Physiological Factors of Autism

Yuanjie Xu

, Kesui Deng

and Qiqi Yao

School of Humanities, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, China

Keywords: Autism, Autism Spectrum Disorder, Physiological Factors.

Abstract: Autism is a group of neurodevelopmental disorders caused by psychological and physiological factors. It

mostly occurs in infants and young children, and the disease process is long, which has brought great material

and spiritual pain to the patients themselves and their families. Studying the factors of autism is of great

significance to develop treatment methods and alleviate the disease. This paper summarizes the physiological

factors of autism by combing the literature on the causes of autism. The results show that heredity, heavy

metals, maternal factors, nutrition, brain structure and function, intestinal microorganisms, and immune

system are important factors for autism. Autism may be affected by a variety of factors. However, at present,

the etiology of autism is not completely clear, and researchers need to further take interdisciplinary

exploration and deepen existing research to further clarify the pathogenesis of autism.

1 INTRODUCTION

Autism, also known as autism disorder, is common in

infants and young children. Its core symptoms are

impaired social function, lack of verbal

communication ability, and the emergence of

repetitive and stereotyped behavior. Asperger

syndrome, childhood disintegrated disorder, and

other developmental disorders not otherwise

specified (PDD-NOS) and autism or classic autism

spectrum disorders are collectively referred to as

autism spectrum disorder (ASD).

The incidence rate of autism has been rising since

Kanner reported its autism in 1943. It has become a

worldwide health issue. According to the statistics of

the Centers for Disease Control and Prevention, the

rate of autism spectrum disorder diagnosed before e

the age of 8 in 2016 was 1 / 54, while the statistical

data in 2014 was 1 / 59, and the prevalence increased

by about 10%. By the middle of adulthood, the rate of

autism increased to 1/45, and the incidence rate of the

male was significantly higher than that of females,

reaching 4:1. In China, there is no reliable national

epidemiological survey report on autism, but

according to the sampling survey of Hainan Province

in 2017, the total prevalence of autism among

children aged 0-6 years in Hainan Province is 0.62%,

https://orcid.org/0000-0002-5222-3586

https://orcid.org/0000-0001-5113-0786

including 0.99% for men and 0.17% for women (Li

2018).

Because the etiology and pathogenesis of autism

are not clear, there are some difficulties in prevention

and treatment, and the treatment cost is relatively

expensive, which leads to a lot of economic burden

and emotional pain for autistic patients and their

family members. At present, patients often use

rehabilitation training combined with certain drugs

for long-term treatment, and researchers have not

reached an agreement on the treatment and

pathogenesis of autism. This paper reviews the

influencing factors (focusing mainly on the biological

aspects) of autism found in recent years. Hopefully, it

might provide some references and help for research

on the pathogenesis and treatment of autism.

2 PHYSIOLOGICAL FACTORS

OF AUTISM

2.1 Genetics

2.1.1 Family and Twin Studies

Researchers' research on family members of autistic

patients found that the risk of autism in immediate

https://orcid.org/0000-0001-5126-8187

Xu, Y., Deng, K. and Yao, Q.

Physiological Factors of Autism.

DOI: 10.5220/0011187400003444

In Proceedings of the 2nd Conference on Artiﬁcial Intelligence and Healthcare (CAIH 2021), pages 97-103

ISBN: 978-989-758-594-4

relatives is affected by genetic factors. If one child in

the family already has autism, the probability of

having another child with autism can reach 5 ~ 6%

(Duan 2015). Family members with autistic children

often have affective disorders and more social skills or

repetitive behavior abnormalities. Another study

showed that the recurrence rate of autism spectrum

disorders in the same family was 10 ~ 35%. At the

same time, about 20 ~ 25% of the brothers and sisters

of autistic families have language defects (Wu 2016).

In the study of twins, one of the identical twins has

autism, and the other has a probability of 60% ~ 90%,

While only 5% of fraternal twins. This series of

studies show that autism has obvious familial heredity.

2.1.2 Gene Variation Research

The research on genetic factors of autism mainly

focuses on gene variation and chromosomes,

including point mutation, copy number variations

(CNVs), linkage region, and microRNAs. The

pathogenic genes of some syndromic ASD patients

have been identified. For example, Rett syndrome is

caused by MeCP2 mutation. Neuroligin (NLGN3 and

NLGN4) was the first mutant gene found in patients

with non-syndromic ASD (Cao 2015). Copy number

variations (CNVs) are a structural variation of genes,

which refers to the loss or increase of genetic material

due to deletion, insertion, or gene rearrangement,

which affects gene expression. The results show that

CNVs may have a certain impact on the specific

components and severity of ASD (Huang 2018).

Some studies believe that autism is more likely to be

controlled by multiple genes.

Cytogenetic studies have found that chromosome

aneuploidy is associated with autism and is likely to

be associated with language disorders. A study found

that XYY individuals showed a significant

impairment of language and social communication,

and the incidence rate of ASD in aneuploidy males

was higher than that in the general population (Lisa

2018).

Figure 1: Comparison of the rate of ASD between XYY

men and normal men (Joseph 2018).

After comparing the samples of nearly 4000

patients with "autism spectrum disorder" with the

control group, researchers from Icahn School of

medicine at Mount Sinai and other institutions in the

United States found more than 100 genetic variants

that increase the risk of autism. In addition, the

researchers also focused on the genetic differences

between autistic patients and their healthy siblings

and speculated that the above genetic variation may

be related to more than 20% of the incidence of

autism (Deng 2016). Gene variation has a great

impact on autism.

2.2 Heavy Metal

Although thiomersal has been shown not to increase

the risk of autism in children, other heavy metals still

have some effects on ASD. A controlled study of

autistic children and normal children found that heavy

metals were higher in the blood and urine of autistic

children. Among them, the content of lead in the

blood of children with autism is 41% higher than that

of the normal group, the content of lead, thallium, tin,

and other metals in urine are 74%, 77%, and 115%

higher than that of the control group, and the content

of calcium in the blood is 19% lower than that of the

control group (Duan 2015). Another study found that

children with high concentrations of hair lead and nail

arsenic had a higher risk of autism than those with low

concentrations; The risk of autism in children with

higher concentrations of hair manganese and nail zinc

is lower than that in children with low concentrations

(Huang 2019). In addition, methylation of mercury

can damage the nervous system and lead to brain

atrophy (Duan 2015).

Table 1: Partial metal levels in autistic and control children

(μg/g). (Huang 2019).

Hai

Case

rou

Control

rou

Lead

(

)

1.60 0.80

nesium

(

17.29 27.92

Man

anese

(

)

0.14 0.31

Zinc

(

)

92.51 146.85

Calcium

(

)

244.41 317.49

Nail

Lead

(

)

1.36 0.57

Zinc

(

)

105.50 89.90

Arsenic

(

)

0.17 0.13

2.3 Maternal Factors

2.3.1 Age of Parents

Research shows that the increase of parents' age will

increase the risk of ASD in children, but the influence

of mother's age is nonlinear, while the influence of

CAIH 2021 - Conference on Artiﬁcial Intelligence and Healthcare

father's age is linear, and the influence of mother's age

on ASD is greater than that of father's age (Selma

2014). Duan Yanrui et al. obtained the conclusion that

the proportion of mothers with childbearing age

greater than 35 in the autism group is higher than that

in the normal group through the comparative study of

children in the autism group and healthy group (Duan

2021). It can be seen that parents who are too old at

childbirth increase the possibility of children

suffering from ASD.

2.3.2 Influencing Factors during Pregnancy

The disorder of the intrauterine environment during

pregnancy is a potential risk factor for autism. In the

study of 190 autistic children in Tianjin, Chinese

scholars found that smoking, chronic diseases

unrelated to pregnancy, affective disorders,

pregnancy complications, and edema are all risk

factors for ASD (Cao 2015). Another study found that

after injecting pregnant female mice with the human

influenza virus, their offspring will have autism-like

abnormal behaviors such as lack of inquiry behavior

and communication behavior. Prenatal stress may

have a similar effect on the human body (Duan 2015).

In addition, Huang Danni found that prenatal

depression in mothers increases the risk of autism in

children. In terms of life behavior, the daily use of

microwave ovens by mothers will increase the risk of

autism in children (Huang 2019). Duan Yanrui et al.

found that the proportion of mothers with depression

during pregnancy in the autistic children group was

higher than that in the normal group, which supported

the above research conclusions (Duan 2021).

Figure 2: Association Between Any Maternal Use of

Valproate During Pregnancy and Autism Spectrum

Disorder (Christensen 2013).

Drugs also have an impact on the prevalence of

ASD in children. Studies have shown that the use of

acetaminophen by pregnant women is associated with

ASD in boys, and also harms children's attention. The

degree of correlation is related to the frequency of

exposure (Huang 2018). Christensen, J. et al.

analyzed the prenatal use of valproate by mothers of

5437 ASD children in Denmark from 1996 to 2006

and found that taking valproate significantly

increased the risk of ASD in their offspring

(Christensen 2013).

2.4 Nutrients

2.4.1 Glutenin and Casein

The study found that there were unresolved glutenin

and casein in the urine of patients with autism

spectrum disorders. This suggests that patients with

ASD may have the disorder of decomposing glutenin

and casein. The opioid excess theory holds that

children's intake of glutenin and casein will have

adverse effects on their behavior and development

(Duan 2015).

Figure 3: Schematic diagram of the opioid excess theory.

Knivsberg randomly divided 20 ASD children

into experimental groups and control groups and gave

them glutenin-free, casein-free diet (GFCFD), and

ordinary diet respectively. After one year, the

stereotyped behavior of children in the experimental

group was reduced, and the nonverbal cognitive level

and motor disorder were significantly improved

(Knivsberg 2002). In addition, a study from Denmark

investigated the impact of GFCFD on the social

interaction of ASD children. The results showed that

children given GFCFD for one year had significantly

Physiological Factors of Autism

lower scores on the Autism Diagnostic Observation

Schedule (ADOS), the Gilliam Autism Rating Scale

(GARS), and the Attention-Deficit Hyperactivity

Disorder IV scale (ADHD-IV). This shows that the

failure of normal decomposition of glutenin and

casein is closely related to ASD.

2.4.2 Other Nutrients

The nutrients in food are very important to maintain

the normal physical and mental health of the human

body. Clinical studies have found that a lack of

vitamins, minerals, and other nutrients will lead to

psychological and behavioral changes. The

occurrence of ASD may be caused by the abnormality

of nutrients. For example, B vitamins and trace

elements are very important for brain tissue health.

After taking vitamin B6 and magnesium, ASD

children's symptoms are improved, their alertness is

improved, and their negative, self-mutilation and

stereotyped behaviors are significantly reduced.

Vitamin B12 injection can significantly improve the

language ability, social communication behavior, and

other problems of ASD patients (Duan 2015).

Manohar's experiment shows that children with ASD

have a lower level of breastfeeding than normal

developing siblings, and exclusive breastfeeding can

protect vulnerable children. Tseng Pt and others

believe that breastfeeding can prevent ASD. Wang

Yu's study found that infants who did not receive

breastfeeding six months ago were risk factors for

ASD in children (Huang 2018).

2.5 Brain Structure and Function

2.5.1 MRI Study

People with autism have the problem of early brain

development abnormalities. Liu Yang extracted the

brain sMRI data of 59 ASD children aged 2-4 years

and compared them with 50 normal children. The

results showed that there were significant differences

between the ASD group and the normal control group

in 66 of 150 cerebral cortex and volume indexes. The

cortical thickness of the parietal lobe, occipital lobe,

frontal lobe, temporal lobe, precuneus, brainstem, and

amygdala was significantly higher than that of normal

children, and there was overdevelopment of brain

structure (Liu 2020). At the same time, the excessive

development of the frontal lobes and temporal lobes

of the brain is mainly concentrated in cortical white

matter and limbic structures. These regions play an

important role in social communication and sports.

The study also found that ASD patients have

problems with cerebellar hemisphere

overdevelopment and corpus callosum volume

atrophy (Wu 2016). In addition, fMRI study found

that there was extensive blood supply deficiency in

the early brain of ASD patients, resulting in delayed

or abnormal brain development (Deng 2016).

2.5.2 EEG Study

Using electroencephalography (EEG), researchers

found that ASD patients had extensive functional

integration disorders, mainly manifested in the

asynchronous activation of signals (Wu 2016). Duan

Keyi found that the brain network topology of ASD

patients is different from that of normal people. This

difference makes the performance of autistic people

in cognitive behaviors such as visual-spatial attention,

environmental perception, and language expression

lower than that of normal people (Duan 2019).

Figure 4: Topological differences of brain networks

between autistic children and normal children in resting

state. The red and blue solid lines represent respectively the

weak and strong coupling relationship between autistic

children and normal children. (Duan 2019).

2.5.3 Broken Mirror Theory

The broken mirror theory originated in the early

1990s. Researchers found some neurons in rhesus

monkeys. When the monkeys themselves made action

or observed the researchers doing the same action,

these neurons showed a similar activation response.

Therefore, these neurons were named mirror neurons.

Later, a similar nervous system was found in the

human brain, which is mainly composed of the

inferior parietal lobe, inferior frontal gyrus, and

superior temporal sulcus, called the mirror neuron

system, MNS. According to the broken mirror theory,

the abnormal function of MNS leads to the social

cognitive defects of autistic patients. Individuals have

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100

inconsistent social cognitive functions, such as

empathy, imitation, and movement understanding,

which leads to the diversity of symptoms among

autism patients.

Oberman used EEG research results to show that

normal subjects showed significant μ -wave

suppression when observing and performing actions,

whereas autistic subjects had μ -wave suppression

when performing actions, but not when observing

actions (Oberman 2005). This indicates that the

sensorimotor cortex of autistic patients performing

movements is normal, but MNS involving movement

imitation is abnormal. In addition, many studies by

dapretto et al. have found abnormal MNS function in

patients with autism (Meng 2017). However, many

scholars have questioned the theory. For example,

Hamilton analyzed 25 research reports on MNS

function and found that there was no conclusive

evidence for the statement of abnormal MNS in

patients with autism; Raymaekers, Dinstein, fan, et al.

also concluded that MNS function in patients with

autism is normal (Pan 2016). Therefore, the broken

mirror theory is still controversial in academic circles,

and its correctness needs to be further verified.

2.6 Intestinal Microorganisms

Intestinal microorganisms can help the human body

digest and absorb nutrients. By secreting various

enzymes, they synthesize some vitamins and

bioactive substances, affect human metabolism,

control body weight, shape the human immune

system and help resist the invasion of pathogenic

microorganisms. About 70% of the substances in the

blood come from the intestine. The balance of

intestinal microorganisms is very important to human

health. Once this balance is broken, it may lead to a

variety of diseases.

It is found that the development of intestinal

microorganisms is synchronized with the

development of children's brains, and the occurrence

time of ASD is similar to the development node of

intestinal microorganisms. The intestinal microbiota

of ASD patients was unbalanced, and the composition

and proportion of bacteria and fungi changed. This

change can affect ASD through metabolites,

immunity, neuroendocrine, and vagus nerve. For

example, most ASD patients suffer from

gastrointestinal diseases, and the symptoms of

gastrointestinal diseases are positively correlated

with the severity of ASD. ASD patients with

gastrointestinal diseases may also have abnormal

behaviors such as anxiety, self-mutilation, and

attacking others. Functional constipation is associated

with stereotyped obsessive-compulsive behavior in

ASD children (Wu 2018). Gastrointestinal symptoms

and behavioral abnormalities are affected by

intestinal microorganisms, suggesting that ASD is

related to the changes of intestinal microorganisms.

2.7 Immune System

Autism is closely related to the immune system.

Studies have found that autoimmune diseases are

related to autism. The percentage of autistic family

members with autoimmune diseases is significantly

higher than that of normal families. About 46% of the

families of children with autism have more than two

members who have suffered from autoimmune

diseases, and the more patients, the greater the risk of

children suffering from autism (Duan 2015).

Autism may also be related to immune factors.

Some studies have found that the contents of some

immune factors such as tumor necrosis factor (TNF),

interferon, and interleukin (IL) in the blood of ASD

patients increased. Pro-inflammatory cytokines in the

cerebral spinal fluid (CSF) also increased (Wu 2016).

Autism is often accompanied by an excessive

inflammatory response of the nervous system. In the

central nervous system of autistic patients, the

inflammatory response can activate microglia. Some

researchers believe that microglia may be the

intermediate hub between immune response and

ASD. Microglia are phagocytes that settle in brain

tissue. Under inflammatory stimulation, antigenicity

is enhanced, and nerve cells are killed. The excessive

inflammatory reaction leads to abnormal activity of

microglia, and a large number of normal brain cells

are attacked and phagocytized, thus affecting

individual neural activities (Jin 2018).

In addition, using the method of identifying genes

that promote the generation of autism, other

researchers have found evidence that several

pathways associated with the immune system are

disturbed to promote the generation of autism

spectrum disorders (Anonymous 2013), which

strongly shows that immune function plays a role in

autism.

3 CONCLUSION

With the development of science and technology,

people's understanding of autism has also stepped

onto a new level. Autism is not caused by a single

factor, but by a variety of factors. Biological factors

are very important. Genetics, heavy metal intake,

maternal health during pregnancy, nutrients, brain

Physiological Factors of Autism

101

function and structure, intestinal health, and immune

system may cause autism. The exploration of etiology

has also made continuous progress in treatment

methods. Microbial intervention therapy, food

therapy, and other methods have also entered the

vision of doctors. These emerging therapies have

made some achievements in combination with the

original methods of behavioral intervention, special

education, drugs, psychotherapy, and so on.

However, due to the complex etiology of autism,

we can not fully understand its pathogenesis. For

example, heredity can only explain 10% - 30% of the

causes of autism, and many autistic patients do not

show any genetic signs; The intestinal microbial

population is also affected by individual living habits,

diet, drug use, and other factors, so it is difficult to

determine the specific intestinal microbial map of

patients with autism. When the researchers reported

that these abnormalities were related to autism, they

simply explained a statistical connection, and could

not explain the causality and the underlying

physiological principles. At the same time, due to the

limitations of sample size or research methods, the

scientificity of emerging hypotheses such as broken

mirror theory has not been unanimously recognized

by scholars. Therefore, these conjectures need more

and more convincing research to support.

In the future, we need to carry out cross-

exploration of different disciplines. The causes of

autism span a wide range, and the differences in

theories and methods of different disciplines will help

us better eliminate irrelevant variables and improve

the credibility of the research. At the same time, it is

necessary to continue to deepen the research on the

conclusions already obtained, dig out the complex

causal relationship, clarify the pathogenesis behind it,

and improve the cognitive level. Moreover, it is

important to design and conduct more convincing

studies to verify the emerging hypotheses and

reference the research methods of other types of

mental disorders to provide new ideas for autism

research.

ACKNOWLEDGEMENTS

I would like to express my heartful thanks to my

honored advisor, Professor Deng Kesui. During the

whole process of thesis writing, she gave me careful

guidance and instruction in all aspects of the paper

from conception, topic selection to the final draft, so

that I could complete this paper. Her rigorous

academic attitude, rich and profound knowledge,

keen academic thinking, and excellent working

attitude are my models.

In addition, I also got a lot of friends' care support,

and help. I would like to express my gratitude to all

the people who helped me with my thesis writing.

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