Magnetic resonance spectroscopy studies

Magnetic resonance spectroscopy is increasingly being used to study metabolic and neurochemical abnormalities in
specific brain regions. Chugani et al. [28] studied nine autistic children and five of their siblings to determine levels of
brain lactate and N-acetyl aspartate (NAA). They found significantly lower levels of cerebellar NAA in the autistic
children compared with the sibling group. Lactate was detected in the frontal lobe of one of the autistic subjects and none
of the controls. The investigators also reported that lactate levels were significantly higher in 15 autistic children compared
with 15 children with epilepsy. Both of these findings suggest that energy metabolism may be altered in autistic children.
In another MRS study, Otsuka et al. [29] also found lower levels of NAA in both the cerebellum and
hippocampusamygdaloid region in 27 subjects with autism (ages 218years) compared with 10 normal controls (ages 614
years). They hypothesized that lower levels of NAA in these regions may indicate neuronal hypofunction or immature
neurons.

Magnetic resonance spectroscopy termasuk sering digunakan untuk mengetahui kelainan pada metabolisme dan

neurokimia pada bagian otak. Pada suatu penelitian, 9 dari anak autisme terdapat penurunan kadar N-acetyl aspartate

(NAA) secara signifikan yang dapat ditemukan pada lobus frontal, serebelum dan daerah hipokampus. Penurunan kadar

NAA pada beberapa bagian mengindikasikan adanya gangguan/penurunan fungsi pada syaraf otak. Tetapi pada penelitian

lainnya, laktat ditemukan meningkat signifikan pada 15 anak dengan gangguan autsime bila dibandingkan dengan anak

gangguan epilepsi. Kedua penemuan ini menunjukkan bahwa pada anak autisme terdapat perubahan metabolisme di dalam

tubuh.

Positron emission tomography studies

In autistic children, they found that 5-HT synthesis capacity increased gradually between the ages of 2 years and 15 years
to 1.5 times adult normal values. This was in contrast to nonautistic children who exhibit elevated 5-HT synthesis capacity
(two times adult normal values) until age 5 years, but then a decline toward adult values between the ages of 5 and 14
years. This study provides support for a developmental dysregulation in brain 5-HT synthesis in persons with autism.

Pada anak autisme ditemukan peningkatan sintesis 5-HT pada saat umur 2 tahun hingga 15 tahun melebihi 2 kali kadar
normal pada orang dewasa. Normalnya kadar serotonin meningkat pada umur 5 tahun, lalu menurun pada saat dewasa
saat umur 5-14 tahun. Penelitian ini menunjukan adanya kelainan regulasi dari perkembangan sintesis serotonin pada anak
dengan gangguan autisme.

Functional magnetic resonance imaging studies

Functional MRI has recently been used to study brains of individuals with autism during various
neuropsychologic tasks. Using fMRI, they studied the orbitofrontal cortex, STG, and amygdala
during a test of judging from the expressions of another persons eyes what that other person may
be thinking or feeling. They found that the STG, amygdala, and some parts of the prefrontal
cortex showed activation with this
task in normal subjects.

Functional MRI termasuk pemeriksaan yang sering digunakan dalam penelitian untuk
menunjukkan kelainan-kelainan neuropsikologis yang terdapat pada individu gangguan autisme.
Dengan mengguanakan fMRI dapat dilihat fungsi dari korteks orbifrontal, girus temporalis
superior, dan amygdala untuk menilai ekspresi mata seseorang dalam melihat apa yang mungkin
orang lain pikirkan atau rasakan.

Dalam penelitian ini ditemukan perbedaan pada anak autisme dengan anak normal, terdapat
aktivasi dari beberapa area korteks prefrontalis pada anak normal yang tidak ditemukan pada
anak autisme. Tetapi pada autis ditemukan aktivitas yang lebih pada daerah ventral
occipitotemporal. Penemuan ini menunjukkan bahwa individu dengan autisme menggunakan
cara/jalan yang berbeda dalam bidang kognitif yang tergantung pada interpretasi system visual
dan system memory.
Ditemukan aktivitas yang berlebih pada gyrus temporalis inferior dan pengurangan aktivitas
pada gyrus fusiform dalam fungsi diskriminasi wajah pada anak autisme dibandingkan anak
normal lainnya.

That same group studied the same subjects using fMRI during the Embedded Figures Task (a
task that persons with autism perform better than controls). They found that normal controls
activated certain areas of the prefrontal cortex that were not activated in those with autism. The
autistic subjects showed greater activation of
the ventral occipitotemporal regions. These findings suggest that individuals with autism use
different cognitive strategies that depend to a greater extent on visual systems and less on
working memory systems.
They discovered that individuals with autism showed greater activation of the ITG and less
activation of the fusiform gyrus (FG) during the facial discrimination task than control subjects.

Peneliti menyimpulkan bahwa abnormalitas pada ITG dan FG memiliki peran dalam gangguan
persepsi wajah pada gangguan autistik yang berbeda dengan anak normal lainnya.

This is in contrast to findings usually seen, in which the FG

responds preferentially to faces and the ITG is activated during the processing of objects. Thus,
the authors concluded that individuals with autism process faces in a
different way from normal subjects and more similar to how normal subjects process objects. In
addition, they hypothesized that abnormalities in the FG or brain
regions affecting the FG (eg, the amygdala) may be responsible for the difficulties autistic
subjects have with facial perception.

Neurochemical studies

serotonin
They found that prepubertal autistic subjects had a significant elevation in platelet 5-HT compared with controls, but that
this difference was not statistically significant in postpubertal subjects. In addition, race had a marked effect on platelet 5-
HT levels in the prepubertal subjects with white children showing much lower platelet 5-HT levels than black or Latino
children.

Pada kelompok autis prepubertas terdapat peningkatan signifikan dari serotonin platelet bila dibandingkan dengan sampel
kontrol, tetapi berbeda halnya pada autis postpubertas. Peningkatan kadar serotonin ini juga lebih terlihat bermakna pada
anak-anak Latin atau berkulit hitam dibandingkan denga anak berkulit putih. Bila perbandingan dari usia dan gender,
presentase peningkatan serotonin di dalam darah 51% dari ibu, 45% ayah dan 87% saudara kembar.

Compared with age- and sex-matched controls, hyperserotonemia was present in 51% of mothers, 45% of fathers, and
87% of siblings. The investigators also discovered that WBS levels tended to decrease with age in controls, but that WBS
levels in autistic subjects were age-independent.

Tryptophan levels were also significantly decreased in the autistic subjects. However, the significance of this is uncertain
because the ratio of tryptophan to competing amino acids was not decreased and free tryptophan was not measured (both
are important for determining how much tryptophan crosses the blood-brain barrier). Other markers of 5-HT function,
including WBS and 24-hour urinary excretion of 5- hydroxy-indoleacetic acid, were not significantly different between
groups.

Kadar triptofan juga menurun signifikan pada gangguan autistik, tetapi perubahanya tidak menentu karena rasio dari
triptofan terhadap asam amino tidak menurun dan free triptofan tidak diukur ( kedua hal tersebut penting untuk
menentukan seberapa banyak kadar triptofan yang dapat menembus blood-brain barrier). Tanda-tanda lain dari fungsi
serotonin yang dapat ditemukan, yaitu serotonin darah lengkap dan ekskresi urin 24 jam dari 5-hydroxy-indoleacetic acid
yang tidak berbeda signifikan.

(Penn, 2006)
One of the most consistently reported findings in autism research involves enlarged brain
volume. More recent research suggests that approximately 20% of individuals with autism have
macrocephaly (head circumference greater than the 97th percentile). Similar rates of
macroencephaly have been reported in samples of children and adolescents as in samples with
wider age ranges.
Using retrospective head circumference
records, they found that brain volumes appeared normal for all children at birth. However,
90% of the 24 year-olds with autism had brain volumes larger than the 24 year-old controls
average (brain volume was 18% larger on average and 37% of this group showed
brain volume consistent with macrocephaly). In summary, postmortem and MRI research
combine to provide converging evidence
that autism is associated with increased brain size in childhood, although the persistence
of this abnormality is unclear.

Salah satu penemuan yang paling konsisten dilaporkan pada anak gangguan autisme yaitu

adanya pembesaran volume otak. Terdapat 20% dari anak autisme yang memiliki ukuran kepala

abnormal/makrosefalus. Pembesaran kepala ini sering ditemukan pada awal-awal kelahiran. 90%

anak-anak autisme berumur 2-4 tahun memiliki volume otak yang lebih besar daripada anak

normal seusianya. Pada pemeriksaan MRI ditemukan bukti bahwa autisme berkaitan dengan

pembesaran ukuran kepala pada masa kanak-kanak, walaupun pemahaman dari kelainan ini

masih belum dapat dijelaskan.

Neuronal dysregulation growth

Evidence for neuronal growth dysregulation in autism is beginning to

emerge from a
number of different research areas. Cell migration errors and
decreased dendritic branching (e.g., Blatt et al., 2001) have been
detected in postmortem
research. In addition, a recent examination of cortical minicolumn
formation in a preselected
area of the prefrontal cortex and two areas of the temporal lobe in nine
individuals
with autism and nine controls revealed that individuals with autism had
cell columns that
were more closely packed, smaller and more numerous than controls,
and that cells within
minicolumns were more dispersed (Casanova, Buxhoeveden, Switala, &
Roy, 2002).
Although the full implications of this finding are unclear, this research
adds support to the
theory that autism is associated with altered central nervous system
development

In further support of a link between autism and growth dysregulation,

some evidence
suggests that proteins associated with neuronal growth may be
dysregulated in
autism. The RELN gene, which codes for an extracellular protein that
guides neuronal
migration, has been linked to autism (Persico et al., 2001) and
significant decreases in a
protein that inhibits apoptosis (Bcl-2) have been found in the cerebellum
and parietal cortex
of individuals with the condition
Further research suggests that individuals with autism may have
abnormally elevated neurotrophin and neuropeptide levels at birth.
detected significantly higher levels of vasoactive intestinal peptide
(VIP), calcitonin generelated peptide (CGRP), brain-derived
neurotrophic factor (BDNF), and neurotrophin 4/5 (NT4/5) in archived
neonatal blood samples obtained from 69 children with autism spectrum
disorders. These elevations could provide the molecular basis
for early and accelerated brain growth in autism, as both VIP and
neurotrophins regulate the production and elimination of neural
synapses.

Neurotransmitters
A number of abnormalities in neurotransmitter systems have been
detected in individuals with autism. Recent research emphasizes
serotonergic abnormalities, but abnormalities in GABA, glutamate,
dopamine, opioids, and oxytocin have also been detected. Other research
suggests that drugs that decrease serotonergic neurotransmission
exacerbate symptoms in individuals with autism and that serotonin re-
uptake inhibitors (which increase serotonin neurotransmission) improve
repetitive behaviors, compulsions, and social impairments in some
adults and adolescents with the condition.

Sejumlah kelainan dari system neurotransmitter telah terdeteksi pada

individu dengan autisme. Penelitian terakhir menekankan mengenai
abnormalitas serotonergik, tetapi ditemukan pula abnormalitas pada
GABA, glutamat, dopamine, opioid dan oxytocin pada autisme.
Penelitian lainnya membuktikan bahwa obat-obat yang menurunkan
neurotransmitter serotonin dapat memperburuk gejala pada autisme dan
pemberian SSRI (selective serotonin reuptake inhibitor) yang
meningkatkan neurotransmitter dapat memperbaiki gejala gangguan
perilaku repetitif, kompulsif, dan gangguan interaksi sosial pada remaja
dan dewasa autisme.
Evidence that serotonin pathways may mature abnormally in autism is
important in light of research suggesting that serotonin plays an
important role in regulating brain development, affecting neurogenesis,
neuronal differentiation, axon myelination, synaptogenesis, and
hippocampal and cortical dendrite formation.

Terdapat bukti bahwa jalur serotonin menjadi abnormal pada autisme dan serotonin memiliki

peran yang penting dalam regulasi perkembangan otak, mempengaruhi neurogenesis, diffensiasi

neuron, myelinisasi akson, pembentukan sinaps, hipokampus dan formasi dendrit kortikal.

In further support of the link between autism and cerebellar abnormality

detected decreased blood flow in the cerebellar hemispheres in 20 out of
23 children with autism using Single Photon Emission Computed
Tomography (SPECT). Furthermore, have reported abnormal activation
of the cerebellum in autism during both motor and attentional tasks.

ditemukan juga abnormalitas pada serebelum dan penurunan aliran darah pada hemisfer,

sehinggga muncul aktivasi abnormal dari serebelum yang dapat mengganggu fungsi motorik dan

pusat perhatian.

There is some evidence that cerebellar abnormalities in autism

may be linked to deficits shifting and orienting attention. However, other
research is needed to build upon these findings and assess links between
the cerebellum and other morphological and behavioral correlates.
The link between cerebellar deficits and autistic symptomatology is
unclear. Initial links between the cerebellum and autism challenged
traditional views that the cerebellum is exclusively involved in motor
coordination. Research now suggests that the cerebellum is implicated in
multiple functions, such as shifting attention
language, procedural memory , and nonmotor learning.
Terdapat beberapa bukti bahwa abnormalitas serebelum pada autisme berhubungan dengan

perubahan defisit dan perhatian orientasi. Ditemukan adanya pengaruh kelainan serebelum

dengan gangguan perilaku, koordinasi motorik, perubahan pusat perhatian, perubahan dalam

komunikasi, dan pembelajaran non motorik

Temporal lobe
Lesion, postmortem, and imaging studies link temporal lobe abnormalities to autism. Some postmortem research has
detected unusually small and densely packed neurons in the
medial temporal lobe in individuals with autism. In a large postmortem study
reported amygdala abnormalities, predominantly in cortical, medial, and
central amygdala nuclei, in nine out of nine cases.

In further support of the link between the temporal lobe and autism, a number of case reports reveal that children
who have experienced temporal lobe damage due to viral encephalitis or tumors may develop autistic symptoms.
Furthermore, autistic symptomatology in children with tuberous sclerosis is strongly related to the presence of
abnormalities in the temporal lobes. are relatively common in children with autism spectrum disorders, and may be
more common in children who experienced a regression of language, sociability, or behavior in
early childhood. Although the implication of increased epileptiform activity is unclear, it may be linked to the
emergence or maintenance of language and behavioral symptoms

selain itu, terdapat hubungan antara lobus temporal dan gangguan pada autisme, beberapa laporan kasus
menunjukkan bahwa anak yang memiliki riwayat gangguan pada lobus temporal yang disebabkan virus ensefalitis
atau tumor dapat meningkatkan gejala autistik. Gejala autistik pada anak dengan tuberosklerosis berkaitan erat
dengan adanya abnormalitas pada lobus temporal. Kelainan pada lobus temporal ini dapat menyebabkan
kemunduran dalam berkomunikasi, berinteraksi, maupun gangguan dalam berperilaku pada awal masa kanak-kanak.

In contrast to results from structural MRI research, functional imaging studies have
consistently detected abnormalities in the activation of temporal lobe structures in individuals
with autism.

Pada pemeriksaan fMRI ditemukan bukti konsisten kelainan pada struktur lobus temporal dan amygdala pada anak
dengan gangguan autisme.

Although MRI research has not produced consistent findings,

fMRI research clearly demonstrates abnormal activation of the amydgala and other temporal
lobe structures during facial processing, theory of mind, and language tasks. Temporal
lobe abnormalities could account for a number of behavioral impairments associated
with autism, including impaired language, impaired facial processing, impaired theory of
mind, difficulties with cross-modal association, impaired stimulus generalization, and difficulty
taking context into account (see Dawson, Webb, et al., 2002). As important aspects
of social and language functioning have been linked to temporal lobe structures, it is likely
that this neural region will continue to be a focus of research into the pathophysiology of
autism.
Penelitian dengan fMRI membuktikan dengan jelas gangguan pada amygdala dan lobus temporal yang berpengaruh
pada gangguan perilaku pada autisme, termasuk gangguan bahasa, perasaan, berfikir, gangguan fungsi sosial.

Frontal lobe

The frontal lobe has received much attention in recent autism research. Although
structural abnormalities have not consistently been found, neuropsychological and behavioral
findings suggest a link between autistic symptoms and frontal lobe deficits.

Lobus frontal mendapat banyak perhatian dalam penelitian mengenai autisme. Walaupun

kelainan struktural tidak secara konsisten dilaporkan, tetapi dari neuropsikologis dan tingkah

laku mengarahkan gejala autisme ini kepada defisit lobus frontalis.

Found abnormal minicolumn structure in the frontal lobe, suggesting atypical

neuronal migration. In further support of a link between autism and the frontal lobe,
abnormal blood flow in childhood (Zilboicius et al., 1995), abnormal serotonin synthesis
(Chugani et al., 1997), and reduced dopaminergic activity (Ernst et al., 1997) have been
detected in this neural region.

Ditemukan kelainan struktur minicolumn pada struktur lobus frontalis, menunjukkan migrasi neuron atypical.
Terdapat bukti-bukti yang mendukung antara autisme dan lobus frontalis dengan adanya gangguan aliran darah,
kelainan pada sintesis serotonin dan menurunnya aktivitas dopamine

Abnormal frontal lobe volume has not consistently been found in MRI studies of
individuals with autism. A wide range of neuropsychological and behavioral findings suggest that the prefrontal
(PF) cortex may play a role in autistic symptomatology. Furthermore, medial prefrontal
or orbitofrontal lesions can lead to theory of mind impairments (orbitofrontal lesions
are associated with milder deficits) (Stone, Baron-Cohen, & Knight, 1998).

Abnormalitas pada volume lobus frontal ini belum ditemukan secara konsisten pada anak autisme dengan
menggunakan MRI. kelainan perilaku dan neuropsikologi yang luas membuktikan bahwa korteks prefrontalis
memiliki peran pada gejala-gejala yang ditemukan pada anak dengan gangguan autisme

Another cognitive model linking the prefrontal cortex to autism symptoms suggests
that impaired joint attention may be central to autistic symptoms (see Mundy & Neal,
2000). Children with autism show deficits in joint attention by failing to follow the gestures
of others, failing to share interest in objects, and failing to shift their gaze between
objects and people during interactions (Whalen & Schreibman, 2003). Research involving
typical infants has linked joint attention abilities to the medial frontal, orbitofrontal,
and dorslateral frontal cortical regions.

Autism is associated with deficits in theory of mind, joint

attention, executive function, and central coherence, and these deficits have been linked to
the prefrontal cortex in both typical populations and individuals with autism. The relationship
between functional abnormalities in the frontal lobe and structural abnormalities in
both the frontal lobes and subcortical areas requires further examination.
Autism yang menunjukan gangguan pada fungsi kognitif , pusat perhatian dan koordinasi pusat, memiliki kaitan
dengan kortkeks prefrontalis pada anak autistik.

Discussion
Research regarding basic neural structures and processes is presented
first, with either replicated findings within specific research areas (denoted ++) or a
weight of evidence across research areas supporting a link between autism and atypical
brain volume, neuronal growth dysregulation, and neurochemical abnormalities. Histopathological,
structural imaging, and head circumference studies link autism with
increased brain volume in childhood, and some postmortem and neural growth protein
research suggests that autism may be linked to neuronal growth dysregulation. Serotonin,
dopamine, GABA, glutamate, opioid, and oxytocin have been implicated in autism and
recent animal research suggests that atypical serotonin exposure in early development
may lead to morphological abnormalities associated with the condition.

autism is also associated with abnormalities in a number of

specific neural sites. Converging evidence implicates the cerebellum, the medial temporal
lobe, and the frontal lobe in autism. Replicated research suggests that autism involves reduced Purkinje neurons in
the cerebellar vermis and hemispheres, and there is some evidence
of abnormal volume of cerebellar vermis lobules and atypical patterns of cerebellar
activation. A link between the amygdala and autism is supported by histopathological
research, animal and human lesion studies, and replicated evidence of atypical activation
of temporal lobe structures during theory of mind and language tasks. Lastly, the frontal
lobe is implicated in autism due to recent evidence of structural abnormalities in some
postmortem cases and links between the prefrontal cortex and core neuropsychological
deficits. Other research suggests that autism involves reduced corpus callosum volume
and that enlarged caudate volume in the basal ganglia may be correlated with repetive

the medial temporal lobe and the ventromedial prefrontal cortex make up a brain system
specialized for social processing that is deficient in autism, reducing attention to faces,
impairing facial processing ability, and leading to difficulties with theory of mind, language,
and social skills. Conversely, Carper and Courchesne (2000) emphasize the role of
the cerebellum and its links to frontal lobe functioning when explaining autism symptoms.
A number of recent models emphasize neuronal growth dysregulation and decreased interconnectivity
of neural structures in autism. For example, Akshoomoff et al. (2002) propose
that early imbalances in neurotrophins and neuropeptides may lead to abnormal initiation
or cessation of neuronal and glial growth, causing premature overgrowth in some structures
and reduced growth in other structures, and that varied strategies to compensate for these
abnormalities could account for differing degrees of impairment, idiopathic functional
maps, and atypical lateralization