INTRODUCTION:

Autism Spectrum Disorder is a highly genetic neurodevelopmental disorder. It is characterized by behavioral criteria like impairment in social communication and interaction. The term autism was first introduced by Leo Kanner in 1943. Kanner et al¹ investigated a case study with 11 children and found new symptoms like a repetitive, stereotyped activity, lack of language developmental and communication skills. Later that new disease is named as autism.

The aim of this review is to present the structural abnormalities in ASD. The ASD can be primarily identified using diagnostic statistical manual (DSM) of mental disorders, Autism diagnostic observation schedule (ADOS), and Autism diagnostic interview revised (ADI-R). The DSM is prepared by the American Psychiatric association to identify all types of brain related diseases^2-4.

DSM first version was published in 1952. According to DSM-5, ASD symptoms are divided into social interaction and communication domain (SICD) and repetitive domain (RD)⁵. The ASD is identified in primary stage, if the children have minimum two symptoms from SICD and three symptoms from RD. The ADOS is an instrument with structures and semi structured activities. It is used to assess the social behavior of the ASD children. This method can be used for 12 to 30 months age children⁶. The ADI-R is other tool used to detect the autism children. In this method interview is conducted for autistic children’s parents by doctor. It is used for only above 18 months children⁷.

Early sMRI studies of ASD have a number of limitations like less magnetic field strength, thickness of slices and less number of samples. Early studies used computed tomography (CT) images to detect the ASD controls. Several studies have been failed to identify brain abnormalities in autism controls due to ionization effect and poor spatial resolution of CT scan images⁸. In 1970, new technology was introduced which is called magnetic resonance imaging (MRI). It provides high spatial resolution images without using ionization effect. MRI is used to identify structural abnormalities in brain⁹. Later, diffusion MRI was invented in 1985. Diffusion MRI measures white matter fibers in brain by calculating the diffusivity and fractional anisotropy¹⁰. But the above two techniques are structural quantities of brain but fails to provide information about functioning of brain. In 1995 functional MRI was invented to measure the brain activity. Functional MRI identifies the active regions in brain by calculating the blood flow and neural activity in the specific region¹¹.

According to the centers for decease control and prevention (CDC) statistics, in the year 2000, ASD was identified in 1 child out of 150 children. In 2004 it was fund in 1 child out of 125 children. In 2008, it was detected in 1 child out of 88 children, in 2012, 1.5% of population was suffering from ASD i.e., 1 child out of 69 children. Later in 2016, it was identified 1 child out of 59 children. Finally, by 2020 ASD will reach to 1 child out of 50 children.

MATERIAL AND METHODS:

This review was based on a systematic search of published articles available through November 2019, and conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. PubMed, PsycINFO, Science Citation Index and Scopus Journals were searched for relevant literature. No language or date constraint was used. Search terms used for this review are <ASD> or <total brain volume> or <gray and white matter> or <cerebellum> or < basal ganglia> or <Amygdala> or <Insula>.

Eligibility Criteria:

Our study is focused on autism patients between 6 months to 60 years patients. We have compared healthy control group with autistic disorder group, pervasive developmental disorder not otherwise specified (PDD-NOS) group, and Asperger syndrome (AS) group.

Inclusion criteria:

I. Only human participants were included in study

II. Clinically diagnosed ASD patients were included

III. Only sMRI studies were included

Exclusive Criteria:

I. Articles not published in English were excluded

II. Structural MR images acquired from less than 1.5 Tesla were excluded

III. Encyclopedia, book chapters and books were excluded

Study Selection:

The following PRISMA search strategy was implemented for this study¹². Total 490 case studies were identified from all databases using the above search strategy. From 490 case studies 184 duplicate studies were eliminated. According to inclusion and exclusion criteria 249 case studies were eliminated from 306 case studies. Finally, only 57 studies were included in this review.

RESULTS AND DISCUSSION:

Nero imaging approach is widely used in MR imaging studies. Especially structural MR imaging directly provides the volumetric abnormalities of the brain. In general, ASD patients brain functions abnormally compared to the healthy controls. The following brain regions plays important role while identifying ASD patients: Total brain volume, cerebellum, Amygdala, Hippocampus, Insula, Basal Ganglia, Thalamus, Corpus callosum, Cingulate gyrus, Planum template, gray and white matter. This review presents the abnormalities of the above brain regions (Table 1).

Total brain volume:

The most common finding in ASD is enlarged total brain volume (TBV). The Structural MRI is a noninvasive tool which is widely used for measuring volumetric data of brain. ASD children had decreased brain size at birth, but increases rapidly throughout early childhood and no change was found in adolescence¹³. In likewise, Aylward et al.¹⁴ investigated 67 autism controls with 83 healthy age-matched controls and reported that the TBV was increased before 12 years of age and later no difference was found in autism controls. The first twenty-four months of life is crucial in human brain growth. The first evidence of the abnormal brain growth is reported by Courchesne et al.¹⁵. The brain of the ASD children is enlarged during 2 to 4 years old and decreased during 12 to 16 years old. Hazlett et al.¹⁶ examined 51 autism individuals with 25 healthy controls between 18 months to 36 months of age and reported that the total brain volume is increased by 5 to 10% in autism individuals. In addition, Janet et al.¹⁷ revealed that the enlarged TBV found in between birth and 6 to 14 months of ASD children. In contrast, many researchers had reported that significant differences were not found in autism controls^18,19. In autism controls head size was decreased at birth and decreased during 1to 2 months and 6 to 14 months of age compared to PDD NOS controls. Reduced cerebellum GM volume at birth and increased cerebral cortex volume during 1 to 2 and 6 to 14 months of age were found in autism infants²⁰.

Gray matter and White matter:

Gray matter (GM) and White matter (WM) volumetric measurements significantly differ in ASD patients. The autism controls were found with increased GM in occipital cortex, thalamus, central gyrus, insula, superior temporal gyri, claustrum, caudate, fusiform gyrus, and cerebellum and decreased WM in middle occipital gyrus, superior frontal gyri, inferior parietal lobule, para hippocampus gyrus and cingulated gyrus²¹. In addition, Rojas et al.²² investigated 24 autism subjects with 23 healthy age-sex matched subjects and reported autistic controls found with decreased GM in left hippocampus, medial frontage matched gyrus, right fusiform gyrus, left ore-central gyrus, caudate nuclei and right post central gyrus. But GM was decreased in cerebellum of autism subjects. In contrast, Autism controls were found with no change in parietal and occipital lobe²³.

Table 1: Structural MRI abnormality findings in autism patients

Author	Year	ASD controls	Comparisons	Findings in ASD
Aylward et al.¹⁴	2002	83 Autism patients (age: 12-46 years)	67 Healthy controls (age: 12-46 years)	Brain size was increased up to 12 years and No differences were found after 12 years
Courchesne et al.¹⁵	2001	60 Autism patients (age: 2-16 years)	52 Healthy controls (age: 2-16 years)	TBV was increased during 2 to 4 years and decreased during 12 to 16 years
Hazlett et al.¹⁶	2005	51 Autism patients (age: 18-35 years)	25 Healthy controls (age: 18-35 years)	Enlargement of TBV was started at 12 month of age
Hazlett et al.¹⁸	2012	98 High risk autism patients (age: 6 months)	36 Low risk autistic controls (age: 6 months)	No significance differences were found in autism patients
Redcay et al.¹⁹	2005	15 Autism patients (age: 2-4 years)	10 Healthy controls (age: 2-4 years)	No significance differences were found in both groups
Courchesne et al.²⁰	2003	17 Autism controls (age: 0-2 years)	5 PDD NOS controls (age: 0-2 years)	Head size decreased at the birth and increased during 1-2 months and 6-14 months of age.
Rojas et al.²²	2006	24 Autism patients (age: 7-47 years)	23 Healthy controls (age: 7-47 years)	GM was decreased in left hippocampus, medial frontal gyrus, right fusiform gyrus, left ore-central gyrus, caudate nuclei and right post central gyrus.
Hazlett et. al.²³	2006	23 Autism patients (age: 13-29 years)	15 Healthy controls (age: 13-29 years)	GM was increased in temporal lobe and frontal lobes.
Courchesne et. al.²⁴	1988	18 Autism patients (age: 6-30 years)	12 Healthy controls (age: 9-37 years)	Cerebellar vermal lobules VI and VII were significantly decreased
Courchesne et al.²⁵	1994	50 Autism patients (age: 6-30 years)	53 Healthy controls (age: 3-37 years)	Cerebellar vermal lobule VI and VII were decreased in hypoplasia and increased in hyperplasia
Piven et al.²⁶	1992	15 Autism patients (age: 21-53 years)	15 Healthy controls (age: 25-46 years)	No significant differences were found in cerebellar vermis
Hardan et al.²⁷	2001	22 Autism patients (age: 12-52 years)	22 Healthy controls (age: 13-52 years)	Cerebellar hemispheres were increased
Schumann et al.²⁸	2004	16 LFA controls 27 HFA controls 25 Autism controls (age: 7.5 to 18.5 years)	27 TD controls (age: 7.5 to 18.5 years)	Left and right amygdala was increased
Schumann et al.²⁹	2009	41 Autism patients (age: 1-5 years)	41 Healthy controls, (age: 1-5 years)	Right and left amygdala was increased in males and females. Only left amygdala was increased in females.
Aylwarde et al.³⁰	1999	14 Autism patients (age: 11-37 years)	14 Healthy controls (age: 12-52 years)	Hippocampus was significantly decreased
Nicolson et al.³¹	2006	21Autism patients (age: 6-16 years)	24 Healthy controls (age: 6-16 years)	Right medial posterior hippocampus volume was decreased
Sparks et al.³²	2002	45 autism controls (age: 38-54 months) 26 DD controls (age: 36-56 months)	26 TD controls (age: 36-56months)	Right and left hippocampus was increased by 8.54% and 9.16% respectively. Right and left amygdala was increased by 16.67% and 13.64% respectively.
Bigler et al.³³	2003	38 Autism patients (age 7–31 years)	27 Healthy controls (age 7–22 years)	No significant differences were found in hippocampus
Piven et al.³⁴	1998	35 Autism patients (age: 12-29years)	36 Healthy controls (age: 12-17 years)	No significant differences were found in hippocampus
Kosaka et al.³⁵	2010	32 Autism patients (age: 17–32 years)	32 Healthy controls (age: 18–34years)	GM was decreased in right IFG, IPL, right posterior and anterior insula.
Doyle-Thomas et al.³⁷	2013	27 Autism patients (age: 7–39years)	25 Healthy controls (age: 7–39years)	Surface area of the right cingulate cortex right isthmus, right parietal lobe, and left temporal lobe was increased
Sears et al.³⁸	1999	35 Autism patients (age: 12-29years)	36 Healthy controls (age: 12-29years)	Caudate nucleus was significantly increased
Sato et al.³⁹	2014	29 Autism patients (age: 18-46years)	29 Healthy controls (age: 21-43years)	Lack of non-verbal communication and social interaction. Also putamen volume was increased in high functioning autism patients
Sparks et al.⁴⁰	2011	77 Autism patients (age: 3-4 years)	25 TD controls 34 DD controls (age: 3-4 years)	Left caudate, left and right striatum was increased. Left striatum, thalamus, right putamen were decreased.
Gaffney et al.⁴¹	1989	13 Autism patients (age: 4-19years)	33 Healthy controls (age: 4-19years)	No significant differences were found in basal ganglia
Tsatsanis et al.⁴²	2003	12 HFA patients (age: 11-38 years)	12 Healthy controls (age: 11-38 years)	Thalamus volume was reduced in large brain group.
Herbert et al.⁴³	2003	17 Autistic Control (age: 7-11years)	15 Healthy controls (age: 7-11years)	Thalamus volume was increased
Hardan et al.⁴⁴	2006	40 HFA patients (age: 9-43 years)	41 Healthy controls (age: 8-45 years)	No significant differences were found in thalamus
Hardan et al.⁴⁵	2008	18 Autism patients (age: 8-15 years)	16 healthy controls (age: 8-15 years)	Positive correlation found between TBV and thalamus
Gaffney et al.⁴⁶	1987	18 Autism patients (age: 5-12 years)	35 healthy controls (age: 4-19 years)	Fourth ventricle was decreased
Egaas et al.⁴⁷	1995	51 Autistic controls (age: 3-42 years)	51 Healthy controls (age: 3-42 years)	Corpus callosum was reduced
Saitoh et al.⁴⁸	1995	33 Autism patients (age: 6-42 years)	23 Healthy controls (age: 6-42 years)	The midsagittal area of the corpus callosum was significantly decreased
Piven et al.⁴⁹	1997	35 Autism patients (age: 12-29 years)	36 Healthy controls (age: 12-17 years)	Posterior and body corpus callosum was decreased
Hardan et al.⁵⁰	2000	22 Autism patients (age: 17-23 years)	22 Healthy controls (age: 17-23 years)	Anterior corpus callosum was decreased
Freitag et al.⁵¹	2009	15 Autism patients (mean age 17.5)	15 Healthy controls (mean age 18.6)	Corpus callosum volume and thickness was decreased
Prigge et al.⁵²	2013	68 Autism patients (age: 3-36 years)	47 TD controls (age: 3-36 years)	Corpus callosum volume was increased
Haznedar et al.⁵³	1997	7 Autism patients (age: 17-47 years)	7 Healthy controls (age: 17-47 years)	Right anterior cingulate area 24’ was decreased and Cingulae area 24’ and 24 are metabolically not active
Rojas et al.⁵⁵	2002	15 Autism patients (age: 19-47 years)	15 Healthy controls (age: 17-47 years)	Planum temporal left hemisphere was decreased
Herbert et al.⁵⁶	2002	16Autism patients (age: 7-11 years)	15 Healthy controls (age: 7-11 years)	Right FLR was 27% enlarged and PLR was found with 25% leftward asymmetry

DD: developmentally delayed; FLR: frontal language region; HFA: high functioning of autism; IFG: inferior frontal gyrus; IPL: inferior parietal lobule; LFA: low functioning autism; PDD-NOS: Pervasive developmental disorders Not otherwise specified; PLR: posterior Language asymmetry; TD=typically developing; WADIC=wing autistic disorder interview checklist.

Cerebellum:

The primary functions of the cerebellum are motor learning, language, coordinating body movements and eye movements. Volumetric investigation of the cerebellum with autism control includes the vermis. Courchesne et al.²⁴ examined 18 autistic controls with 12 healthy age-sex matched controls and reported cerebellar vermal lobules VI and VII are significantly smaller in autism controls. Courchesne et al.²⁵ examined large group of autism controls and divided cerebellum vermis into two groups one is hyperplasia and another one is hypoplasia. In autism controls VI and VIII lobules of hyoplassia group are decreased and VI and VIII lobules of hyperplasia group VI and VIII lobules up are increased. In contrast, Piven et al.²⁶ reported that no significant differences were found in cerebellar vermis VI and VII.In addition, the cerebellar hemispheres have been increased in autism controls compared to healthy controls²⁷.

Amygdala:

Schumann et al.²⁸ investigated amygdala abnormalities among four groups: Asperger yndrome, autism with and without mental retardation group and TD control group with the age between 7.5 years to 18.5 years. The increased left and right amygdala were found in autism with and without mentally retarded groups compared to other groups. Also, the amygdala volume was disproportionately increased with TBV in ASD children. Schumann et al.²⁹ investigated large number of male and female autistic controls and reported that the right amygdala volume was increased in both genders. But only left amygdale volume was increased in female autistics. Interestingly, males with autism had shown significance difference in social and communication impairment compared to females with autism.

Hippocampus:

The hippocampus plays important role in spatial navigation and long term memory of human beings. Inconsistent results have been found in volumetric analysis of autism controls. Several researchers reported that hippocampus was decreased in autism controls³⁰. Nicolson et al.³¹ examined 21 male subjects and 24 healthy age-sex matched controls and reported that right medial posterior hippocampus volume was significantly decreased and thickness of right medial anterior hippocampus was increased. In addition, Sparks et al.³² investigated hippocampus abnormalities in three groups: ASD, DD and TD groups. In ASD controls right and left hippocampus increased by 8.54% and 9.16% respectively. In contrast, few researchers have found no significant differences in hippocampus structure^33,34.

Insula:

The insula is responsible for the functioning of perception, and cognitive. In autism controls decreased gray matter was found in right insula, inferior frontal gyrus, and inferior parietal lobule³⁵. In addition, hypoactivity in right anteriorinsula was found in autism controls³⁶. Doyle-Thomas et al.³⁷ investigated 27 autism controls and 25 healthy age-sex matched controls between 7 to 39 years of age. Interestingly, they reported that surface area of the right insula and left isthmus was significantly increased in autism controls.

Basal ganglia:

The basal ganglia are associate with eye movements, procedural leaning, motivation, habit learning, cognition and emotion functions. The basal ganglia are divided into putamen, caudate nucleus, claustrum and globus pallidus. Sears et al.³⁸ investigated 35 autism controls with 36 age-sex matched controls and reported that the caudate nucleus was significantly increased in autism controls. In addition, several researchers reported that left caudate nucleus, left and right putamen were significantly increased in autism controls^39,40. Gaffney et al.⁴¹ examined 13 autistic and 33 age-matched controls and did not find significant differences in basal ganglia.

Thalamus:

The thalamus mainly involved in receiving and interpreting the information. Tsatsanis et al.⁴² investigated 12 high functioning autism controls with 12 healthy age matched controls. Samples are divided into two groups according to the volume of the brain, one is large brain group and the other one is small brain group. Decreased thalamic volume was found in large brain group ASD controls and No significant differences were found in small brain group ASD controls. The thalamus and TBV volume correlation were non-linear in autism controls. In addition, High functioning autism (HFA) controls found with increased thalamus volume⁴³. In contrast, Hardan et al.⁴⁴ investigated 40 HFA controls with 41 healthy controls and reported that no significant differences were found in right and left thalamus. After two years, Hardan et al.⁴⁵ investigated by taking different age groups samples and found the positive correlation between TBV and thalamus volume both groups.

Corpus Callosum:

The corpus callosum is used to integrate sensory, motor and cognitive performances of the brain. Mainly CC contains three sub regions posterior, anterior and body corpus callosum. Decreased fourth ventricle volume was found in autism controls⁴⁶. Many researchers reported that the posterior CC was decreased in autism controls^47,48. Piven et al.⁴⁹ examined three CC regions (Posterior, anterior, and body CC) of the autistic patients and reported that no significant difference was observed in anterior CC.But decreased posterior and body CC were found in ASD patients. In contrast, Hardan et al.⁵⁰ examined 22 non-mentally retarded autism individuals with 22 healthy matched controls by dividing CC cross sectional area into 7 sub regions and found that the decreased anterior CC region in ASD individuals. In addition, decreased area of CC and thickness of posterior was found in autism individuals⁵¹. Recently, Prigge et al.⁵² documented a decrease in anterior and body of the corpus callosum.

Cingulate gyrus:

The cingulate gyrus (CG) mainly involved in the functioning of language expression, coordinates sensory input with emotions, decision making, and material bonding. Initially CG was divided into three sub regions broadmann’s area 24’, 24 and 25. The volume of the right CG 24’ is small and remaining two areas are less active in ASD controls⁵³. Korkmaz et al.⁵⁴ reported that the volume of the right CG was reduced. In addition, glucose metabolism in both posterior and anterior CG was reduced. As of now only two researchers have been investigated CG abnormalities in autistic controls.

Planum template:

The planum template (PT) involved in functioning of language and music. Rojas et al.⁵⁵ investigated 15 autism controls with 15 healthy age-sex controls and reported significantly reduced left PT in autism subjects. The decreased left PT volume indicates an early neurodevelopmental abnormality in autism which impacts on language development. In contrast, Herbert et al.⁵⁶ reported significantly increased left PT in autism controls compared to healthy controls. In addition, Knaus et al.⁵⁷ investigated autism controls and TD controls by grouping them into two groups according to the age of the controls. First group is younger group with age 7 to 11 years and second group is older group with age 12 to 19 years. Interestingly, the enlarged left PT volume was found in older group of autism controls.

CONCLUSION:

This review congregates recent studies and the considerable common findings in ASD patients. The primary finding of enlarged head circumference in ASD was determined by sMRI studies. In ASDs, the brain volume rapidly increases in childhood and was followed by a plateau in brain development. But no change was found in adolescence. Consistent findings were found in the temporal lobe, frontal lobe, CSF, cortical white and gray matter volumes. In addition, several inconsistent findings were found in the basal ganglia, thalamus, amygdala, and hippocampus. In order to overcome the inconsistent findings, feature research should be done using large number of samples and 3T scanning.

ACKNOWLEDGEMENTS:

We thankfully acknowledge the participants who helped us to collect reliable and meaningful information about the study subjects.

CONFLICT OF INTEREST:

The authors declare that they have no conflict of interest.

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Received on 21.04.2020 Modified on 26.05.2020

Research J. Pharm. and Tech. 2021; 14(4):2341-2347.

DOI: 10.52711/0974-360X.2021.00413