistic, whereas in nonidentical twins, it is in the 0–30%

range. Siblings of an affected individual have 2–18% chances of being autistic (CDC, 2014).

Different forms of autism Autism is expanded to ASD representing a range of disorders affecting an individual’s communication, behavior, 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 variations in feature and visual search tasks (Figure 3). This unique characteristic acts as an anomaly in autistic individuals as they are biased to variations in the surrounding (Brandwein et al., 2013). These variations, distracting the normal population, help in stimulus information processing (Elsabbagh et  al., 2013). Around 10% of the autistic population has special skills called ‘savant’ skills. These

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S. Bhat et al.: Autism: cause factors, early diagnosis, and therapies      843

Figure 3 Illustration 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 administrator named Gary McKinnon hacked most of the US government computers in 2002 (Kushner, 2011) and discovered multiple errors in their system. Table 1 describes three major types of ASD. Table 2 presents autism categorization 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 18–24 months and then regresses to autistic symptoms; childhood disintegrative disorder, a rare disorder 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 (Chahrour et al., 2008). Seizure in epileptic patients hampers their neurological 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). According to Gabis et  al. (2005), the frequency of epilepsy in

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



Also termed as  

Clinical features

Autistic disorder



Classic autism  







High functioning  autism  

Impairment in interactive,   cognitive, communication and language skills Self-injurious and unusual   behavior Normal language and cognitive   ability Unusual behavior, social   impairment Challenges in social interaction  and communication

Asperger’s syndrome

  Pervasive developmental   disorder—not otherwise specified

Atypical autism  



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Percentage affected 20% of the population

Majority of the population

Below 5%–7% of the population

844      S. Bhat et al.: Autism: cause factors, early diagnosis, and therapies Table 2 Autism categorization according to the latest clinical research (Venker et al., 2013). Types



Persistently   severe Persistently   moderate Improving   Worsening  

Clinical features Difficulty with daily living activities, selfinjurious behavior, severe cognitive disability Impairment in social interaction and communication Improvement in development due to behavioral therapies 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, summarized in Figure 4. The gene expression is varied due to copy number variations 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 et al., 2012). The de novo genes are responsible for neuron motility, axon guidance, and synaptic development (Gilman et al., 2011). Studies reveal that de novo copy number variations (structural changes) are more common in autistic children compared with normal children, as illustrated in Figure 2B (Levy et al., 2011; Sanders et  al., 2011). According to the latest research on genetics, 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 4 Possible causes of ASD.

Stereotyped behavior, impaired social interaction, and weak synaptic transmission are associated with the irregular 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, maternal 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 mother’s metabolic conditions during pregnancy to ASD, developmental delay, and cognitive impairment in the offspring. It has also been found that gestational maternal hypothyroxinemia is linked to ASD (Roman et al., 2013). Autism is a neurobiological abnormality affecting the size of the corpus callosum (He et al., 2010), a collection of nerve fibers connecting the two hemispheres (left and right) of the brain and playing a major role in the transmission of sensory, motor, and cognitive information. Agenesis of the corpus callosum contributes to developing autism, depicted in Figure 5 (Paul et al., 2014). Zielinski et al. (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 connectivity. The intrinsic wiring potential of a brain region corresponds 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 brain’s 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 functional 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 information is reduced due to less specialized autistic brain, i.e., overconnectivity between neural assemblies (Misic et al., 2014) and underconnectivity of the functional brain regions (Mostofsky and Ewen, 2011; Just et  al., 2012), resulting in language impairment (Verly et al., 2013) and reduced learning rate (Schipul et al., 2012). Dinstein et al. (2011) reported weak interhemispheric neural synchronization (Anderson et  al., 2011) in toddlers with autism. The disrupted neural synchronization

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S. Bhat et al.: Autism: cause factors, early diagnosis, and therapies      845

A

B

Figure 5 Corpus 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 correlated in autistic subjects, whereas it is positively correlated in subjects with verbal ability. Atypical autonomic processing resulting in low skin conductance (EilamStock 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

Disorders, 5th edition (DSM, 2013) and Autism Diagnostic Observation Schedule (Lord et al., 2012). Early diagnosis of autism helps to provide behavioral therapies to the affected individuals. Toddlers with developing autism concentrate more on the mouth region of the face compared with the eye region (Rutishauser et al., 2013; Shic et al., 2014) and have weak judgmental ability. Hence, detection of gaze and position can help in the diagnosis of autism (Lahiri et al., 2011; Guillon et al., 2014). Bekele et  al. (2013) used a virtual-reality-based (Bohil et al., 2011; Carozza et al., 2014) facial expression intervention system that monitors eye gaze and physiological 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 quantitative 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 autistic subjects, and they show increased response to averted gaze than the direct gaze (Hagen et al., 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 considered. 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 (γ-amino butyric acid) and inhibitory modulation. The study also suggested that high abnormalities 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 connectivity between the different brain regions and the lateral region of fusiform gyrus (Weisburg et al., 2014). Chromosomal microarray analysis, exome sequencing (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 attention networks including alerting, orienting, and executive control network to autism. Autistic individuals lack communication skills, speech perception (Kujala et al., 2013),

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846      S. Bhat et al.: Autism: cause factors, early diagnosis, and therapies

Intrinsic wiring of the brain

Normal brain

Autistic brain

Minimum distance between the two different points along the cortical surface (Geodesic distance)

Shorter geodesic distance

Significantly lower geodesic distance due to the abnormal connectivity

Normal behavior

Repetitive behavior

Figure 6 Intrinsic wiring of the normal and autistic brain.

and comprehension (Jones et al., 2014). The left temporal cortex activity is responsible for social language comprehension in typically developing children, but it is reduced in autistic children and the activity rate decreases with age (Eyler et al., 2012). The early diagnosis of lateralized abnormalities of temporal cortex processing can lead to early neurodevelopmental pathology in autism. Stevenson et al. (2014) reported on the link between multisensory temporal function and speech processing in ASD individuals. The ASD and typically developing participants underwent three tasks: (a) an audiovisual simultaneity judgment task that includes single stimulus per run, audio, and visual-leading stimuli, (b) a McGurk task including audio only, visual only, and audiovisual presentations, and (c) auditory and visual temporal-order judgment 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 function and audiovisual speech processing using the McBurk effect that in turn causes communication impairment in ASD individuals.

A recent development is automated electroencephalogram-based diagnosis (Adeli and Ghosh-Dastidar, 2010; Cong et  al., 2013; Kimiskidis et  al., 2013; Herrera et  al., 2013) of ASD (Ahmadlou et al., 2010, 2012a,b) using three different computational paradigms of signal processing such as wavelets (Tao et al., 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 et al., 2012, 2013) and chaos theory (Cen et al., 2013; Hsu, 2013). This is the subject of another review article by the authors (Bhat et al., 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 interactive and communicative skills in toddlers at high risk

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S. Bhat et al.: Autism: cause factors, early diagnosis, and therapies      847

(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 et al., 2013). Rodriguez and Kern (2011) suggest that therapies addressing neuroinflammation can be introduced to control microglial activation and enhance neuronal connection. The concentration of methionine, cystine, and glutathione in ASD children is less, and oxidized glutathione concentration is high. The lower concentration of cystine in autistic children results in high oxidative stress. Thus, zonisamide, an antiepileptic drug, can be administered that enhances the influx of cystine to reduce the oxidative stress (Ghanizadeh, 2011). Lai et al. (2012) reported that the left inferior frontal gyrus in ASD subjects is highly activated during song stimulation 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 3 Summary of psychological therapies in the treatment of ASD. Applied therapies



Areas of improvement 

Authors

Neurofeedback training   and speech therapy  

Enhancement in   cognitive skills Reduction in   aggressive behavior Attention control Increase in learning   rate Attention control   Skill development   Communication   Attention control   Social interaction   Enhancing activity   involvement quality Increase in nonverbal   communication Speech development   Communication   Interactive skills   Developing reading   and comprehending skills

Karimi et al., 2011

Psychoeducation therapy



  Applied behavioral   analysis   Interactive three  dimensional technology  and graphics   Dolphin-assisted therapy Virtual assessment tools (entertainment technology) Assistive reading tool

         

Zdravkovic et al., 2010 Matson et al., 2012 Dorsey and Howard, 2011 Cai et al., 2013 Munson and Pasquel, 2012 Pavlov, 2014

Iuculano et  al. (2014) studied the brain activity patterns 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 disability to ability. Studies have revealed that alterations in the chromosome structure due to environmental factors, variations in the neural connectivity, and different parts of the brain converge to autistic symptoms. Atypical behavior in children arises after 18–24 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 scientific understanding of ASDs help in the innovation of several pharmacotherapies. The increase in parent-child interactions, applied behavioral analysis, developmental psychopathology, cognitive neuroscience, and neurobiology has led to the development of effective treatments after the early diagnosis of autistic symptoms.

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Autism: cause factors, early diagnosis and therapies.

Autism spectrum disorder (ASD) is a complex neurobiological disorder characterized by neuropsychological and behavioral deficits. Cognitive impairment...
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