North American Journal of Medicine & Science - NAJMS: The North ...

North American Journal 

of 

Medicine & Science 

Vol.4, Issue 3 

JULY, 2011 

A Review of the Neurobiological Basis of Autism 

Michelle Hartley-McAndrew, MD, Arie Weinstock, 

MD 

Synaptic Dysfunction Attributes to Autism 

Spectrum Disorder 

Yougen Zhan, MD, PhD, Xuejun Kong, MD 

A Pilot Study on the Diagnostic Performance of 

DMS-IV and DMS-V for Autism Spectrum 

Disorder 

Yang You, MD, Bai-Lin Wu, PhD, Yiping Shen, PhD 

Do Apparent Overlaps between Schizophrenia 

and Autistic Spectrum Disorders Reflect 

Superficial Similarities or Etiological 

Commonalities 

William S. Stone, PhD, Lisa Iguchi, PhD 

Prospect of Stem Cell Therapy for Autism 

Spectrum Disorders 

Xuejun Kong, MD, Xiaochun Wang, PhD, William 

Stone, PhD 

Autism Disease: Neural Network Going Awry and 

Therapeutic Strategy Underlying Neural Plasticity 

Mei Zhang, MD, PhD 

Advances in Autism 

A special Issue of 

NAJMS 

Effective Treatments for Auditory Sensitivities in 

Autism 

Karen Chenausky, MS, CCC-SLP 

Behavioral Treatment for Children with Autism 

Paulina Peng-Wilford, PhD, Xuejun Kong, MD 

Autism of Acupuncture Perspective 

Jing Liu, MD, PhD, Zeng Xiaoqing, MD, Ping Yao, 

MD 

Current Status of Autism Spectrum Disorder in 

China-Summary on the 369th Xiangshan Science 

Conferences 

Bai-Lin Wu, PhD, Zhenyu Zhang, PhD 

Editor-in-Chief: 

Published: 

Distributed: 

Xuejun Kong, MD 

Boston, MA, USA 

Worldwide 

ISSN: 

1946-9357

Still 0% 

resistance at Years 1, 2, and 3 

(Studies 102 and 103) 

Indication and Important Safety Information 

Indication and Usage 

VIREAD ® (tenofovir disoproxil fumarate) is indicated for the treatment of chronic hepatitis B in adults. 

Patients were primarily nucleoside–treatment-naïve with compensated liver disease 1 

In Studies 102 (HBeAg–) and 103 (HBeAg+), 641 adult patients with chronic hepatitis B (CHB) and 

compensated liver disease entered a 48-week, randomized, double-blind, active-controlled treatment 

period comparing VIREAD 300 mg to Hepsera ® (adefovir dipivoxil) 10 mg. 585 patients then rolled over 

to open-label VIREAD for analysis through Week 144. 1-3 

Cumulative VIREAD genotypic resistance was evaluated annually with the paired HBV reverse 

transcriptase amino acid sequences of the pre-treatment and on-treatment isolates from subjects 

who received at least 24 weeks of VIREAD monotherapy and remained viremic with HBV DNA 

≥400 copies/mL at the end of each study year (or at discontinuation of VIREAD monotherapy) 

using an as-treated analysis. 1 

• No specific substitutions occurred at a sufficient frequency to be associated with resistance to VIREAD 

(genotypic or phenotypic analysis) 1 

• From 4 ongoing VIREAD trials (Studies 102, 103, and 106* in subjects with compensated liver disease 

and Study 108 † in subjects with decompensated liver disease), 10% (69/660) of VIREAD recipients 

with compensated liver disease receiving up to 144 weeks of VIREAD monotherapy and 18% (7/39) of 

VIREAD recipients with decompensated liver disease receiving up to 48 weeks of VIREAD monotherapy 

remained viremic at their last time-point on VIREAD monotherapy 1 

• Treatment-emergent amino acid substitutions in the HBV reverse transcriptase were identified in 

46% (32/69) of those subjects in Studies 102, 103, 106, and 108 with evaluable paired genotypic 

data; no specific substitutions occurred at a sufficient frequency to be associated with resistance to 

VIREAD (genotypic or phenotypic analysis) 1 

The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection: 

• This indication is based primarily on data from treatment of subjects who were nucleoside–treatment-naïve and a smaller number of subjects who had previously 

received lamivudine or adefovir dipivoxil. Subjects were adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease 

• VIREAD was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease 

• The numbers of subjects in clinical trials who had lamivudine- or adefovir-associated substitutions at baseline were too small to reach conclusions of efficacy 

WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH 

STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS 

• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, 

including VIREAD, in combination with other antiretrovirals 

• Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, 

including VIREAD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in 

patients who discontinue anti-hepatitis B therapy, including VIREAD. If appropriate, resumption of anti-hepatitis B therapy may be warranted 

* Study 106 is an ongoing Phase 2 study involving Hepsera–treatment-experienced subjects previously treated for 24 to 96 weeks with Hepsera for chronic HBV infection and had plasma HBV DNA ≥1000 copies/mL at screening. 1 

† 

Study 108 was a small, double-blind, randomized, active-controlled trial comparing the safety of VIREAD and other oral antivirals in patients with CHB and decompensated liver disease through 48 weeks. 1 

Please see continued Important Safety Information and brief summary of full Prescribing Information for VIREAD on the following pages. 

My liver. 

My fight. My VIREAD.

Important Safety Information (cont’d) 

Warnings and Precautions 

• New onset or worsening renal impairment: New onset or worsening 

renal impairment, including cases of acute renal failure and Fanconi 

syndrome (renal tubular injury with severe hypophosphatemia), have been 

reported with the use of VIREAD. Assess creatinine clearance (CrCl) before 

initiating treatment with VIREAD. Monitor CrCl and serum phosphorus in 

patients at risk, including those who have previously experienced renal 

events while receiving HEPSERA ® (adefovir dipivoxil). Avoid administering 

VIREAD with concurrent or recent use of nephrotoxic drugs. Dosing 

interval adjustment of VIREAD and close monitoring of renal function are 

recommended in all patients with CrCl 5% of patients 

treated with VIREAD included: abdominal pain, diarrhea, headache, 

dizziness, fatigue, nasopharyngitis, back pain, and skin rash 

• In HBV-infected patients with decompensated liver disease: 

Most common adverse reactions (all grades) reported in ≥10% 

of patients treated with VIREAD were abdominal pain (22%), 

nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), 

dizziness (13%), and pyrexia (11%) 

Drug Interactions 

• Didanosine: Coadministration increases didanosine concentrations. 

Use with caution and monitor for evidence of didanosine toxicity 

(eg, pancreatitis, neuropathy). Didanosine should be discontinued in 

patients who develop didanosine-associated adverse reactions. In 

adults weighing >60 kg, the didanosine dose should be reduced to 

250 mg when it is coadministered with VIREAD. Data are not available 

to recommend a dose adjustment of didanosine for patients 

weighing

VIREAD ® 

(tenofovir disoproxil fumarate) Tablets 

Brief summary of full prescribing information. Please see full prescribing 

information including Boxed WARNINGS. Rx only 

WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH 

STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS 

• Lactic acidosis and severe hepatomegaly with steatosis, including 

fatal cases, have been reported with the use of nucleoside analogs, 

including VIREAD, in combination with other antiretrovirals (See 

Warnings and Precautions). 

• Severe acute exacerbations of hepatitis have been reported in 

HBV-infected patients who have discontinued anti-hepatitis B 

therapy, including VIREAD. Hepatic function should be monitored 

closely with both clinical and laboratory follow-up for at least several 

months in patients who discontinue anti-hepatitis B therapy, 

including VIREAD. If appropriate, resumption of anti-hepatitis B 

therapy may be warranted (See Warnings and Precautions). 

INDICATIONS AND USAGE: VIREAD is indicated for the treatment of chronic 

hepatitis B in adults. The following points should be considered when initiating 

therapy with VIREAD for the treatment of HBV infection: 

• This indication is based primarily on data from treatment of subjects who 

were nucleoside-treatment-naïve and a smaller number of subjects who 

had previously received lamivudine or adefovir dipivoxil. Subjects were 

adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with 

compensated liver disease (See Adverse Reactions). 

• VIREAD was evaluated in a limited number of subjects with chronic 

hepatitis B and decompensated liver disease. 

• The numbers of subjects in clinical trials who had lamivudine- or 

adefovir-associated substitutions at baseline were too small to reach 

conclusions of efficacy. 

DOSAGE AND ADMINISTRATION: For the treatment of chronic hepatitis B in 

adults, the dose is one 300 mg VIREAD tablet once daily taken orally, without 

regard to food. The optimal duration of treatment is unknown. Dose 

Adjustment for Renal Impairment in Adults: Significantly increased drug 

exposures occurred when VIREAD was administered to subjects with moderate 

to severe renal impairment. Therefore, the dosing interval of VIREAD should be 

adjusted in patients with baseline creatinine clearance 990 U/L; F: >845 U/L) 2% 3% 

Serum Amylase (>175 U/L) 4% 1% 

Glycosuria (≥3+) 3% 180 U/L; F: >170 U/L) 4% 4% 

ALT (M: >215 U/L; F: >170 U/L) 10% 6% 

The overall incidence of on-treatment ALT flares (defined as serum ALT >2 × 

baseline and >10 × ULN, with or without associated symptoms) was similar 

between VIREAD (2.6%) and HEPSERA (2%). ALT flares generally occurred within 

the first 4–8 weeks of treatment and were accompanied by decreases in HBV 

DNA levels. No subject had evidence of decompensation. ALT flares typically 

resolved within 4 to 8 weeks without changes in study medication. 

Clinical Trial in Adult Subjects with Chronic Hepatitis B and 

Decompensated Liver Disease: In a small randomized, double-blind, 

active-controlled trial (0108), subjects with CHB and decompensated liver 

disease received treatment with VIREAD or other antiviral drugs for up to 48 

weeks. Among the 45 subjects receiving VIREAD, the most frequently 

reported treatment-emergent adverse reactions of any severity were 

abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), 

vomiting (13%), dizziness (13%), and pyrexia (11%). Two of 45 (4%) subjects 

died through Week 48 of the study due to progression of liver disease. Three 

of 45 (7%) subjects discontinued treatment due to an adverse event. Four of 

45 (9%) subjects experienced a confirmed increase in serum creatinine of 

0.5 mg/dL (1 subject also had a confirmed serum phosphorus _10 and MELD score >_14 at entry) developed renal failure. Because 

both VIREAD and decompensated liver disease may have an impact on renal 

function, the contribution of VIREAD to renal impairment in this population is 

difficult to ascertain. One of 45 subjects experienced an on-treatment hepatic 

flare during the 48 week study. 

Postmarketing Experience: The following adverse reactions have been 

identified during postapproval use of VIREAD. Because postmarketing 

reactions are reported voluntarily from a population of uncertain size, it is not 

always possible to reliably estimate their frequency or establish a causal 

relationship to drug exposure: allergic reaction, including angioedema, lactic 

acidosis, hypokalemia, hypophosphatemia, dyspnea, pancreatitis, increased 

amylase, abdominal pain, hepatic steatosis, hepatitis, increased liver 

enzymes (most commonly AST, ALT gamma GT), rash, rhabdomyolysis, 

osteomalacia (manifested as bone pain and which may contribute to 

fractures), muscular weakness, myopathy, acute renal failure, renal failure, 

acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, 

interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, 

renal insufficiency, increased creatinine, proteinuria, polyuria, asthenia. The 

following adverse reactions listed above, may occur as a consequence of 

proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, 

muscular weakness, myopathy, hypophosphatemia. 

DRUG INTERACTIONS: Didanosine: Coadministration of VIREAD and 

didanosine should be undertaken with caution and patients receiving this 

combination should be monitored closely for didanosine-associated adverse 

reactions. Didanosine should be discontinued in patients who develop 

didanosine-associated adverse reactions. When administered with VIREAD, 

Cmax and AUC of didanosine (administered as either the buffered or 

enteric-coated formulation) increased significantly. The mechanism of this 

interaction is unknown. Higher didanosine concentrations could potentiate 

didanosine-associated adverse reactions, including pancreatitis and 

neuropathy. Suppression of CD4 + cell counts has been observed in patients 

receiving tenofovir disoproxil fumarate (tenofovir DF) with didanosine 400 mg 

daily. In patients weighing >60 kg, the didanosine dose should be reduced to 

250 mg when it is coadministered with VIREAD. Data are not available to 

recommend a dose adjustment of didanosine for adult or pediatric patients 

weighing

NORTH AMERICAN JOURNAL OF MEDICINE & SCIENCE 

July 2011 (Volume 4, Issue 3) 

SPECIAL ISSUE OF AUTISM 

I 

PREFACE 

Etiology Overview 

107 A Review of the Neurobiological Basis of Autism 

Michelle Hartley-McAndrew, MD, Arie Weinstock, MD 

112 Synaptic Dysfunction Attributes to Autism Spectrum Disorder 


Diagnostic Advances 

116 A Pilot Study on the Diagnostic Performance of DMS-IV and DMS-V for Autism Spectrum Disorder 

Yang You, PhD, Bai-Lin Wu, PhD, Yiping Shen, PhD 

124 Do Apparent Overlaps between Schizophrenia and Autistic Spectrum Disorders Reflect Superficial Similarities or 

Etiological Commonalities 


Treatment Perspective 

134 Prospect of Stem Cell Therapy for Autism Spectrum Disorders 

Xuejun Kong, MD, Xiaochun Wang, PhD, William Stone, PhD 

139 Autism Disease: Neural Network Going Awry and Therapeutic Strategy Underlying Neural Plasticity 


151 Effective Treatments for Auditory Sensitivities in Autism 


158 Behavioral Treatment for Children with Autism 


Autism in China 

164 Autism of Acupuncture Perspective. 

Jing Liu, MD, PhD, Zeng Xiaoqing, MD, Ping Yao, MD 

167 Current Status of Autism Spectrum Disorder in China - Summary on the 369th Xiangshan Science Conferences 

Bai-Lin Wu, PhD, Zhenyu Zhang, PhD

Preface 

Autism has been widely regarded to be a group of the most 

complicated neurodevelopment disorder affecting 1 in 110 

children in USA and costs the nation over $35 billion per 

year, expected to increase significantly the next decade. CDC 

has called autism a national public health crisis. Autism has 

become a huge healthcare burden and threat globally. Autism 

is characterized by the difficulty to communicate and interact 

with others, often accompanied by significant behavioral 

challenges, defined as a clinical syndrome. The etiology of 

autism is largely unknown, its patho-physiology is poorly 

understood, and it currently has no universally accepted 

therapy. Autism is regarded as century myth affecting more 

and more families that needs to be addressed urgently. 

Unraveling this complex disorder requires more research 

dedicated to change the way we understand and treat this 

very serious condition. 

This issue of North American Journal of Medicine and 

Science (NAJMS) provides newest research findings and 

comprehensive review of autism spectrum disorder, from 

advances in pathogenesis of Autism, new diagnostic criteria 

research, to novel and alternative therapeutic approaches, and 

current autism status in China. I feel honored to receive so 

much help and support from a group of expert clinicians and 

scientists who has made possible of this issue. 

The issue is started with the paper by Drs. Hartley- 

McAndrew and Weinstock provided a systemic review of the 

neurobiological basis and advances of Autism; Drs. Zhan and 

Kong demonstrate impairment in synaptic function is an 

etiology of Autism Spectrum Disorder; The paper by Drs. 

You, Wu and Shen reported their research findings of a pilot 

study on comparison of diagnostic performance of DMS-IV 

and DMS-V for autism spectrum disorder, pointed out that 

the stricter new criteria will have immediate impact on the 

clinical diagnosis and management of autism spectrum 

disorder; An interesting research review of Drs. Stone and 

Iguchi, demonstrated significant similarities characterized 

comparisons in schizophrenia and autism in four domains of 

function; Drs. Kong, Wang and Stone provided a detailed 

review article on prospects of stem cell therapy for Autism 

Spectrum Disorders in the regard of its promising rational, 

preclinical and clinical pictures and barriers to success; The 

comprehensive review article of Dr. Zhang illustrated neural 

network going awry in autism, proposed neuroplasticity as 

therapeutic basis is highly indicated by the disease features of 

autism, also offered great review of labeled and off labeled 

use of medications for autism; The paper by Mrs. Chenausky, 

MS, CCC-SLP addressed effective treatments for auditory 

sensitivities in Autism, including behavioral and 

desensitization therapies; Drs. Peng-Wilford and Kong 

provided a review article on behavioral treatment for children 

with Autism, described the ABA behavioral treatment 

process for children with autism, and review several key 

studies on its effectiveness; Dr. Liu’s paper summarized the 

reports from about 20 clinical trials of acupuncture for autism 

in the last decade in China offered very interesting data in 

this alternative therapeutic methodology; Lastly Dr. Wu and 

Zhang reported current status of Autism Spectrum Disorder 

in China via his insightful and lengthy summary on the 369th 

Xiangshan Science Conferences of Autism Consortium 

China. We truly believe this issue would be welcomed and 

be helpful in our tough battle against Autism. 

I would like to thank all the contributing authors for sharing 

their great expertise in the area, their trust and support; thank 

all the peer reviewers including but not limited to Drs. Maria 

Mody, Arron Cho, Wendy Qiu, Weidong Lu, Yiqing Song, 

Jianghe Niu, Cindy Levine, Elena Volonzhania, Brian 

Wilford and many others, for their valuable critiques, 

comments and precious time, 

I would like to have the special acknowledgement to my 

editorial associate Dr. Shirley Shi for her great contribution 

in critical review of each manuscript, valuable editorial 

works and coordinating assistance. I would like to also thank 

her daughter Ms. Irene Zhao for her editing assistance and 

proof reading. 

Finally, I would like to thank my family members, my 

husband Xiaochun Wang for his executive editing and 

technological works and constant great support and my sons 

Raymond and Bryan Wang for giving me continuous courage 

and strength. 


Department of Medicine 

Beth Israel Deaconess Medical Center 

Harvard Medical School 

i

North American Journal of Medicine and Science Jul 2011 Vol 4 No.3 107 

Review 

A Review of the Neurobiological Basis of Autism 

Michelle Hartley-McAndrew, MD, Arie Weinstock, MD 

ABSTRACT 

This manuscript reviews ongoing developments in autism 

research that defines it as a behavioral phenotype with 

many known neurobiological and molecular causes. 

Strides in neuroimaging, histopathology, 

neurophysiology, genetics and metabolic disorders are 

discussed that support the understanding of autism as a 

pervasive abnormality of neural systems with particular 

dysfunction of neuronal connections that impacts the 

development of socialization, communication and 

behavior. The aim of this review is to provide insight into 

the current knowledge of the complex pathophysiology of 

autism. 

[N A J Med Sci. 2011;4(3):107-111.] 

KEY WORDS: Autism, Seizures, Neurobiological basis, 

connectivity 

Introduction 

Autism, as defined by the Diagnostics and Statistics Manual 

of Mental Disorders, 4 th ed. (DSM-IV), is a disorder 

consisting of variable degrees of abnormal social reciprocity 

and interaction, communicative intent, and repetitive, 

stereotyped patterns of behavior, interests and activities with 

onset before three years of age. Autism has been recognized 

as a biologically and molecularly based complex neurodevelopmental 

disorder that appears to be heritable involving 

Received 7/5/2011; Revised 7/25/2011; Accepted 7/25/2011 

Michelle Hartley-McAndrew, MD 

Clinic Assistant Professor, Department of Child Neurology 

State University of New York at Buffalo School of Medicine 

and Biomedical Sciences 

Medical Director, Children’s Guild Autism Spectrum 

Disorder Center 

Women and Children’s Hospital of Buffalo 

219 Bryant Street Buffalo, NY 14222 

Assistant Professor of D’Youville College 

Tel: 716-878-7600 

Email: mhartley-mcandrew@kaleidahealth.org 

Arie Weinstock, MD 

Associate Professor of Clinical Neurology 

State University of New York at Buffalo School of Medicine 

and Biomedical Sciences 

Chief of Division of Child Neurology 

Women and Children’s Hospital of Buffalo 

219 Bryant Street, Buffalo, NY 14222 

Tel: 716-878-7840 

multiple genes and demonstrates varied phenotypes with 

heterogenous etiology. 1 Increasingly researchers refer to “the 

autisms” rather than a single autism phenotype. 2 The 

reported prevalence of autism has increased to an estimated 

rate of 10-17% per year. It does not appear to have 

correlation with gender, race, ethnicity or socio-economic 

level. The neurobiological findings have led to the current 

understanding of autism as a disorder of neural systems and 

connections, mainly affecting local intra-cortical connections, 

cortico-cortical connections and cortico-subcortical 

connections. 

MACROCEPHALY AND INCREASE IN BRAIN 

VOLUME 

Children with autism have a larger head circumference, with 

frank macrocephaly occurring in about 20%. MRI Voxel 

Brain Morphometry (VBM) studies have reported increase in 

total brain volume. This volume increase has been 

documented to begin between ages 2 to 4 years, the earliest 

age of clinical recognition and persists into childhood but not 

adolescence. The tissues contributing to this increase are 

total cerebral white and total cortical gray matter. 3,4 The 

onset of brain overgrowth coincides with the onset of signs 

and symptoms of autism, indicating that this critical period of 

overgrowth is part of a pathologic process that disrupts the 

development of normal brain structure and function. It 

occurs during a period of synapse formation, pruning and 

myelination that takes place during early postnatal periods. 

Synaptic pathology and abnormal connectivity appears to be 

a common denominator in autism etiologies and may have an 

important role in the increased prevalence of seizures in the 

autistic population. We will discuss below studies related to 

epilepsy, molecular and genetic studies, histopathologic 

studies, imaging studies and findings of abnormal 

metabolism in mitochondrial disorders as they relate to 

autism. 

EPILEPSY 

The relationship between autism and epilepsy has been 

recognized since the 1960’s. 5 This distinct relationship gives 

insight into the neurobiological basis of autism. Seizures are 

common, occurring in 20-30% of patients diagnosed with the 

more symptomatic subset of individuals with autism as 

compared to 0.5-1% of the general population. 6 The risk of 

epilepsy in autism appears to be associated with the degree of 

intellectual disability and the severity of autistic symptoms. 7 

The relationship between epilepsy, epileptiform discharges 

without clinical seizures and cognitive language and 

behavioral symptoms is not clearly understood, however it is 

likely due to a common underlying pathology. Subclinical 

epileptiform abnormalities are seen in 6.1-31% of patients

108 Jul 2011 Vol 4 No.3 North American Journal of Medicine and Science 

with autism. 8 It was suggested that the dysfunction of the 

specific neuronal network accounting for the behavioral 

syndrome of autism is due to a wide variety of insults to the 

developing brain and these insults affect more than one single 

neuronal network. 9 Environmental factors and prenatal 

exposures are explored in recent immunological studies 

supporting a fetal brain antibody in those with regressive 

autism 10 as well as history of maternal infection and 

medications that contribute to the autism phenotype. 11 

Although antibodies towards brain proteins in children were 

reported to be associated with lower adaptive and cognitive 

function as well as core behaviors associated with autism, it 

is unclear whether these antibodies have direct pathologic 

significance, or if they are merely a response to previous 

injury. 10 

Certain seizure syndromes are often associated with cognitive 

and behavioral impairments. The presence of seizures and 

not just epileptiform abnormalities has been associated with 

more difficult behavior in autistic patients. 12 Additionally 

epilepsy has been noted to be significantly more frequent in 

autistic children with a history of regression. 13 Of great 

importance is that children with epilepsy appear to be at the 

greatest risk of developing autism when seizures start at 

around age 2 years or earlier. Early onset seizures are known 

to affect synaptic reorganization that likely hinders normal 

cognitive and behavioral development. 5 In autistic patients, a 

bi-modal distribution of seizures has been described with a 

peak before five years of age and an additional peak after 10 

years. While the early peak during early development is 

likely due to significant insults to the developing brain, the 

second peak is known to occur in patients with the more 

moderate to severe mental retardation. This is perhaps due to 

a more progressive disease representing a disorder of energy 

metabolism such as a mitochondrial disease. 5 There is 

significant overlap in the development of Tuberous Sclerosis, 

Rett syndrome, epilepsy and the presence of autistic features 

which leads to the idea that genetic models can give a 

framework from which an etiology for autism can be 

deduced. 

GENETIC TESTING 

Family studies have shown that there is a 50-100 fold 

increase in the rate of autism in first degree relatives of 

autistic children. Although at least one autism linked 

abnormality has been found on almost every chromosome, 

the most significant correlations appear to be associated with 

chromosomes X, 2,3, 7, 15, 17 and 22. 1 A chromosomal 

abnormality seen in Prader-Willi Sydrome and Angelman 

Syndrome is reported in more than 1% of autistic individuals, 

and involves the proximal long arm of chromosome 15 

(15q11-q13). Patients with Angelman syndrome typically 

have a happy, excitable demeanor with frequent smiling and 

laughter, a short attention span, and hand flapping 

movements. They present with global developmental delay, 

hypotonia, wide-based ataxic gait, seizures and spasticity. 

These patients lack appropriate social and language 

reciprocity and therefore often meet the criteria for autism. It 

is associated with a loss of maternally expressed ubiquitin 

protein ligase gene on a 15q deletion. A specific gene 

(SHANK3) known to encode a synaptic protein critical for 

brain development has been identified due to deletions of 

22q13 which causes developmental disabilities, absent or 

delayed speech or other autistic behaviors. Findings of 

autistic features in macrocephalic patients with mutations in 

the PTEN tumor suppressor gene on chromosome 10 have 

been recently reported. 14 

Neurofibromatosis type 1 (NF1) is an autosomal dominant 

disorder that affects neural crest cells and a mutation in the 

NF1 gene on chromosome 17 results in the development of 

tumors or neurofibromas on nerve tissue. This 

neurocutaneous disorder has been associated with autistic 

features. The NF1 gene product, neurofibromin, regulates 

activation of the Ras intracellular signaling pathway in 

Schwann cells. It was suggested that NF1-dependent 

signaling cascades in neurons, fibroblasts, as well as 

Schwann cells, are required for normal myelination. 15 

Another syndrome associated with autism is Fragile X 

disorder. It is the most common known inherited genetic 

cause of mental retardation. It accounts for about one half of 

cases of X-linked mental retardation and is the most common 

cause of genetic mental impairment after trisomy 21. It is 

caused by a mutation in the FMR1 gene. The abnormality is 

caused by a trinucleotide (CGG) repeat expansion of greater 

than 200 repeats. Its phenotype includes intellectual 

disability, macrocephaly, large pinnae, large testicles, 

hypotonia and joint hyperextensibility. While the yield of 

DNA testing has a mean of 3-4%, 30-50% of patients with 

Fragile X demonstrate autistic features. 16 Since there are 

significant similarities between the autism that has been 

associated with Fragile X syndrome and idiopathic forms of 

autism, it is thought that the autism of the Fragile X 

syndrome may represent a paradigm for the study of possible 

common molecular pathways that lead to all forms of 

autism. 17 

One of the five pervasive developmental disorders, Rett 

syndrome is present in females who demonstrate autistic-like 

regression, microcephaly, seizures and hand-wringing 

stereotypies. This diagnosis is confirmed with DNA testing 

finding a mutation in the X-linked MECP2 gene. Newer 

studies have found that although previously thought to be 

lethal in males, this mutation can be found in males with 

intellectual disability. 18 Tuberous Sclerosis is another 

neurocutaneous disorder that is characterized by 

hypopigmented macules, fibroangiomata, kidney lesions, 

CNS hamartomas, seizures, intellectual disability, and very 

commonly autistic and/ or ADHD-like behaviors. Mutations 

are seen at 9q and 16p. De novo mutations contribute to 70% 

of Tuberous Sclerosis cases. The discovery of the mTOR 

signaling pathway has contributed to further understanding of 

the neurobiological basis of autism in that mutations seen in 

Tuberous Sclerosis, Fragile X syndrome, Neurofibromatosis 

and autism associated with PTEN mutations alter this


cascade which disrupts the regulation of numerous cellular 

processes in the developing and mature brain. 14 

Autism is thought to be due to the culmination of mutations 

in multiple genetic categories of function that includes genes 

that regulate expression of other genes, alter actin 

cytoskeleton dynamics, affect synapse formation, operate as 

components of second messenger systems, influence 

neuronal migration, guide neuronal connectivity and inhibit 

or stimulate synaptic connections. 17 For example, certain 

genetic studies supported by mouse models have proposed 

mutations in the Neurexin 1-alpha gene, a gene that helps 

neurons form brain synapses. Deletions in the Neurexin 1- 

alpha gene were identified in patients with autism or 

schizophrenia. This was further supported when mouse 

models that were Neurexin 1-alpha deficient displayed 

behaviors that included increased grooming behaviors and an 

impairment in nesting abilities, a phenotype that begins to 

approximate impairments seen in human subjects with 

autism. 19 Various discoveries in the genetic and molecular 

basis of autism indicate that rather than a single gene 

disorder, it is likely mutations influencing multiple genetic 

pathways that results in the phenotype of autism. This 

alteration in normal connectivity and circuitry likely aid in 

maldevelopment of socialization, communication and 

behavior with more severe symptomatology in those with 

seizures as evidenced by genetic disorders such as Tuberous 

Sclerosis and Rett syndrome. 

NEUROIMAGING 

Both functional magnetic resonance imaging (fMRI) and 

diffusion tensor imaging (DTI) have supported the 

conceptual basis of autism as a disorder of aberrant 

connectivity. The discovery and study of mirror neurons 

through fMRI technique has been monumental in the 

understanding of autism. These were first discovered in the 

ventral premotor cortex of monkeys which fired not only 

while performing actions but also while observing the same 

actions performed by others. The mirror neuron system has 

been implicated in the underlying mechanism for social 

cognition and appears to provide the anatomic basis for 

understanding the actions and intentions of others. 20 

Activity of mirror neurons has been found in the premotor 

cortex, supplementary motor area, primary somatosensory 

cortex and inferior parietal cortex. Most consistently 

reported to be activated during imitation, actions observation 

and intention understanding is the pars opercularis in the 

inferior frontal gyrus. During the imitation of emotional 

expressions, bilateral activation of striate and extra striate 

cortices, primary motor and premotor regions, limbic 

structures, the cerebellum and pars opercularis has been seen. 

It was also found that the greater the activity in the pars 

opercularis in children during imitation of facial expression 

as determined by fMRI, the higher the child’s level of 

functioning as determined by ADOS (autism diagnostic 

observation schedule) and ADI-R (autism diagnostic 

interview-revised) testing. 20 

One of the most important cognitive skills for social 

interaction is the ability to attribute mental states to self and 

others referred to as “theory of mind” or the ability to look at 

a situation from another person’s perspective. Evidence 

from fMRI studies investigating theory of mind tasks in 

control subjects has shown activation in a network consisting 

of the amygdala, the medial prefrontal cortex, the cingulate 

cortex, extra-striate cortex and the temporo-parietal junction 2 

Additionally, the brain areas that have been implicated in the 

three areas of core behaviors noted in children with autism 

have been identified. Regions implicated in social behavior 

include the frontal lobe, superior temporal cortex, parietal 

cortex and the amygdala. 2 Language function has been 

identified in the inferior frontal gyrus (Broca’s area), 

supplementary motor cortex and superior temporal sulcus 

(Wernicke’s area). Repetitive behaviors have been found to 

originate in the orbitofrontal cortex and the caudate nucleus. 2 

(Table 1.) Patients with autism fail to activate the amygdala 

normally when processing emotional facial and eye 

expressions. Also, the fusiform face area is activated less in 

subjects with autism compared with control subjects during 

face perception tasks in fMRI studies. 21 A recent study 

determined that there was decreased neural synchronization 

in sleeping autistic patients using fMRI techniques. This 

disruption of neural synchronization during sleep may be 

generated by abnormal anatomical connectivity, synaptic 

function, local neural network or abnormal 

excitation/inhibition balance. These abnormalities in 

interhemispheric synchronization were seen significantly in 

the inferior frontal gyrus and superior temporal gyrus which 

was not seen in either controls or patients with language 

delay. 22 

Table 1. Brain Regions implicated in the three defining 

features of autism. 

Autistic Feature 

Social Interaction 

Brain Regions 

Frontal Lobe 

Superior Temporal Cortex 

Parietal Cortex 

Amygdala 

Language Function Inferior Frontal Gyrus 

(Broca’s Area) 

Supplementary Motor Cortex 

Superior Temporal Sulcus 

(Wernicke’s Area) 

Repetitive Behaviors 

Orbitofrontal Cortex 

Caudate Nucleus 

While many techniques including fMRI, magnetoencephalography 

and PET (positron emission tomography) scanning 

have elucidated functional connectivity differences between 

the autistic and typically developing populations, structural 

connectivity between gray matter areas associated with 

intermediating white matter tracts are best evaluated with 

DTI. DTI is an MRI based technique that measures the


directional diffusion profile of water molecules which 

manifests the axonal architecture of the brain at the 

micrometer level. Fractional anisotropy and mean diffusivity 

provide an index for the integrity of neural tissue. DTI has 

been shown to be a sensitive measure of white matter 

maturation. Abnormalities in myelination, axonal number, 

diameter and orientation can all lead to changes in fractional 

anisotropy and apparent diffusion coefficient. 23,24 While 

several imaging studies discuss abnormal neural connectivity 

between grey matter areas, many DTI studies have shown 

decreased fractional anisotropy and thus directionality of the 

white matter microstructural architecture in the frontal white 

matter, temporal white matter, corpus callosum, superior 

temporal gyrus and cerebellum in the autism population. 25 

HISTOPATHOLOGY 

Minicolumns are composed of radially oriented arrays of 

pyramidal neurons (layers II-VI), interneurons (layers I-VI) 

axons and dendrites. Minicolumns have been hypothesized 

to be the smallest radial unit of information processing in the 

cortex. They organize neurons in cortical space. 

Minicolumn formation has been associated with early stages 

of cortical development when post-mitotic neurons migrate in 

linear arrays along radial glial scaffolding. Therefore, 

changes based on circuitry may affect this unit of cortical 

structure. 26 As the brain develops there is an almost 1,000 

fold increase in cortical surface which likely stems from an 

increase in number of ontogenetic cell columns. Although in 

autism while an increase in processing units occur in the 

developing brain, normal selective pruning may not occur. 

Therefore they may experience a chronic state of overarousal 

and exhibit behaviors in order to diminish this 

arousal. Within the first year of life, there is a dramatic 

increase in dendritic growth and by three years of age, the 

minicolumns are spaced farther apart with a lower cell 

density. In autism, minicolumns have been reported to be 

increased in number and narrower in width with reduced 

neuropil space with smaller neuron cell bodies and nucleoli. 

These abnormalities have been observed bilaterally in the 

primary somatosensory cortex, primary motor cortex, 

dorsolateral prefrontal cortex, primary visual cortex, middle 

temporal gyrus and superior temporal gyrus. This narrowing 

of the minicolumns which was related to a reduction in 

neuropil space occupied by unmyelinated projections of 

gamma-aminobutyric acid (GABA) interneurons led to the 

hypotheses of a deficit of cortical inhibition, giving rise to 

increased seizure susceptibility. This phenomenon is 

postulated to explain the increased prevalence of seizures, 

sensory sensitivities and bias towards low level perceptual 

processing. 27 

MITOCHONDRIAL DISORDERS 

Due to the critical role the mitochondria have in muscle, 

brain and nerve tissue, mitochondrial dysfunction results in 

disorders that have characteristics of poor growth and muscle 

coordination, weakness and often neurodegeneration and 

neuropathies. The mitochondria converts food molecules into 

adenosine triphosphate (ATP) giving the cell energy for 

routine functions. Disorders in mitochondrial function are 

caused by mutations in mitochondrial DNA or nuclear genes 

that code for mitochondrial components. Increasingly, 

mitochondrial disorders are being associated with autism 

spectrum disorders. Mitochondrial dysfunction has also been 

seen more commonly in childhood epilepsy including those 

associated with autism. 28 While an elevated lactate level in 

children with confirmed autism was found in 20.3%, 

mitochondrial respiratory chain dysfunction as determined by 

muscle biopsy was seen in rates of approximately 7.2%. 29 A 

study comparing lymphocytic mitochondria of autistic 

children to controls found that there were abnormalities in 

low PDHC (Pyruvate Dehydrogenase Complex) activity 

accompanied by low lactate to pyruvate ratios, impaired 

complex I alone or in combination with other complexes, 

enhanced mitochondrial rate of hydrogen peroxide 

production and mtDNA over-replication and/or deletions. 30 

While a causal role cannot be determined, it is conceivable 

that mitochondrial dysfunction may propagate brain 

dysfunction given the high energy demand of brain tissue. 29 

In summary, new developments continue to characterize 

autism as a neurobiologically based disorder of aberrant 

connectivity. Observations are supported where the more 

severe disorders of connectivity occur in those with seizures. 

Whether the more affected individuals have more disrupted 

circuitry as a result of genetic susceptibility, environmental 

factors or abnormal energy metabolism or epileptiform 

discharges propagate the dysfunction of the synaptic 

connections remains unclear. The quest to unearth the 

multifaceted and multilayered etiology and phenotype of 

autism lies in the wealth of present and future studies and 

perhaps will afford us with the mechanism of a hidden final 

common pathway resulting in this disorder. 

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Review 

Synaptic Dysfunction Attributes 

to Autism Spectrum Disorder 


ABSTRACT 

Autism spectrum disorders (ASD) are a range of high 

prevalent disorders that can be characterized as a 

syndrome of social communication deficits, repetitive 

behavior or restrictive interest. Rapid advance beyond 

environmental influence is made through identifications 

of associated genetic variations. Emerging evidence from 

human and animal models demonstrate impairment in 

synaptic function is an etiology of ASD. This review 

focuses on several synaptic proteins that are mutated in 

some patients and their autistic behaviors and cognitive 

deficits are recapitulated in animal models. 

[N A J Med Sci. 2011;4(3):112-115.] 

KEY WORDS: ASD, synapse, mutation, neurexin, 

neuroligin and SHANK. 

Introduction 

Autism, Asperger's syndrome and other related conditions 

comprise autism spectrum disorder (ASD). ASD is a 

developmental brain disorder and the disease may slightly 

differ in individual symptoms, but all share characteristic 

problems in personal and social communications, stereotyped 

and repetitive behaviors and narrowed interest. Autism itself 

is usually associated with language and intelligence deficits. 

ASD is reported to have a high prevalence rate. A study in 

the general Korean population showed a prevalence of 3.74% 

in males and 1.74% in females, 1 whereas Central for Disease 

Control reported in 2006 the average prevalence for ASD in 

the USA is 1 in 110 (http://www.cdc.gov/mmwr/preview/- 

mmwrhtml/ss5810a1.htm). Monozygotic twin studies have 

demonstrated greater than 90% of genetic heritability for 

ASDs. 2,3 This gives a very strong genetic inheritance over the 

environmental effect on the disease etiology. ASD is mostly 

diagnosed between two to three years age, a period that 


(Corresponding Author) 

Yougen Zhan, MD, PhD 

Department of Medicine, Brigham and Women’s Hospital, 

Harvard Medical School, Boston, MA 02115 

Email: ygzhan@gmail.com 


Department of Medicine, Beth Israel Medical Center, 

Harvard Medical School, Boston, MA 02115 

human brain undergoes active remodeling and 

synaptogenesis. Recent advance in this field has pointed 

synaptic dysfunction as one of etiology of ASD. This review 

will briefly describe these mutations found in synaptic 

component proteins and the associated dysfunctions in the 

synapse. 

PATHOLOGY IN DEVELOPMENTAL BRAIN 

Most brain disorders have their characteristic brain 

pathology. For instance, Alzheimer’s disease is associated 

with neurofibrillary tangles and amyloid plaques. Muscle eye 

brain disease and Walker-Warburg syndrome have 

malformation of brain and neuronal migration defects. 4,5 The 

structural abnormalities in ASD brains were revealed by 

magnetic resonance imaging (MRI) studies, which showed an 

increased brain volume with a peak around 2-4 years of 

age, 6,7 followed by a decreased volume at adolescence. 

Increased cortical thickness was found throughout the brain 

at 2-4 years of age. 8 As we know that some neurons and 

primitive neural circuitries are normally eliminated during 

the afterbirth period due to synaptic competitions. This failed 

elimination in ASD patients was found to form atypical 

connections and result in abnormal function in functional 

MRI studies. 9,10 These atypical neural connections may link 

to the abnormal social communications and repetitive 

behavior in ASD. At least, there is evidence showing 

increased dendritic spines in this area of brain. 11 However, 

some questions remain unknown, for example, what atypical 

neural circuitries are developed during this period and 

whether there is any neuronal migration defect. 

ETIOLOGY OF ASDS REFLECTS SYNAPTIC 

DYSFUNCTIONS 

Perhaps the most exciting discoveries made in recent years 

are identifications of genetic mutations and genomic deletion 

associated with ASDs. Over 100 gene mutations or genomic 

deletions have been identified. 12 Of them, many synaptic 

gene mutations have been found. Synapse is the fundamental 

unit of our brain, where external information is processed, 

amplified and consolidated. It’s conceivable that abnormal 

synaptic functions are found in diseases such as ASD, Rett 

syndrome, schizophrenia and many other 

neurological/psychological disorders and cognitive 

dysfunctions. Many synaptic proteins are found to have 

mutations in ASD, which includes neurexin, 13-15 

neuroligins, 16-18 voltage calcium channels, 19 cadherin 20,21 and 

SHANK3. 22,23


have not been reconstituted in animal models for these 

neurexin mutations. 

Figure 1. This figure illustrates a synapse within which 

synaptic components were mutated in some of autistic 

patients. Neurexin, neuroligin, SHANK, cadherin and L-type 

calcium channel are all found to bear mutations in some 

patients. At the synapses, neurexin form trans-synaptic 

linkage which link CASK to postsynaptic SHANK (including 

SHANK1, 2, 3) and actin. Cadherin forms homophilic transsynaptic 

linkage which connects to intracellular catenin. 

Glutamate receptors are clustered in the postsynaptic 

membrane and are inserted in PSD-95 formed postsynaptic 

scaffolding structures. 

NEUREXIN AND NEUROLIGIN 

Neurexin is a pre-synaptic transmembrane adhesion 

molecule, and is connected to postsynaptic membrane 

through an interaction with neuroligin. Neurexin also 

connects to CASK intracellularly in the presynaptic terminus 

whereas neuroligin interacts with PSD95 in the postsynaptic 

density (Figure 1). 24 This normal linkage between pre- and 

post-synapse is crucial to drive normal pre- and post-synaptic 

24, 25 

differentiation and maturation in both excitatory and 

inhibitory synapses. In animal models, neurexinshow 

impaired presynaptic voltage-gated calcium channel 

function, and, thus, suppressed calcium-mediated presynaptic 

vesicle release. 26 Analysis in single nucleotide 

polymorphism (SNP) array in 1200 families identifies two 

individuals with ASD having deletion in neurexin gene. 27 

Subsequent studies also identified other neurexin deletions 

and chromosomal abnormalities in neurexin gene in ASD 

patients. 15,28 Most recently, missense mutations in a neurexin 

family protein CNTNAP2 have also been linked to ASD. 29 

However, the autistic behavior and cognitive dysfunction 

Neuroligin is a postsynaptic cell adhesion molecule that 

promotes both pre- and post-synaptic formations. Five genes 

encode different neuroligin proteins, and three or more of 

which are mutated in autism or Asperger syndrome 16, 18 . 

Autism mutations of neuroligin decrease its accumulation in 

postsynaptic membrane and reduce its binding affinity with 

neurexin. 30-32 Numerous experiments have demonstrated the 

critical importance of neurexin-neuroligin linkage. Targeted 

deletion of either neurexin gene 26 or neuroligin gene 33 in 

mice causes synaptic transmission defects. Especially, in 

neuroligin knock-out mice, the aggregation and recruitment 

of glutamatergic, GABAergic and glycinergic receptor to the 

postsynaptic membrane are altered. 33 Very interestingly, 

mutations of neuroligin in ASD patients are recapitulated in 

animal models. R451C knock-in mice, which reconstitute the 

human ASD neuroligin mutation in mice, have an enhanced 

inhibitory synaptic transmission and inhibited social 

communication. 34 Moreover, in Aplysia, deletion of 

neuroligin abolishes the long term facilitation, and R451C 

mutation causes reduced long term synaptic facilitation, 35 

implicating an impaired memory formation in ASD. Taken 

together, these studies in human and mice strongly locate 

ASD to the impaired function of neurexin and neuroligin. 

SHANK 

SHANK is a postsynaptic scaffolding protein localized in the 

postsynaptic density (Figure 1), which binds directly or 

indirectly with neuroligin. SHANK forms a huge protein 

complex with PSD95 and SAPAP between glutamate 

receptors and actin cytoskeletion (Figure 1), 36 and serves as 

a regulator of dendritic spine morphology. 37 There are three 

subtypes of SHANK including SHANK1,2,3. Overexpression 

of SHANK3 in cultured neurons promotes 

maturation and enlargement of dendritic spines whereas 

knock-down of SHANK3 leads to decreased spine 

formation. 37,38 The first evidence of involvement of SHANK3 

in speech and intellectual deficits comes from chromosomal 

translocation in 22q13.3 that disrupts SHANK3 gene 39 . 

Subsequent analysis demonstrated in some individuals with 

autistic behaviors that SHANK3 gene is disrupted by microinsertions 

within intron 8, 39 de novo mutations and two 

deletions. 40 In addition, deletions and stop mutation in 

SHANK2 gene were also found in ASD patients. 41 In a recent 

mouse model, targeted deletion of SHANK3 gene leads to 

reduced dendritic spines, abnormal postsynaptic structure and 

reduced synaptic transmission. 42 Most importantly, these 

mice demonstrated autistic behaviors with repetitive 

grooming and reduced social interactions. 42 These studies 

fully establish that disruption in normal SHANK3 function 

can be the etiology of ASD. 

OTHER SYNAPTIC PROTEINS 

In synapses, L-type voltage gated calcium channels and 

cadherin are also associated with ASD. L-type calcium 

channel mutation G406R is found in cardio-myocytes with


Timothy syndrome, and these patients also show ASD 

phenotype. 19 Because this channel is also found in neuronal 

dendritic spines and shafts, studies have shown this type of 

calcium channel is a regulator of post-synaptic long-term 

potentiation and synaptic plasticity. 43 Cadherins forms 

homophilic interactions in synaptic clefts to link the pre- and 

post-synapses (Figure 1). They promote synaptic 

differentiation and maturation, and synaptic plasticity. 44 

Mutations or chromosomal abnormalities in cadherin 9, 

cadherin 10 and cadherin 15 genes are found in individuals 

with ASD. 17,20,45 These mutations destabilize cell-cell 

connections and impair normal differentiation of synapses, 

thus, leads to autistic behaviors. 

ASD also exists as a comorbid disease with Rett syndrome 

and tuberous sclerosis. Rett syndrome is caused by 

mutations in MECP2 gene, a transcriptional regulator. 

Targeted deletion of MECP2 gene in GABA-releasing 

neurons leads to reduced inhibitory synaptic vesicle release 

and demonstrates many characteristics of Rett syndrome and 

autistic repetitive behavior. 46 Tuberous sclerosis is caused by 

mutations in tumor suppressor gene TSC1/TSC2. Data show 

that, of the 103 patients with tuberous sclerosis, 40% were 

diagnosed with an ASD. 47 Tuberous sclerosis forms 

abnormal tubers in brain, but target deletion of TSC1and 

TSC2 shows abnormal dendritic spines and altered shape and 

size of neurons. 48 This suggests tubers in brain might not be 

the cause of autistic behavior but the abnormal morphology 

of neuron and altered synaptic connections shall be counted 

as reason for autistic features in tuberous sclerosis. 

CONCLUSION 

In the past several years, researchers have identified a 

number of synaptic proteins mutated in autistic individuals. 

These proteins are functional components of normal 

synapses. They are either involved in synaptic maturation, 

synaptic vesicle release, or synaptic stabilization. Most 

importantly, the typical autistic behavior defects have been 

recapitulated in animal models that bear these mutations, 

which confirm the synaptic origin of ASD. The clustering of 

synaptic genes in ASD may be specific to this disease, but, 

please keep in mind that over 100 genetic abnormalities were 

found to give autistic features, only handful are synaptic 

component proteins or directly involved in synaptic 

transmission. Moreover, ASD is not merely a single gene 

disease, multiple gene mutations can be found in one autistic 

individual. 49 Further mechanistic studies in ASD will reveal 

the common pathway for the disease genesis and provide 

potential therapeutic strategies to the patients. 

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May 25. [Epub]


Original Research 

A Pilot Study on the Diagnostic Performance of DMS-IV 

and DMS-V for Autism Spectrum Disorder 

Yang You, MD, Bai-Lin Wu, PhD, Yiping Shen, PhD 

ABSTRACT 

The new diagnostic criteria for autism spectrum 

disorders (ASD) are due to be released in May 2013. The 

impact of changes made in the new criteria is yet to be 

evaluated. Here we performed a retrospective study on a 

cohort of ASD patients diagnosed by DSM-IV criteria, 

aimed to compare the diagnostic performances between 

DSM-IV and DSM-V. We reviewed the medical records 

of 163 patients with possible clinical diagnosis of ASD. 

Ninty-three (57%) of them met the DSM-IV criteria for 

Autistic disorder, the rest 70 cases were either PDD-NOS 

(n=39) or Asperger’s disorder (n=3) or without sufficient 

information in medical record to perform a clinical 

diagnosis (n=28). Upon re-evaluation using the new 

diagnostic criteria in DSM-V, only 60% of patients with 

previous diagnosis of autistic disorder met the new 

criteria. One individual who was previous diagnosed as 

PDD-NOS met the new diagnostic criteria for autistic 

disorder. The present study revealed a significant 

difference in diagnostic yield by new and old criteria. 

This pilot comparative study reveals that the ASD 

diagnostic criteria in DSM-V are stricter than that in 

DSM-IV and autism patients diagnosed using DMS-V 

criteria tend to be more severely affected. The new 

criteria will have immediate impact on the clinical 

diagnosis and management of individuals with 

neuodevelopmental disorders and it will affect the 

prevalence estimate of ASD in population as well. 

[N A J Med Sci. 2011;4(3):116-123.] 

KEY WORDS: autism spectrum disorder, autistic disorder, 

PDD-NOS, DSM-IV, DSM-V 


Yang You, MD, 1,2 Bai-Lin Wu, PhD, 1,3 Yiping Shen, 

PhD 1,2 

1. Departments of Laboratory Medicine and Pathology, 

Children's Hospital Boston, Harvard Medical School, Boston, 

MA 02115 

2. Department of Child Development and Behavior, Shanghai 

Children’s Medical Center, Shanghai Jiaotong University 

School of Medicine, Shanghai, China, 200127 

3. Children's Hospital and Institutes of Biomedical Science, 

Fudan University, Shanghai, China, 200032 


Yiping Shen, PhD 

Email: yiping.shen@childrens.harvard.edu 

INTRODUCTION 

Autism spectrum disorders are a group of clinically 

diagnosed neurodevelopmental disorders who share a set of 

complex behavioral phenotype involving difficulties in 

communication and reciprocal social interaction, as well as 

stereotypic repetitive behavior and unusually narrow 

interest. 1 The current clinical diagnostic criteria were 

delineated in the Diagnostic and Statistical Manual of Mental 

Disorders, 4th. Edition, better known as the DSM-IV, 

published by the American Psychiatric Association in 1994 

(text revision in 2000). 2 Based on DSM-IV, autism spectrum 

disorder (ASD) refers to three categorical groups: autistic 

disorder, Asperger’s disorder (AS) and pervasive 

developmental disorder - not otherwise specified (PDD- 

NOS). By DSM-IV criteria, patients with autistic disorder 

exhibits common characteristics such as severe difficulty in 

relations and communication associated with deficit in 

regulating sensory, attention, cognitive, motor and affective 

processes, with onset before age 3. The diagnostic criteria 

include qualitative impairment in social interaction, 

qualitative impairment in communication and restricted, 

repetitive and stereotyped patterns of behavior, interests and 

activities. AS patients are distinct from autistic disorder by 

their relatively normal language and cognitive development 

but involves all other diagnostic criteria in DSM-IV. 2,3 PDD- 

NOS are referred to as atypical PDD or atypical autism for 

children who do not meet full criteria in all three diagnostic 

domains. This group includes children with milder symptoms 

in all three diagnostic domains and those meeting full criteria 

for autism in two of the three domains. Sometimes PDD- 

NOS is used as an initial or tentative diagnosis for younger 

children or before diagnostic evaluations are completed. 3 The 

lack of clear definitions for this relatively heterogeneous 

group of children presents problems for research on this 

condition as well as for patient care. The DSM-IV had been 

criticized for relaxed criteria that may have lead to the 

widening of ASD diagnosis. 

The draft DSM-V has been published recently. 4 In the 

proposed revision, there are only two domains as opposed to 

the three domains in DSM-IV (see the appendix 1 for details 

of the diagnostic criteria of both DSM-IV and DSM-V). The 

two domains are: 1) social/communication deficits, 2) fixated 

interests and repetitive behaviors. Unusual sensory behaviors 

are included within a subdomain of stereotyped motor and 

verbal behaviors with examples particularly relevant for 

younger children. In DSM-V, Asperger’s disorder will be 

subsumed into an existing disorder: autism spectrum 

disorder.


The changes made in DSM-V are quite substantial. It is not 

known if this revision will have significant impact in the 

clinical diagnosis of patients with suspected ASD and how 

the new criteria will affect the ASD prevalence in the 

population level. Here we performed a retrospective pilot 

study to compare the diagnostic performance of DSM-V with 

that of DSM-IV. 

PATIENTS AND METHODS 

Subject and Data Collection 

We reviewed the medical records of 163 patients with 

suspected ASD diagnosis at the Department of 

Developmental Medicine in Children’s Hospital Boston. A 

standard coding system including information of initial and 

follow-up evaluation was used to score each individual using 

both DSM-IV and DSM-V diagnostic criteria (see appendix 

2). The clinical characteristics of the cohort are as following: 

80% of the cases were boys and 20% were girls (M:F=4:1); 

the average age was 2 years and 10 months at their initial 

diagnosis of ASD (range from 18 months to 56 months, 

SD=10.4 months). All patients underwent ASD clinical (by 

DSM-IV) and neurological evaluation, as well as play 

observation. Two thirds of patients also underwent 

psychological, MRI and EEG evaluations. About half of the 

patients had metabolic evaluation (thyroid function (43%), 

plasma amino acids/plasma and urine organic acids (53%)). 

Regarding genetic evaluation, the majority of patients had 

chromosomal microarray analysis (94%), 44% had G- 

banding karyotyping, 38% had Fragile X testing, and 20% 

had MECP2 testing. 

Statistical Analysis 

Subject characteristics were described according to study 

group (cases met the criteria or not by DSM-IV or DSM-V) 

and compared by using χ 2 tests. Association of items in 

DSM-IV with the positive diagnosis of autistic disorder by 

DSM-V was estimated using unconditional logistic 

regression. All p-values are two-sided, and all analyses were 

carried out using SPSS software packages (version 11, SPSS, 

USA). 

The study is approved by the internal review board of 

Children’s Hospital Boston. 

Table 1. Results of physical examination and clinical evaluation by DSM-IV and DSM-V. 

DSM-IV 

Cases (%) 

DSM-V 

Cases (%) 

70 cases did not meet 

Variables 

93 cases met the 

57 cases met the 

the diagnosis of 

diagnosis of autistic 

diagnosis of autistic 

autistic disorder by 

disorder by DSM-IV 

disorder by DSM-V 

DSM-IV 

ID/MR 45(48.39) 27(38.57) 28(49.12) 44(41.51) 

Seizures 37(39.78) 23(32.86) 22(38.59) 38(35.84) 

Positive family history 51(54.84) 26(37.14) 33(57.89) 44(41.51) 

ASD 20(21.51) 8(11.43) 12(21.05) 16(15.09) 

ID/MR, learning disability, 20(21.51) 14(20.00) 15(26.32) 19(17.92) 

language delay 

Mood problem 11(11.83) 4(5.71) 7(12.28) 8(7.55) 

Hypotonia 29(31.18) 18(25.71) 19(33.33) 28(26.42) 

Hypertonia 10(10.75) 3(4.29) 5(8.77) 8(7.55) 

Macrocephaly 15(16.13) 11(15.71) 9(15.79) 17(16.04) 

Microcephaly 9(9.68) 7(10.00) 8(14.04) 8(7.55) 

106 cases did not meet 

the diagnosis of autistic 

disorder by DSM-V 

RESULTS 

Characteristics of participants by DSM-IV and DSM-V 

Table 1 listed all patients in the cohort, their physical 

examination and clinical evaluation by both DSM-IV and 

DSM-V. As a result, 93 out of 163 cases met the DSM-IV 

criteria for autistic disorder. 48% of patients had intellectual 

disability/mental retardation (ID/MR) and 40% had seizure; 

55% of patients had positive family history of ASD (22%), 

ID/MR, learning disability, language delay (22%) or mood 

problem (12%). Of the 163 cases, 70 patients did not meet 

the DSM-IV criteria for autistic disorder. Among them, 39% 

had ID/MR and 33% had seizure; 37% of patients had 

positive family history of ASD (11%), ID/MR, learning 

disability, language delay (20%) or mood problem (6%). 

Also detailed results of physical examination and clinical 

evaluation by DSM-V are shown in Table 1. There is no 

statistically significant difference in physical examination 

and clinical evaluation between two groups classified by 

DSM-IV or DSM-V. 

Items Comparison between Two Groups By DSM-V 

We found a significant ASD diagnostic difference between 

DSM-IV and DSM-V criteria. Among the 93 patients who 

met the diagnostic criteria by DSM-IV, there are only 56


individuals that also met the diagnostic criteria by DSM-V. 

The concordant rate between the two criteria is about 60%. In 

order to identify the cause of such significant difference, we 

examined the presence or absence of each diagnostic item in 

DSM-V for every patient. The results are showing in Table 

2. By definition, all autistic disorder patients have to meet all 

three items in domain A, thus their positive rate are 100%; 

for domain B items, B1 has the highest positive rate (98%) 

and B2 has the lowest positive rate (32%) in patients with 

autistic disorder. The items that contributed significantly to 

the difference of diagnostic yield are A2, A3, B2, B3 and B4 

(P≤0.001). 

We further performed logistic regression analysis for the 93 

cases with diagnostic items in the three domains of DSM-IV. 

In Table 3, the item C1 (stereotypic and restricted interest) of 

DSM-IV showed statistically significant association 

(OR=12.97, 95%CI: 2.76-60.89) with the positive diagnosis 

of autistic disorder by the new criteria. The item C 2 

(inflexible to routine) appears to have the least predictive 

power in DSM-IV for positive diagnosis by DSM-V. 

In addition, there is one PDD-NOS patient by DSM-IV met 

the diagnosis of autistic disorder by DSM-V (patient # 67 in 

Appendix 2). 

Table 2. Comparison of positive rates of items between two groups classified by DSM-V. 

Items 

DSM-V 

in 

56 cases met the diagnosis of 

autistic disorder by DSM-V 

37 cases did not meet the 

diagnosis of autistic disorder 

by DSM-V 

YES NO YES NO YES NO 

70 cases did not meet the 

diagnosis of autistic disorder 

by DSM-IV χ 2 * P-value 

A1 56 0 35 2 25 45 1.06 0.3037 

A2 56 0 27 10 19 51 14.26 0.0004 

A3 56 0 29 8 24 46 10.64 0.0011 

B1 55 1 37 0 30 40 0.04 0.8338 

B2 18 38 0 37 2 68 12.76 0.0004 

B3 32 24 4 33 4 66 18.25 0.0001 

B4 42 14 4 33 15 55 34.2 0.0001 

Chi square tests were between the group of 56 cases who met the diagnosis of autistic disorder by DSM-V and the group of 37 cases who did not 

meet the diagnosis of autistic disorder by DSM-V 

Table 3. Logistical regression coefficients and their standard errors (S.E) for items in DSM-IV and autistic disorders by DSM-V. 

Items in DSM-IV Correlation coefficient S.E. OR(95% CI) P-value 

A1 0.18 0.32 1.19(0.64-2.22) 0.580 

A2 0.32 0.43 1.37(0.59-3.20) 0.465 

A3 0.49 0.88 1.64(0.29-9.20) 0.575 

A4 0.51 0.37 0.60(0.29-1.25) 0.175 

B1 0.63 0.42 1.87(0.82-4.25) 0.135 

B2 0.12 0.59 0.88(0.28-2.83) 0.835 

B3 0.25 0.58 0.78(0.25-2.45) 0.672 

B4 0.13 0.41 1.14(0.51-2.56) 0.757 

C1 2.56 0.79 12.97(2.76-60.89) 0.001 

C2 21.56 8.14E+03 2.30E+09(0.00-.) 0.998 

C3 0.43 0.43 1.54(0.67-3.58) 0.310 

C4 1.60 1.15 4.94(0.52-47.29) 0.166 

Constant 1.73 1.14 0.18 0.129 

DISCUSSION 

It is known to the autism research and clinical community 

that DSM-IV has limitations when it applies to children with 

ASD. There has been a lot of criticisms regarding the ASD 

diagnostic criteria in DSM-IV. 5 In particular, the PDD-NOS 

subgroup is not well defined in terms of what should be 

excluded from their definition, and the distinction between 

Childhood Autism and PDD-NOS in terms of functioning is


unclear. Sometimes PDD-NOS is used as a tentative 

diagnosis for young children, this practice may have lead to 

the widening of ASD diagnosis.Newly published DSM-V 

reduced three domains to two and three subgroups of PDD in 

DSM-IV were combined to one: no more PDD-NOS and 

Asperger diagnosis by DSM-V. While the new criteria is 

aimed to remedy the deficit existed in the old criteria, and 

their performance in real clinical practice are yet to be 

systematically evaluated. This pilot study used a cohort of 

patients with prior ASD diagnosis by DSM-IV. The 

preliminary results showed that there are significant 

differences in diagnostic yield using the old and new criteria. 

Generally, ASD patients diagnosed by DSM-V have more 

symptoms on all three domains compared to those by DSM- 

IV (Table 2). DSM-V criteria tend to be stricter since only 

60% of children with autistic disorder diagnosed by DSM-IV 

met the criteria of DSM-V. Almost all patients, except one, 

with PDD-NOS no longer meet the diagnostic criteria of 

DSM-V. Overall, the adjustment made in the new diagnostic 

criteria may be responsible for such difference. In DSM-V, 

12 items in all of three domains were reduced to 7. Language 

related items were reduced to a part of item 1 in B domain. 

Six positive items required by DSM-IV were reduced to five 

in DSM-V. In the social/communication domain, all three 

items must be met in DSM-V while in DSM-IV only 2 of 4 

items need to be met. In the domain of fixated interests and 

repetitive behaviors, 2 of 4 items in DSM-V and 1 of 4 items 

in DSM-IV are needed. It seems that DSM-V has less 

selection and thus, is stricter than DSM-IV. It also suggests 

that the new criteria place more focus on the 

social/communication, fixated interests and repetitive 

behaviors aspects of the clinical manifestation. The language 

function on the other hand is less emphasized. Emphasizing 

language deficit by DSM-IV may account for higher 

prevalence of ASD diagnosis when using DSM-IV. Based on 

the positive rate comparison between the two groups of 

patients in Table 2 (ASD patients still met the diagnostic 

criteria by DSM-V and those did not meet the new diagnostic 

criteria), it showed that the majority of patients in both 

groups have very high positive rate for the item 1 in A 

domain (social-emotional reciprocity) and the item 1 in B 

domain (stereotypic repetitive behavior) of DSM-V. These 

are essential features of patients with ASD but insufficient 

for the new diagnostic criteria. The item 2, 3 in A domain 

and the item 2, 3, 4 in B domain of DSM-V are the ones that 

differentiate patients in this cohort whether or not meet the 

new diagnostic criteria. Consistent with the previous study, 6 

these items that showed significant differences (P


Appendix 1. Diagnostic criteria of DSM-IV for autistic disorder and draft DSM-V for ASD. 

DSM-IV diagnostic criteria for autistic disorder: 

I. A total of six (or more) items from (A), (B), and (C), with at least 

two from (A), and one each from (B) and (C) 

II. 

(A) Qualitative impairment in social interaction, as manifested by 

at least two of the following: 

1. marked impairments in the use of multiple nonverbal 

behaviors such as eye-to-eye gaze, facial expression, body 

posture, and gestures to regulate social interaction; 

2. failure to develop peer relationships appropriate to 

developmental level; 

3. a lack of spontaneous seeking to share enjoyment, interests, 

or achievements with other people, (e.g., by a lack of showing, 

bringing, or pointing out objects of interest to other people); 

4. lack of social or emotional reciprocity ( note: in the 

description, it gives the following as examples: not actively 

participating in simple social play or games, preferring solitary 

activities, or involving others in activities only as tools or 

"mechanical" aids ). 

(B) Qualitative impairments in communication as manifested by at 

least one of the following: 

1. delay in, or total lack of, the development of spoken 

language (not accompanied by an attempt to compensate 

through alternative modes of communication such as gesture 

or mime); 

2. in individuals with adequate speech, marked impairment in 

the ability to initiate or sustain a conversation; with others 

3. stereotyped and repetitive use of language or idiosyncratic 

language; 

4. lack of varied, spontaneous make-believe play or social 

imitative play appropriate to developmental level. 

(C) Restricted repetitive and stereotyped patterns of behavior, 

interests and activities, as manifested by at least one of the 

following: 

1. encompassing preoccupation with one or more stereotyped 

and restricted patterns of interest that is abnormal either in 

intensity or focus; 

2. apparently inflexible adherence to specific, nonfunctional 

routines or rituals; 

3. stereotyped and repetitive motor mannerisms (e.g hand or 

finger flapping or twisting, or complex whole-body; 

movements) 

4. persistent preoccupation with parts of objects. 

Delays or abnormal functioning in at least one of the following 

areas, with onset prior to age 3 years: (A) social interaction, (B) 

language as used in social communication, (C) symbolic or 

imaginative play 

Draft DSM-V diagnostic criteria for ASD: 

Must meet criteria A, B, C, and D: 

A. Persistent deficits in social communication and social interaction 

across contexts, not accounted for by general developmental delays, 

and manifest by all 3 of the following: 

1. Deficits in social-emotional reciprocity; ranging from abnormal 

social approach and failure of normal back and forth 

conversation through reduced sharing of interests, emotions, and 

affect and response to total lack of initiation of social 

interaction, 

2. Deficits in nonverbal communicative behaviors used for social 

interaction; ranging from poorly integrated- verbal and 

nonverbal communication, through abnormalities in eye contact 

and body-language, or deficits in understanding and use of 

nonverbal communication, to total lack of facial expression or 

gestures. 

3. Deficits in developing and maintaining relationships, 

appropriate to developmental level (beyond those with 

caregivers); ranging from difficulties adjusting behavior to suit 

different social contexts through difficulties in sharing 

imaginative play and in making friends to an apparent absence 

of interest in people 

B. Restricted, repetitive patterns of behavior, interests, or activities as 

manifested by at least two of the following: 

1. Stereotyped or repetitive speech, motor movements, or use of 

objects; (such as simple motor stereotypies, echolalia, 

repetitive use of objects, or idiosyncratic phrases). 

2. Excessive adherence to routines, ritualized patterns of verbal 

or nonverbal behavior, or excessive resistance to change; (such 

as motoric rituals, insistence on same route or food, repetitive 

questioning or extreme distress at small changes). 

3. Highly restricted, fixated interests that are abnormal in 

intensity or focus; (such as strong attachment to or 

preoccupation with unusual objects, excessively circumscribed 

or perseverative interests). 

4. Hyper-or hypo-reactivity to sensory input or unusual interest 

in sensory aspects of environment; (such as apparent 

indifference to pain/heat/cold, adverse response to specific 

sounds or textures, excessive smelling or touching of objects, 

fascination with lights or spinning objects). 

C. Symptoms must be present in early childhood (but may not become 

fully manifest until social demands exceed limited capacities) 

D. Symptoms together limit and impair everyday functioning.


Appendix 2. Patients with ASD classified by DSM-IV and draft DSM-V respectively. 

Cases DSM-IV DSM-V 

12 items in three domains 

A 

1 

A 

2 

A 

3 

A 

4 

B 

1 

B 

2 

B 

3 

B 

4 

C 

1 

C 

2 

C 

3 

C 

4 

Diagnosis 

(case number) 

AD AS 

(93) (3) 

PDD-NOS 

(39) 

7 items in two domains 

1 1 0 0 1 1 1 1 0 0 0 1 0 1 0 0 1 1 0 1 0 0 0 0 

2 0 0 0 1 0 1 0 0 0 0 0 0 0 0 0 1 0 1 0 0 0 0 0 

3 0 0 0 1 1 1 1 0 0 0 1 0 1 0 0 1 0 1 1 0 0 0 0 

4 1 1 1 1 1 1 1 1 0 0 1 0 1 0 0 1 1 1 1 0 0 0 0 

5 1 0 0 1 0 1 1 0 0 0 1 0 1 0 0 1 1 0 1 0 0 0 0 

6 1 1 1 1 1 1 1 1 0 0 1 0 1 0 0 1 1 1 1 0 0 1 1 

7 1 1 1 1 1 1 1 1 1 0 1 0 1 0 0 1 1 1 1 0 1 0 1 

8 1 0 0 1 0 1 0 1 0 0 1 0 1 0 0 1 1 1 1 0 0 0 0 

9 1 1 0 1 1 1 1 1 1 0 1 1 1 0 0 1 1 1 1 0 1 0 1 

10 1 1 0 1 1 0 1 1 1 0 1 0 1 0 0 1 1 1 1 0 1 1 1 

11 1 0 0 0 0 1 1 0 0 0 1 0 0 0 1 0 1 0 1 0 0 0 0 

12 1 1 1 1 1 1 1 1 1 1 1 0 1 0 0 1 1 1 1 1 1 0 1 

13 0 1 0 1 1 1 0 1 0 0 1 0 1 0 0 1 0 1 1 0 0 0 0 

14 0 0 0 1 0 0 0 1 0 0 1 0 0 0 1 1 0 1 1 0 0 1 0 

15 0 0 0 0 0 1 1 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 0 

16 1 0 0 1 1 1 1 0 0 0 1 0 1 0 0 1 1 1 1 0 0 0 0 

17 1 1 0 1 1 1 1 1 1 1 1 1 1 0 0 1 1 1 1 1 1 0 1 

18 1 1 0 1 1 1 1 1 1 0 1 1 1 0 0 1 1 1 1 1 1 0 1 

19 1 1 0 1 1 1 0 1 0 0 1 0 1 0 0 1 1 1 1 0 0 0 0 

20 1 1 1 1 1 1 1 0 0 0 1 0 1 0 0 1 1 1 1 0 0 0 0 

21 0 1 0 0 1 1 1 0 1 0 1 0 0 0 1 0 0 1 1 0 1 0 0 

22 1 1 0 1 1 1 1 1 1 0 1 0 1 0 0 1 1 1 1 0 1 0 1 

23 1 1 0 1 1 1 1 1 0 0 1 0 1 0 0 1 1 1 1 0 0 1 1 

24 1 1 0 1 0 1 1 0 1 0 1 0 1 0 0 1 1 1 1 0 1 1 1 

25 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 0 0 0 0 

26 1 0 0 0 1 0 0 0 0 0 1 0 0 0 1 0 1 0 1 0 0 0 0 

27 1 1 0 1 1 1 1 1 0 0 1 0 1 0 0 1 1 1 1 0 0 0 0 

28 0 0 0 1 1 1 0 0 0 0 0 0 0 0 0 1 0 1 0 0 0 0 0 

29 1 1 0 1 1 1 1 1 1 0 1 0 1 0 0 1 1 1 1 0 1 0 1 

30 1 1 0 1 1 1 1 0 0 0 1 0 1 0 0 1 1 1 1 0 0 0 0 

31 1 1 0 1 0 1 0 0 0 0 0 0 0 0 1 1 1 1 0 0 0 0 0 

32 0 1 0 1 0 1 0 0 0 0 0 0 0 1 0 1 0 1 0 0 0 1 0 

33 1 1 0 1 1 1 1 1 0 0 1 0 1 0 0 1 1 1 1 0 0 0 0 

34 1 1 0 1 1 1 0 1 0 0 1 0 1 0 0 1 1 1 1 0 0 1 1 

35 1 1 0 1 1 1 1 0 0 0 1 0 1 0 0 1 1 1 1 0 0 0 0 

36 0 0 0 1 0 1 1 0 0 0 1 0 0 0 1 1 0 0 1 0 0 0 0 

37 1 1 0 1 0 1 1 0 0 0 1 0 1 0 0 1 1 1 1 0 0 0 0 

38 1 1 0 0 0 1 1 0 0 0 1 0 0 0 1 0 1 1 1 0 0 1 0 

39 1 1 0 0 1 1 1 1 0 0 1 0 1 0 0 0 1 1 1 0 0 0 0 

40 1 1 0 1 1 1 1 0 0 0 1 0 1 0 0 1 1 1 1 0 0 0 0 

41 1 1 0 1 1 1 1 1 1 0 1 0 1 0 0 1 1 1 1 0 1 0 1 

42 0 1 1 1 0 0 1 1 0 0 1 1 1 0 0 1 0 1 1 0 1 0 0 

43 1 1 1 1 1 1 1 1 1 0 1 0 1 0 0 1 1 1 1 0 1 1 1 

44 0 0 0 1 1 1 1 0 0 0 1 0 0 0 1 1 0 1 1 0 0 0 0 

45 1 0 0 1 0 1 1 1 0 0 1 1 1 0 0 1 1 1 1 0 1 1 1 

46 1 1 0 1 0 1 1 1 0 0 1 0 1 0 0 1 1 1 1 0 0 1 1 

47 0 0 0 1 0 1 1 0 0 0 1 0 0 0 1 1 0 0 1 0 0 1 0 

48 1 1 0 1 1 1 1 1 1 1 1 0 1 0 0 1 1 1 1 1 1 1 1 

49 1 1 0 1 1 1 1 1 1 0 1 1 1 0 0 1 1 1 1 0 1 1 1 

50 0 0 0 0 1 1 1 0 0 1 1 0 0 0 1 0 0 0 1 1 0 0 0 

51 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 1 0 

52 1 1 1 1 1 1 1 1 0 0 1 0 1 0 0 1 1 1 1 0 0 1 1 

A 

1 

A 

2 

A 

3 

B 

1 

B 

2 

B 

3 

B 

4 

Diagnosis 

(case number) 

AD 

(57)


53 0 0 0 0 1 1 0 0 0 0 1 0 0 0 1 1 0 0 1 0 0 0 0 

54 1 1 0 0 1 1 0 0 0 0 0 0 0 0 1 0 1 1 0 0 0 0 0 

55 1 1 0 1 1 1 1 1 0 0 1 0 1 0 0 1 1 1 1 0 0 0 0 

56 1 1 0 1 1 1 1 1 0 1 1 0 1 0 0 1 1 1 1 1 0 1 1 

57 1 0 0 1 0 1 0 0 0 0 0 0 0 0 1 1 1 1 0 0 0 0 0 

58 1 1 0 1 1 1 1 1 1 0 1 0 1 0 0 1 1 1 1 0 1 1 1 

59 0 0 0 0 1 1 1 0 0 0 1 0 0 0 1 0 0 0 1 0 0 1 0 

60 1 0 0 1 0 1 1 0 0 0 1 0 1 0 0 1 1 1 1 0 0 0 0 

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114 0 0 0 1 0 1 1 0 0 0 1 0 0 1 0 1 0 1 1 0 0 1 0 

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117 1 0 0 1 1 1 1 1 0 0 1 1 1 0 0 1 1 1 1 0 1 0 1 

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161 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 

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Review 

Do Apparent Overlaps between Schizophrenia and 

Autistic Spectrum Disorders Reflect Superficial 

Similarities or Etiological Commonalities 


ABSTRACT 

Study Background: Schizophrenia and autism are both 

neurodevelopmental disorders that were once considered 

to be the same disorder expressed in different 

developmental periods. Although they were separated 

diagnostically about 40 years ago, they share several 

clinical and possibly, etiological features. This paper 

reviews overlaps in four domains of function to consider 

the issue of whether these similarities are sporadic and 

likely to represent superficial similarities, or whether the 

disorders are more likely to share some features in 

common. 

Methods: Representative areas of function were reviewed 

and compared for aspects of cognition (nonverbal 

reasoning, memory and language), social function 

(orienting / joint attention, eye contact and theory of 

mind), brain function (structural differences) and 

genetics. To facilitate comparisons with schizophrenia, a 

focus on high functioning autism / Asperger’s disorder 

was utilized, particularly in the sections on cognition and 

social function. 

Results: Significant similarities (and differences) 

characterized comparisons in each domain. 

Conclusions: Disturbed function in similar clinical (in 

cognition and social function), neurobiological (brain 

volumes) and genetic (e.g., involvement of the same genes 



William S. Stone, PhD 

Department of Psychiatry 


Harvard Medical School, Boston, MA, USA 

Current postal address: 

Harvard Medical School, Department of Psychiatry/BIDMC 

401 Park Drive, 2nd Floor East, Boston, MA 02215 

Tel: 617-998-5035 Fax: 617-998-5007 

Email: wstone@bidmc.harvard.edu 

Lisa Iguchi, PhD 

Tel: 617-998-5035 Fax: 617-998-5007 

Email: liguchi@bidmc.harvard.edu 

or chromosomal locations) domains in autism and 

schizophrenia supports the hypothesis that while they are 

distinct disorders, they are not entirely unique. 

Additional studies of similarities and differences between 

them may thus shed light on common etiological 

mechanisms and hopefully, facilitate the development of 

novel treatment targets. 

[N A J Med Sci. 2011;4(3):124-133.] 

KEY WORDS: Autistic spectrum disorder, cognition, social 

cognition, schizophrenia spectrum disorder 

Autism and schizophrenia are among many psychiatric and 

neurological disorders that share overlapping clinical features 

and involve widespread psychiatric and cognitive 

impairments. Other examples include different dementing 

disorders, which often produce similar clinical symptoms in 

their later stages, and disorders involving psychosis, such as 

schizophrenia and bipolar I disorder with psychotic features. 

The situation is complicated somewhat by a reliance on 

clinical symptoms to make diagnoses in psychiatry, 1 but are 

complicated even more so by the nature of the disorders 

themselves. Many psychiatric (and other medical) disorders 

and normal functions have multiple causes, and many causal 

factors may be sufficient, often in combination with other 

causal factors, to contribute to the development or 

maintenance of a disorder. 2,3 

The multi-factorial and complex nature of autism and 

schizophrenia adds to the difficulty of establishing their 

etiologies. Nevertheless, the importance of identifying 

etiological factors is often an essential step in the 

development of new treatment strategies. While there are 

several potential paradigms that might be utilized to progress 

towards this goal, one is to assess the potential importance of 

overlapping symptoms in these syndromes. This approach 

can help determine whether observed similarities reflect 

common etiological factors, such as a continuum between 

schizophrenic and autistic spectrums, or whether they more 

likely reflect superficial similarities, (such as problems in 

attention that may result from any number of disparate 

causes). 

In this paper, we focus on apparent overlaps between 

schizophrenia and autism spectrum disorders, which both 

reflect common, clinically significant spectrums. Until these


disorders came to be viewed as distinct in the 1970s, they 

were viewed as different phases of the same problem, with 

autism manifesting as an earlier phase of schizophrenia. 4,5 

Although they are viewed separately now, they do intersect 

along several dimensions, including, for example, problems 

with social interaction and emotion, verbal and nonverbal 

communication, and odd or inflexible behavior. It is not 

clear, however, whether these and other shared clinical 

features reflect common underlying etiological factors. 

Moreover, the question is complicated by heterogeneity of 

symptoms, differences in age of onset, environmental factors 

and responses to treatment. In the interests of maximizing 

clarity and also emphasizing cognition, we will focus 

somewhat on adolescents and adults whose overall cognitive 

abilities are above IQs of 70 (i.e., above DSM-IV ranges 

required for diagnoses of mental retardation). 

For the autism spectrum disorders, this mainly includes a 

composite group of individuals who are commonly diagnosed 

with high-functioning autism/Asperger syndrome (HFA/AS). 

Reviews of the schizophrenia spectrum will focus on 

schizophrenia itself, but will also include other DSM-IV 

disorders such as schizoaffective disorder (depressed type) 

and schizotypal personality disorder, where appropriate. The 

aim of this paper is not to argue for or against existing 

theories in either schizophrenia or autism, but to explore 

representative evidence about the nature of overlaps between 

them. Evidence for common etiological components, if 

present, may then provide an impetus for the development of 

research strategies aimed at clarifying etiology further and at 

developing/validating clinical interventions. 

The remainder of the paper is organized into five sections. 

Representative overlaps between schizophrenia and HFA/AS 

will be reviewed briefly in four dimensions, including: 1/ 

cognition, 2/ social functioning, 3/ structural brain 

abnormalities, and 4/ genetics. We conclude by considering 

implications for etiology, clinical interventions and future 

research. 

WHAT EVIDENCE IS THERE FOR OVERLAP 

Cognition 

Cognitive processes are essential for individuals to interact 

with the world and other people in a meaningful way. 

Overall, cognitive deficits are generally milder in high 

functioning autism (i.e., HFA/AS) than they are in 

schizophrenia, 6 and more related to social function. 7,8 They 

are, however, significant clinically, and form the basis of 

some cognitive theories of autism. 9 Representative examples 

of cognitive deficits will be considered for schizophrenia and 

HFA/AS in three domains, including (1) nonverbal 

reasoning, (2) memory, and (3) language. These cognitive 

abilities are all important for social interaction, 

communication, and adaptive behavior, and are impaired in 

both spectra in various dimensions and to varying degrees. 

Nonverbal reasoning 

Nonverbal reasoning is instrumental for abstracting the 

essence of situations, and for assigning meaning to them. It is 

often measured by neuropsychological tasks that involve 

perceiving, organizing, integrating, and associating 

information in the service of goal-directed behavior. In most 

people, this chain of events happens more or less 

automatically. In people with HFA/AS, this chain of events 

may happen more deliberately, abnormally, or not at all. This 

observation contributes to cognitive theories of autism that 

focus on tendencies towards local rather than global 

processing of information. 10 Similarly, organizing and 

integrating information is often impaired in schizophrenia, as 

demonstrated, for example, by difficulties in emotion 

perception in schizophrenia spectrum illness. 11,12 Individuals 

with schizophrenia report normal emotional experiences in 

the presence of emotionally evocative stimuli, but are often 

less expressive and less likely to maintain those emotional 

reactions in the absence of the stimuli. 13 As with 

schizophrenia, emotion perception is impaired in HFA/AS in 

some ways, 14 but not others. Quintin et al showed recently, 

for example, that HFA/AS subjects perceived emotions in 

music normally when verbal IQ was controlled. 15 Wallace et 

al demonstrated impaired facial emotion perception in 

HFA/AS individuals who were matched to healthy controls 

on age, gender and IQ, but these differences were minimized 

for most emotions when facial expressions increased in 

intensity. 16 

Salience is another mediating factor in nonverbal reasoning. 

There is an intrinsic and bi-directional relationship between 

what we attend to and what is judged to be relevant. 

Individuals with schizophrenia often base their actions on 

misinformation due to idiosyncratic meaning attached to a 

particular stimulus, as reflected in loose associations, over- or 

under-inclusive thinking and paranoia. 17,18 Individuals with 

HFA/AS show particular deficits in salience to social stimuli, 

particularly in situations that involve distracters or the need 

to switch attention rapidly between different sensory 

modalities, objects or locations. 19,21 Both groups often fail to 

suppress information that is important, but not salient. 

Memory 

Deficits in declarative memory performance are wellestablished 

in patients with schizophrenia, but involve 

problems with encoding (i.e., learning) more than they 

involve problems with memory storage. 6,22,23 These deficits 

are not only related to other cognitive abnormalities (e.g., 

executive function and attention), but are linked to 

hippocampal abnormalities and to clinical symptoms that 

cause functional impairment. There are fewer published 

studies on declarative memory in HFA/AS than there is in 

schizophrenia spectrum disorders, but some conclusions may 

be drawn. Individuals with HFA/AS often show normal free 

recall, cued recall and recognition, 24 particularly for itemspecific 

material that is subject to rote memorization. 

Individuals with HFA/AS show poorer recall, however, as 

interference increases, contextual relatedness increases, and 

particularly when social contextual information increases. 24-28 

Similarly, adults with HFA/AS have poorer autobiographical 

memories, 29,30 which partly reflects difficulties in taking firstperson 

perspectives. 28 Notably, learning/encoding problems 

in autism and in schizophrenia are both more prominent than 

are problems in recognition, which emphasizes their


vulnerability to problems in executive function (e.g. in 

learning, retrieval, organization and resistance to distraction) 

and attention. Thus, despite differences (e.g., memory 

performance impairments in schizophrenia are broader and 

more robust than they are in HFA/AS), they show significant 

similarities as well. 

These similarities may be particularly significant with respect 

to relational and contextual memory, which involves the 

ability to associate and remember names with faces, the 

locations of objects or people, and the order in which events 

occur. Some researchers attribute declarative memory deficits 

in HFA/AS to problems with processing relational and 

contextual information. 31 Similar deficits have been observed 

in individuals with schizophrenia, using associative inference 

and transitive inference paradigms. 32,33 Almost 20 years ago, 

DeLong 34 postulated that autism was a developmental 

syndrome of hippocampal dysfunction, based on evidence 

that the hippocampus is involved in constructing meaning 

and integrating new experiences with old ones. Recent 

research indicates that the connection between relational and 

contextual memory deficits and hippocampal dysfunction in 

HFA/AS has to do with preferential use of item-specific 

information, rather than with associative learning. 25 

Procedural memory deficits in individuals with HFA/AS are 

sometimes captured diagnostically as DSM-IV 

developmental coordination disorder or as a nonverbal 

learning disorder (which is often diagnosed under DSM-IV 

cognitive disorder, not otherwise specified), with evidence of 

poorer memories for self-performed actions than controls. 35 

These examples of impaired autonoetic awareness (i.e., 

remembering what is involved in episodic memory 

experiences) seem closely related to hippocampal-dependent 

relational and contextual memory impairment. 

Semantic memory deficits observed in schizophrenia and 

HFA/AS are variable. One meta-analysis of 91 studies found 

an uneven profile of impairment in individuals with 

schizophrenia on semantic tasks involving naming, wordpicture 

matching, verbal fluency, priming, and categorization 

36 . There was a large effect size for naming and verbal 

fluency, medium effect size for word-picture matching and 

association and small effect sizes for priming and 

categorization. The conclusion was that there was a link 

between thought disorder and semantic memory impairments 

on tests of naming and verbal fluency, though on other tests 

the evidence was equivocal. These findings are consistent 

with observations of wide semantic boundaries and 

generation of atypical exemplars in schizophrenia. 37 By 

contrast, a PubMed search using key words “semantic 

memory autism asperger” resulted in only 7 articles 

published between 1998 and 2009. The articles examined 

recognition memory, self-other memory, semantic 

association, dream content analysis, and using context and 

pragmatic language. Thus, the variability in semantic 

memory deficits seen in schizophrenia and HFA/AS relates 

not only to thought disorder, but also to language, which will 

be explored next. 

Language 

Language abnormalities play a prominent role in 

schizophrenia and HFA/AS. People with schizophrenia and 

HFA/AS have trouble with coherent communication—that is, 

with packaging and conveying information in a meaningful 

way. But there are subtle differences in how this incoherence 

manifests itself. In schizophrenia, it may take the form of 

neologisms or loose associations that are characteristic of 

thought disorder. Communication difficulties that result from 

thought disorder in schizophrenia are at least partially 

attributable to neuropsychological deficits (e.g., in 

attention/working memory, immediate memory, 

organizational sequencing and conceptual sequencing). 38 

Subjects with HFA/AS often show problems with language, 39 

which may include awkward timing, phrasing or transitions 

during conversations and problems with pragmatic and 

prosodic skills, among other abnormalities, though these 

individuals (i.e., with IQs in the average range) also tend to 

show generally intact formal language capacity. 40 One recent 

study compared subjects who were 11-20 years old who met 

criteria for a clinical high risk (for psychosis) group (CHR), a 

first episode psychosis group (FEP), an autistic spectrum 

disorders (ASD) group and a typically developing individuals 

group (TYP). 41 Each of the three clinical groups showed 

deficits in social function and atypical development of 

language. Notably, the ASD (i.e., HFA/AS subjects) subjects 

showed greater grammatical and pragmatic language 

symptoms (e.g., delayed echolalia, pedantic speech, and 

problems understanding humor, irony and sarcasm) than the 

other groups. 

One way to assess language functioning is to administer tests 

of reading comprehension or narrative writing. Individuals 

with schizophrenia are able to read single words (decoding) 

but take longer to complete reading comprehension tests and 

obtain lower scores. 42-44 With schizophrenia, poor 

comprehension or writing relates to fundamental problems 

with attention and working memory, processing speed, and 

extracting and organizing salient information. With HFA/AS, 

poor comprehension or writing often occurs as a result of 

failure to integrate or assemble complex information to 

derive or produce a meaningful whole. 

Another way to measure a person‟s ability to access and use 

language to demonstrate knowledge is to administer a verbal 

fluency test. Both semantic and phonemic fluency are 

impaired in schizophrenia and HFA/AS, and may be 

associated particularly with deficits in semantic processing. 

For example, one study found that deficits in semantic 

fluency but not phonologic fluency differentiated a group of 

66 young patients at high risk for psychosis from 67 other 

psychiatric, help-seeking controls. 45 Another study reported a 

unique connection between action (verb) fluency and odd 

speech in schizophrenia, rather than a general impairment in 

language or executive demands that are common to fluency 

tasks. 46 Citing research that verbs influence causal 

attributions that are central to interpersonal communication, 

they also linked action-word fluency deficits to deficits in 

social interaction.


In summary, many individuals with either HFA/AS or 

schizophrenia show communication difficulties. Some of 

these problems are related to thought disorder in both spectra, 

but differ somewhat between disorders, with HFA/AS 

showing a somewhat broader and extensive set of 

communication difficulties, on average. 

Social Functioning 

Deficits in social function are among the defining features of 

autism, 39,47 and are among the core features of 

schizophrenia. 48,49 At least one recent study that compared 

subjects with HFA/AS with subjects with schizophrenia on a 

range of social cognition measures showed that they 

performed similar to each other, but worse than controls on 

most measures 50 (but see also 51 ). As reviewed above, both 

groups are affected adversely by cognitive deficits. This 

section reviews overlap in several key areas related to social 

function, including orienting/joint attention, gaze and eye 

contact, and theory of mind. 

Orienting, Joint Attention and Visual Processing Style 

Joint attention is a kind of social orienting that occurs when 

one person turns to look in the same direction that they see 

another person looking. It usually emerges reliably between 

the ages of 1-2, 52,53 and it is one of the foundations of social 

interaction because shared attention is directed to objects of 

mutual interest. As such, it assumes knowledge of others‟ 

interests and helps to develop both „theory of mind‟ 

(described below) and language. Abilities to identify 

emotions or other aspects of mental state emerge between the 

ages of 3-4. 53 Joint attention involves at least two wellresearched 

phenomena: 1/ facial and emotion recognition, 

and 2/ visual processing style. Both of these phenomena 

influence social functioning by driving salient aspects of 

(particularly novel) social situations. Individuals with 

HFA/AS do not attend well to social aspects of the 

environment (though they may attend as well as controls to 

non-social stimuli 

19 ), follow other people‟s gaze 

spontaneously or make normal eye contact. 53 In experimental 

settings using cueing tasks and eye movement (saccade) 

recordings, however, they can show normal overt orienting 

responses in response to explicit eye gaze cues and to arrow 

cues. 54 One implication of these findings is that cueing, as a 

form of rule-based or causal relationship, can be employed to 

improve social functioning. Under implicit cueing conditions, 

individuals with HFA/AS show impaired ability to integrate 

emotion (fear) with gaze direction, which is opposite the 

effect seen in schizophrenia. 

Further, individuals with schizophrenia show impairments in 

recognizing facial affect (particularly fear) and in making 

social judgments based on facial features, 55,56 but intact 

ability to experience emotions. In both HFA/AS and 

schizophrenia, there is difficulty modifying behavior based 

on implicit facial emotional information. In HFA/AS, 

miscuing occurs when a facial emotion is not automatically 

taken as a cue, 57 or when it is taken as cue but is avoided. 58 

People with schizophrenia show some difficulties that are 

similar to those in HFA/AS. In one study, they did not differ 

from controls in gaze discrimination performance, but as 

subjects decided when faces (i.e., facial stimuli) were making 

eye contact, different brain regions were activated between 

groups when the stimuli were rotated from a head-on view. 59 

Interestingly, results of studies that examined gaze 

discrimination in schizophrenia are mixed. 60-62 Miscuing in 

schizophrenia is also more likely to occur when a facial 

emotion / intention is perceived in error. This can occur as a 

function of several factors, including levels of positive 

psychiatric symptoms. Pinkham et al showed, for example, 

that when subjects with schizophrenia were divided into 

groups with and without active paranoid ideation at the time 

of the test, that the groups did not differ in overall task 

accuracy. 63 The paranoid subjects, however, showed more 

errors than the non-paranoid subjects, in labeling neutral 

faces as angry. 

Rondan and Deruelle 64 examined visual processing style in 

adults with HFA/AS and controls. Both HFA/AS participants 

and controls showed a preference for matching targets 

according to global features on a task involving hierarchical 

stimuli (i.e., they matched small squares arranged in the 

shape of a circle to little circles arranged in the shape of a 

circle, instead of to small squares arranged in a square). 

Compared to controls, HFA/AS participants showed a 

preference for details over configuration, however, on a task 

involving inter-elemental spatial relationships (i.e., they 

matched geometric shapes arranged in the shape of a face to 

the same constituent shapes arranged in the shape of a face 

with different spatial proportions, instead of to different 

constituent shapes in the shape of a face with the same spatial 

proportions). Whereas HFA/AS involves problems with static 

aspects of visual processing (e.g., perceiving details rather 

than configurations), schizophrenia also involves problems 

with more dynamic aspects of visual processing. For 

example, individuals with schizophrenia show eye tracking 

dysfunction in a variety of ways, including trouble 

maintaining visual pursuit of predictably moving targets. 65,66 

Despite differences in temporal aspects of visual processing 

between HFA/AS and schizophrenia, there are overlapping 

deficits in relying on discrete details or moments instead of 

relational information or continuity of information to regulate 

behavior. 

Eye Contact 

Eye contact is an important aspect of gaze and social 

behavior in many species, 53 that is also among the 

foundations of communications and social interaction in 

humans. 53,67,68 Eye contact helps modulate gaze, orientation 

and joint attention, and helps to activate and modulate brain 

regions involved in social function. 67,68 Cues from eye 

contact often inform social perception and influence how we 

act or modify our actions (i.e., adapt) in given social 

situations. 

Individuals with HFA/AS show well-documented deficits in 

related areas, such as gaze monitoring and joint attention, as 

noted above. 39 Based on eye-tracking data, individuals with 

autism spectrum disorders showed atypical reflexive gaze by 

actively avoiding eye contact or failing to orient to the eyes. 58 

This effect was seen regardless of whether faces had happy,


fearful, or neutral expressions, and predicted performance on 

an emotion recognition task. These findings suggest that 

avoiding eye contact may be a cause, as well as a result of 

deficits in emotional facial recognition. Moreover, children 

with HFA/AS process eye contact more poorly than typically 

developing children, when shown pictures of faces. 67,69 

Typically developing children performed better when the 

faces were shown in upright positions than when they were 

shown in inverted positions. Children with autistic spectrum 

disorders performed best when the faces were presented in 

full frontal views, regardless of whether they were presented 

in upright or inverted positions. The autistic children did not 

perform as well when facial orientations were turned 

somewhat, suggesting that compared to typically developing 

children, they processed the facial information abnormally, 

such as on the basis of bilateral symmetry. 

As noted in the previous section, individuals with 

schizophrenia also process eye contact information 

differently than controls, even when they show similar levels 

of discrimination, behaviorally. Implicit processing of social 

cues in individuals with schizophrenia was assessed by 

asking them to classify words by pressing “left” or “right” 

while facial expressions with eye gaze averted to the left or 

right flashed in the background. 70 Interestingly, participants 

were slower to classify words that were incongruent to the 

direction of eye gaze than words that were congruent, but this 

effect was observed only for expressions of fear. A similar 

effect of fear in capturing attention has also been seen among 

individuals with schizophrenia. 

Theory of Mind (ToM) 

ToM is a construct that accounts for others having beliefs, 

wants, plans, or intentions that are distinct from ours. It also 

includes an understanding of irony, metaphors and faux pas, 

as examples of ways of understanding the meaning or intent 

of others‟ statements beyond the literal, concrete meaning of 

the words. But any construct of „Other‟ presumes first a 

concept of „Self‟. Although the concept of ToM is 

multidimensional and complex, there is compelling evidence 

that aspects of it are impaired in HFA/AS and in 

schizophrenia. 53,71-73 Taken as a cognitive mechanism, ToM 

operates in a relational context, which as we have seen is 

often impaired in schizophrenia and HFA/AS. 

In individuals with clinically stable, first-episode 

schizophrenia, there may be only a moderate influence of 

cognitive deficits on ToM, and impaired ToM may exist 

independent of clinical state, alexithymia, and capacity for 

empathy. 74 Further, there is evidence of a negative 

correlation between social anxiety and perspective taking, as 

well as a positive correlation between empathy and ToM in 

patients with first-episode psychosis relative to patients with 

chronic schizophrenia. 75 Thus, it may be that the effects of 

targeting cognitive impairment and ToM for remediation may 

not vary as a function of clinical severity, whereas enlisting 

empathy to increase ToM may be more effective earlier than 

later in the clinical course of schizophrenia. 

First-order ToM involves having knowledge of another mind 

state. Second-order ToM involves appreciating that another 

person holds a different belief, and factoring this other belief 

(both that there is another belief, as well as what this belief 

is) into his or her own sense of reality (meaning-making). 

Stratta and colleagues (2010) found that 12-13% of 

schizophrenia patients scored correctly on second-order ToM 

but not first-order ToM. It is interesting to speculate about 

the clinical features of individuals with schizophrenia who 

display intact second-order but impaired first-order ToM. For 

example, it is possible that this discrepancy contributes to 

ontological instability. 76 

Consistent with the role of the hippocampus in integrating 

autonoetic awareness with episodic and procedural memory 

(above), autobiographical memory has been linked with ToM 

abilities in individuals with HFA/AS. 77 Contrary to evidence 

of deficits in facial emotion recognition, however, a recent 

study found no differences in performance on the Eyes Test 

between individuals with HFA, AS, and controls. 78 This may 

provide clues for targeting and designing approaches for 

intervention; for example, matching cognitive abilities (e.g., 

memory) to salient details of social communication (e.g., 

inferring mental states from eyes instead of the whole face). 

Although ToM can be can be dissociated partially from 

several related functions, such as cognition and clinical 

state, 74 it is probably a composite construct that involves a 

family of abilities that includes joint attention, eye contact, 

emotion processing, perceptual recognition abilities, 

empathy, cognitive abilities (e.g., memory, executive 

functions) and language, among others. 79 Moreover, ToM 

develops in accordance with a variety of environmental 

experiences, such as parenting, education, training and social 

interaction. While the focus of this review involves autism 

and schizophrenia, deficits in other neurodevelopmental 

disorders, such as attention deficit/hyperactivity disorder 

(ADHD) and acquired brain disorders (e.g., traumatic brain 

injuries), particularly involving the non-dominant 

hemisphere, are also associated with impairments in ToM. 80- 

82 The multifactorial nature of ToM contributes to variability 

in patterns of impairment in different disorders, as shown in a 

recent study that compared individuals with childhood 

schizophrenia with children who had autism and with 

normally developing children. 83 Children with schizophrenia 

were impaired in „false-belief‟ tasks, but they showed better 

understanding of deception than did the children with autism 

(and the normally developing children). The children with 

autism showed a broader range of ToM impairments 

generally than did the children with schizophrenia. 

Findings such as these raise the point that the breadth and 

severity of ToM deficits in schizophrenia often varies 

between studies. 71 State dependence is a moderator variable 

that might explain some of this variability, as patients with 

higher positive symptoms, such as paranoia and delusions, 

often show greater ToM deficits than patients with lower 

levels of such symptoms. 71,84 A recent meta-analysis 

confirmed this view, in part by showing that „remitted‟


patients showed lower levels of ToM deficits than nonremitted 

patients. 85 The effect sizes of ToM deficits remained 

large, however, in remitted patients (Cohen‟s d = 0.80, versus 

1.21 in non-remitted patients). 

Brain 

The nature and extent of abnormal brain function in 

schizophrenia and HFA/AS are areas of intense interest and 

study. Here we emphasize a few representative areas of 

overlap in brain volumes that may underlie similarities in 

clinical, cognitive or social dysfunctions. Developmental 

features of HFA/AS and schizophrenia are especially relevant 

at this level, as is the passage of time as an organizing 

principle of adaptation. 

Numerous structural and functional brain abnormalities occur 

in both schizophrenia and autism, although results vary 

between and within disorders, at least partly as a function of 

methodological differences between studies. 59,67,86-91 A metaanalysis 

of structural MRI studies in autism showed, for 

example, increased volumes in total brain, both hemispheres, 

the cerebellum and the caudate. 87 Toal et al also found 

increased volume in the right caudate, and in more restricted 

clusters in the brainstem, right middle frontal gyrus, 

precentral and postcentral gyri (that extended bilaterally to 

the cingulate gyrus, among other areas). 88 Cheung et al, using 

a modification of Anatomical Likelihood estimation (ALE), 

did not show global differences in gray matter between 

subjects with autistic spectrum disorders and controls in most 

studies, 86 but they did show lower gray matter volumes in 

several striato-limbic regions that are also lower in 

schizophrenia. 86,92 These included the right parahippocampal 

gyrus, the posterior cingulate, the putamen, the left insula and 

the left thalamus. Somewhat in contrast to HFA/AS, 

schizophrenia is associated more with lowered volume than 

with increased volume, especially in whole brain and in 

hippocampus. 89,93 Differences in cerebellar 86-88 and 

amygdala 87,90,91 volumes are reported in some studies, but not 

others, within schizophrenia and autism spectrum disorders. 

These differences are influenced by both methodological and 

other variables (e.g., younger ages were associated with 

larger amygdala volumes; see 87 ). 

The question of hippocampal volume abnormalities is less 

clear in HFA/AS than it is in schizophrenia. Increased 

bilateral hippocampal volumes were reported in children with 

HFA, 94 whereas differences in adults are more 

equivocal. 87,95,96 By contrast, decreased hippocampal volume 

is characteristic of schizophrenia, with no apparent effect of 

duration of illness. 89,93 Nevertheless, decreased volumes in 

the parahippocamal gyri in both disorders implicate both the 

hippocampal formation and the medial temporal lobe more 

generally in their neuropathologies. It should be emphasized 

that the hippocampus is also a part of a broader system 

involving the social environment. Structural abnormalities 

early in development-such as altered hippocampal volumesshould 

correspond to abnormal development of other brain 

structures and related processes. This is borne out to some 

degree by evidence of association cortex and white matter 

abnormalities in HFA/AS, and by research that defines 

HFA/AS and schizophrenia as disorders of integration and 

connectivity. 97,98 In schizophrenia, smaller hippocampal 

volumes co-exist with problems discriminating relevant from 

irrelevant information or discerning figure and ground 

relationships, as demonstrated by research on thalamic lateral 

inhibition and sensory gating paradigms, respectively. 99,100 

One study found decreased gray matter volume in the right 

insula in adults with pervasive developmental disorders 

versus controls, and that gray matter volume correlated 

negatively with Autism Spectrum Quotient scores. 101 Other 

studies involving HFA/AS relate social and cognitive deficits 

to inefficient connectivity in the mirror neuron system and 

between limbic and prefrontal areas in HFA/AS. 102,103 

Genetics 

Like many complex psychiatric disorders and normal mental 

abilities, schizophrenia and autism result from genetic 

etiological components that interact with environmental 

factors to facilitate either optimal or disordered function. 104 

Evidence for a genetic influence in schizophrenia is 

compelling at this point, 3,105 based on both behavioral genetic 

and molecular biologic studies. 106-109 One recent review of 

twin studies showed, for example, that variance attributable 

to heritability was about 84%, and that if one sibling 

developed the disorder, the risk to the other sibling would 

increase about 12-fold. 106 Although linkage studies have had 

little success in identifying genes that contribute to the 

development of schizophrenia, 105 association studies have 

identified many genes involved in neuronal signaling or other 

aspects of brain structure and function whose dysfunction 

might contribute to schizophrenia. 109 Several of these genes 

may be related to either the diagnostic category of 

schizophrenia, or to quantitative endophenotypes for 

schizophrenia. A recent study from the Consortium on the 

Genetics of Schizophrenia (COGS), for example, examined 

12 heritable endophenotypes 110 in relation to 1594 single 

nucleotide polymorphisms (SNP) identified from 94 genes. 111 

The 47 strongest SNP-endophenotype combinations 

exceeded the number of significant findings expected to 

occur by chance alone. 

Other paradigms have also shed light on genetic mechanisms 

involved in schizophrenia. These include recent work 

showing, for example, differences in gene expression 

between subjects with schizophrenia, bipolar disorder and 

controls, 112 gene splicing 113 and abnormalities in genomic 

copy number variants (CNVs). 108 

Like schizophrenia, autism (including HFA/AS) has a 

significant genetic component. In their review of twin 

studies, Glatt et al reported a heritability estimate of 93% for 

autism, with a relative risk of 22 for siblings if one twin 

develops autism (i.e. they are 22 times more likely to develop 

autism than are individuals drawn from the general 

population). Similar to the notion of a schizophrenia 

spectrum in which non-psychotic relatives show milder 

features of schizophrenia, 114 non-autistic relatives of 

individuals with autism often show milder features of 

autism. 115 Moreover, numerous candidate genes have been 

proposed to contribute to the disorder, 116 and many CNVs 

have been reported. 117


Although family studies of schizophrenia and of autism show 

consistently elevated rates of disorders presumed to lie in the 

schizophrenia and autistic spectrums respectively, it is 

notable that diagnostic overlap also occurs. In one study, for 

example, half of a group of individuals with autism (not 

restricted to HFA/AS) also met DSM-IV diagnostic criteria 

for schizophrenia, disorganized type. 118 In another study, 

20% of subjects in a clinical high risk group for psychosis 

and a first episode psychosis group met diagnostic criteria for 

an autistic spectrum disorder. 41 A few studies showed that 

parental diagnoses of schizophrenia were associated with 

elevated rates of autism in offspring. 119,120 

Moreover, certain co-morbid medical conditions are elevated 

in both disorders, such as amyotrophic lateral sclerosis (ALS) 

and several bleeding disorders (e.g., Gaucher‟s disease), and 

may be related to similar chromosomal regions. 121 

Interestingly, overlapping genetic mechanisms do not 

necessarily produce the same phenotypic effects. Crespi and 

Thiselton showed evidence, for example, that alleles at 

DRB1 influence risk for rheumatoid arthritis, schizophrenia 

and autism in a pleiotropic manner. 122 Alleles at DRB1*04 

increased risk for arthritis and autism but decreased it for 

schizophrenia, while alleles at DRB1*13 alleles reduce the 

risk for arthritis and autism, but increase it for schizophrenia. 

Deletions in the 22q11.2 region (also known as 

velocardiofacial syndrome) is a well-known example of a 

CNV that confers risk for both autism and for 

schizophrenia. 117 Copy number variants at other 

chromosomal locations, such as 16p11.2, are also associated 

with schizophrenia, autism and other disorders. 123-125 

Similarly, CNVs that were associated with another 

neurodevelopmental disorder, ADHD, were reported in both 

autism and schizophrenia at the same chromosomal loci. 126 In 

addition to chromosomal locations, several candidate genes 

have been implicated in both disorders, such as disrupted in 

schizophrenia (DISC1), 127,128 contactin-associated protein-2 

(CNTNAP2) 117 and others. 129 

SUMMARY 

This review focused on several substantive areas of overlap 

between schizophrenia and autism, with an emphasis on 

HFA/AS. Representative examples involving cognitive 

deficits, social dysfunction, brain abnormalities and genetics 

show significant areas of correspondence between these two 

conditions, and the spectra they represent. It should be noted 

that while the sections on cognition and social function 

focused on HFA/AS, the sections on brain function and 

genetics did not maintain that distinction to the same degree, 

but showed similar levels of correspondence with 

schizophrenia. Moreover, the areas selected for review, 

though important functionally or etiologically, are only a 

subset of domains in which the two conditions might overlap. 

Other proposed areas of overlap are related to clinical 

symptoms (including paranoia and psychosis), abnormal 

information processing (as shown by „sensory gating‟ 

problems), minor physical anomalies (such as neurological 

„soft signs) and vitamin D deficiency during pregnancy, for 

example. 86 

Forty years after schizophrenia and autism separated 

diagnostically into distinct disorders, however, the purpose of 

these comparisons is not to conflate them again. Despite 

apparent similarities at several levels of analysis, they remain 

distinct entities, with important differences in clinical 

phenotypes, age of onset, neurobiological mediation and 

treatment. Each of the domains reviewed in this paper 

showed significant differences in addition to the similarities. 

Nevertheless, the similarities in phenotypes (cognition, social 

function and brain structure) and genotypes (overlapping 

genes and genetic mechanisms) support hypotheses that these 

disorders are not entirely unique, either. 86,108,117 

Moreover, the overlap between schizophrenia and autism 

may be part of a broader set of overlaps between these 

neurodevelopmental disorders and others, such as ADHD, 

bipolar disorder and intellectual disability. 108,126 In this view, 

common pleiotropic risk alleles and rarer risk alleles, 

together with protective genetic factors and other 

environmental and biological factors can produce a number 

of different, heterogeneous disorders that may share certain 

features in common, but differ along other dimensions. 

Both the etiological and the functional significance of these 

areas of overlap are uncertain at this time. If several major 

dimensions of function share pathological and possibly 

etiological similarities, however, then the study of these 

concordances may shed additional light on the nature of both 

disorders. Among the questions future research may help to 

resolve are which problems are more etiological, and which 

are more resultant. We proposed that psychosis, for example, 

despite its disruptive effects in schizophrenia, was more 

likely a non-specific consequence of earlier, etiological 

factors. 130 

The resolution of such issues, in turn, may facilitate the 

development of novel treatment targets, or suggest 

approaches that are known to be useful for one disorder, for 

use with the other disorder. Antipsychotic medications, for 

example, which have long been first-line treatments for 

schizophrenia, have been utilized more recently in other 

psychiatric conditions, including autism. 131 The 

administration of oxytocin to subjects with either 

schizophrenia or with autism, shows preliminary promise of 

improving social cognition, mood problems and psychotic 

symptoms in both autism and schizophrenia. 132-134 In this 

instance, positive effects in any of these clinically significant 

domains in either the schizophrenia or autism spectra is likely 

to encourage investigation of these problems in the other 

spectra. Similarly, non-pharmacological treatments such as 

cognitive enhancement therapy, which is a promising 

intervention for cognitive problems in schizophrenia, 135,136 

may have applications for autism as well. More generally, the 

growing range of apparent similarities between autism and 

schizophrenia raises the potentially significant possibility that 

etiological overlaps of their spectra may extend to productive 

overlaps in therapeutic intervention strategies.


ACKNOWLEDGEMENTS 

This work was supported in part by Ortho-McNeil Janssen 

Scientific Affairs, LLC, and by National Institute of Mental 

Health Grant RO1-MH065562 (COGS; Consortium on the 

Genetics of Schizophrenia). 

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2010;120(1-3):210-216.


Review 

Prospects of Stem Cell Therapy for 

Autism Spectrum Disorders 

Xuejun Kong, MD, Xiaochun Wang, PhD, William Stone, PhD 

ABSTRACT 

Autism is a group of highly complicated 

neurodevelopment disorders affecting 1 in every 110 

children born in USA. The etiology and pathophysiology 

are poorly understood and it currently has no universally 

accepted therapy or cure. Stem cell replacement therapy 

via transplantation potentially reverse brain hypo 

perfusion and immune dysfunction, which are considered 

to be two major pathophysiology mechanisms of autism. 

Recent advances in the in vitro study of disease modeling 

of autism reveals disease-specific cellular defects and 

reversible symptoms, opens the possibility of cell therapy 

and offers new hopes for cures. However, this new 

therapy is still in its infancy. There are many 

technological barrier such as immune-rejection, tissue 

migration and integration, cancer risk, safety concern, 

proper development in the inner environment and clinical 

barriers of individual sensitivity and liability, disease 

complexity, and more, which will need to be overcome 

before reaching new era of therapy. It will be necessary to 

conduct in vivo animal studies and then further clinical 

trials, however, before any potential clinical application 

in autism and other human disease can be realized. 

[N A J Med Sci.2011;4(3):134-138.] 

KEY WORDS: stem cell, stem cell therapy, autism 




Department of Medicine 


482 Bedford Street 

Lexington, MA 02420 

Tel: 781-672-2250 Fax: 781-672-2259 

Email: xkong@bidmc.harvard.edu 

Xiaochun Wang, PhD 

Biomedical Solution, Lexington, MA 

William Stone, PhD 

Department of Psychiatry, Beth Israel Deaconess Medical 

Center, Harvard Medical School, Boston, MA 

INTRODUCTION 

Autism is widely regarded as among the most complicated 

neurodevelopment disorders, with rapid increases in 

incidence reported recently. Since the last decades of the 

twentieth century, Autism spectrum disorders (ASD) 

increased steadily in the USA and around the world. In 2007, 

it reached to epidemic proportions, with approximately 1 in 

166 children in the USA. It reached 1 in 110 children at the 

end of 2009 (a 57% jump in just four years). 1 Autism has 

become a huge healthcare burden and threat globally. 

Autism is characterized by difficulties communicating and 

interacting with others, and is often accompanied by 

significant behavioral challenges. It is a clinical syndrome 

rather than a disease, with its diagnosis based on 

psychological testing and DSM-IV-TR criteria. The etiology 

of Autism is largely unknown, but it has significant genetic 

and environmental etiological factors. 2 Current treatments for 

autism can be divided into behavioral, nutritional and 

medical approaches, although no golden standard approach 

exists. Behavioral interventions usually include activities 

designed to encourage social interaction, communication, 

awareness of self, and increase attention. In recent years, 

numerous clinical and research organizations and health care 

providers have put continuous effort exploiting biochemical 

approaches. 3,4 Only small numbers of the treated children 

with autism develop into independent adults, however, and 

medications offer only symptom control and behavioral 

modification. 

Stem cell therapy as a hope of cure for autism has brought 

great attention the last several years, extensive researches has 

been conducted and showed promising results. Parents are 

desperate to try this new therapy because they have no time 

to wait. Stem cell therapy has a potential to help to open a 

new era of treatment for this centuries old mystery. 

OVERVIEW OF STEM CELL THERAPY FOR 

HUMAN DISEASES 

As bone marrow stem cell transplantation became a gold 

standard therapy for bone marrow failure, including the most 

hematologic malignancies the last 20 years, extensive 

research and preclinical studies reveals that stem cell 

treatment is also a promising treatment for a range of human 

diseases. Harris et al estimated, for example, that up to 128 

million individuals or almost 1 in 3 individuals in the US 

might benefit from regenerative medicine therapy (mostly


"stem cell" and “progenitor cell" technologies). 5 In addition 

to treatment of hematologic disease, stem cells are used for 

burns, bone grafting in orthopedics and corneal generation 

from limbal stem cells. Preclinical animal studies show 

therapeutic effects on spinal cord injuries 6 Parkinson 

disease, 7 retinal disease, 8 myocardial infarction, 9 type I 

diabetes, 10 multiple sclerosis, and muscle damage. The 

induced pluripotent stem cells (iPS) as a source of cell 

replacement has used human fibroblast cells. 11-12 Stem cells 

can also alter disease processes without engrafting, 13 as some 

effects through cytokine production 14 are potentially 

therapeutic. Stem cells in adult tissues can be targeted by 

certain drugs, with can activate or change stem cell 

function. 15 

Although stem cell therapy for human disease is quite 

promising, the development of this innovative medicine is 

still in an immature state that is marked by slow progress 

and mixed results 16 in clinical trials. Consequently, bone 

marrow transplantation remains the only established use of 

stem cells approved by the U.S. Food and Drug 

Administration (FDA) at this time. 

THE RATIONALE OF STEM CELL THERAPY IN 

AUTISM 

Autism spectrum disorder is a behaviorally defined clinical 

syndrome that likely involves multifactorial and 

heterogeneous etiological mechanisms. Evidence of 

abnormal brain development and function is compelling and 

well-accepted. Pathophysiological changes remain poorly 

understood, though abnormalities in cerebral 

hypoperfusion, 17 inflammations, 18 oxidative stress, 19 

increased brain volume, 20 immune dysregulation 21 

mitochondrial dysfunction, neurotransmitter abnormality, 22 

excess opioid, impaired detoxification, and functional 

disturbances such as disconectivity 23 offer clues. 

In recent years, brain hypoperfusion and immune 

dysfunctions 17,21 have been generally recognized as two 

major brain pathologic alterations in autism. The areas 

affected by hypoperfusion seem to correlate with regions of 

the brain that show abnormal function of autism. Sasaki et 

al reported the areas of hypoperfusion were also related to 

foci observed on EEG. 24 Gupta SK, et al concluded that 

children with autism have different levels of perfusion 

abnormities in brain causing neurophysiologic dysfunction 

that presents with cognitive and neuropsychological 

defects. 25 It is further indicated that the degree of 

hypoperfusion correlates with the severity of autism 

symptoms. Statistically significant inverse correlations occur 

between extent of hypoxia and IQ. Yang et al recently 

reported that hypoperfusion in autistic brains may be global. 

Asymmetric changes of hemispheric hypoperfusion were 

more obvious in the Asperger group than in the autism group, 

which indicates at least somewhat different neurobiological 

mechanisms between these subgroups. 17 Damage from 

hypoperfusion of temporal areas was associated with onset of 

autism-like disorders, as Bachavelier et al reviewed. 26 

Further studies revealed that improvement of hypoxia 

ameliorates clinical symptoms in autism, which implies that 

hypoperfusion contributes to the development or 

exacerbation of clinical symptoms in autism. Hyperbaric 

Oxygen Therapy (HBOT) provides invaluable clinical data 

on the treatment of hypoperfusion. Encouraging results were 

reported in Jandial et al in 2009, which showed neural 

proliferation after reperfusion in numerous animal models of 

cerebral ischemia. 27 

Immune dysfunction in autism, on the other hand, is also 

widely recognized. Ashwood et al recently reported findings 

suggested that ongoing inflammatory responses may be 

linked to disturbances in autistic behavior. 28 Careaga et al 

proposed that autism may in fact be a systemic disorder with 

connections to abnormal immune responses. 29 Ashwood et 

al pointed out such aberrant immune activity during 

vulnerable and critical periods of neurodevelopment could 

participate in the generation of neurological dysfunction 

characteristic of ASD. 30 

In 2007, Ichim et al 31 published their important review article 

about stem cell therapy for autism; they, proposed a role for 

stem cell therapy in treating autism. More specifically, they 

proposed the administration of CD34+ umbilical cord cells 

and mesenchymal cells as novel treatments for the above two 

major pathologies associated with autism – hypoperfusion 

and immune dysregulation. 

Treatment with umbilical cord blood CD34+ stem cells in the 

damaged areas of the brain may trigger or increase 

angiogenesis, the induction of new blood vessels from 

preexisting arteries, to overcome ischemia. Cord blood 

CD34+ cells are known to be potent angiogenic stimulators. 

Once the hypoperfusion is improved or reversed, it would not 

only improve nervous system functioning, but would also 

promote neural proliferation as an apparent self-repair 

mechanism. 

Since immune system is also critical in stem cell 

administration, mesenchymal cells are considered to be a 

necessary element in the treatment of immune dysregulation 

associated with autism. This approach may improve other, 

nonneurological problems as well, such as “leak gut”. 

Inflammatory bowel disease represents a state of 

dysregulated inflammation. A small pilot study of 

mesenchymal stem cells suggested a benefit in Crohn's 

disease, leading to the launch of multicenter, placebocontrolled 

studies. Larger trials in graft-versus-host disease 

have suggested a benefit, possibly due to reparative effects as 

well as immunomodulatory activity. 32 Other stem cell 

studies, including the use of placenta-derived stem cells, are 

being initiated in Crohn’s disease. Using these two kinds of 

stem cells together may potentially heal both the brain and 

the gut in autism. 33 

THE PRECLINICAL AND CLINICAL PICTURE OF 

STEM CELL THERAPY FOR AUTISM 

Recent studies show that umbilical cord blood CD34+ stem 

cell and mesenchymal stem cells administration for 

therapeutic angiogenesis and immune regulation may be 

effective in treating experimentally in various hypoperfusion


defects such as stroke. 34,35 Angiogenesis is induced through 

the formation of collateral vessels and has been observed in 

hypoperfused tissues. Theoretically, the level of angiogenesis 

needed for autism is lower than that needed for stroke, since 

ischemia in autism is milder than it is in stroke. Cytokines 

production by cultured human umbilical cord blood indicates 

systemic administration of cord blood cells is sufficient to 

induce neuroregeneration related to brain repair. Cellular 

therapies utilizing mesenchymal stem cells (MSCs) may 

provide functional benefits for a wide range of neurological 

insults. 36 One important concern should be noted involving 

the autologous reaction. It was believed that allogeneic cord 

blood cells could not be used without immune suppression, 

but Riordan et al 37 have successfully demonstrated the 

feasibility of cord blood cells administration in the absence of 

immune suppression. 

Autism in vivo studies are a step behind. It is equally 

important to use stem cells in disease modeling which is 

particularly relevant to diseases of complex etiology 38 such 

as autism. In recent years, stem cell research in the USA has 

been helpful in developing new medications for autism, with 

a number of in vitro studies reported. Autism cells have been 

successfully recreated from stem cells in lab studies. A 

collaborative effort between researchers at the Salk Institute 

for Biological Studies and the University of California 

successfully used human-induced pluripotent stem (iPS) cells 

derived from patients with Rett syndrome to replicate autism 

in the lab and study the molecular pathogenesis of the 

disease. 39-40 This study revealed disease-specific cellular 

defects and reversible symptoms that may be treatable. More 

recently Vaccarino FM 41,42 et al indicated exciting advances 

based on the use of induced pluripotent stem cells iPSCs, 

which holds promise for improving early diagnosis and, 

possibly, treatment of psychiatric disorders such as autism. 

Specifically, examination of iPSCs from typically developing 

individuals may reveal how basic cellular processes and 

genetic differences contribute to individually unique nervous 

systems. Gaspard N et al concluded that stem cell-derived 

neural progenitors and neurons could help to rebuild 

damaged brain circuitry, opening the possibility of cell 

therapy. 43 

What about the clinical picture Research in several 

countries, such as China, Mexico and India, include the use 

of cord stem cells to treat autism. The protocol includes 

involves several intravenous infusions over the course of a 

year, which are not covered by insurance. A typical protocol, 

for example, involves 4-5 intravenous injections of 20 

million stem cells over the course of a week, along with stem 

cell growth factors, at a cost of about $25,000 for one course 

of treatment. Data from Mexico reported 44 that 19 US 

patients under supervision of David Howe, MD, US licensed 

physician, traveled to Moscow to receive treatment with 

mesenchymal and neuronal cells for a number of conditions, 

including one autism patient. Improvement in patient status 

was reported in 17/19 (89%) patients. None of the patients 

developed tumors; Chaitanya Stem Cell Therapy Center in 

India 45 claims to have successfully treated 300 cases since 

last 28 months for cerebral palsy, Autism, Mental retardation, 

Spinal Cord Injury and Paraplegia, and Diabetes. China is 

another major stem cell treatment source. 46 

Depite these anecdotal cases and reports about autistic 

children who benefitted from stem cell therapy, no known 

clinical trials are under development. Biohellenika supported, 

free of charge, the therapy of a child who was treated with 

mesenchymal stem cells derived from the child’s own 

adipose tissue, 47 and reported positive short term benefits. 

Unfortunately, positive treatment reports are little more than 

unsubstantiated rumors at this point, 48,49 owing to a lack of 

credible, peer-reviewed articles or even case reports. 50 

Hopefully, this picture will change. Because of epidemic 

nature of autism and the sound rationale of stem cell therapy, 

autism is listed as top three candidates in adult stem cell 

treatments the next ten years. 51 

BARRIERS TO SUCCESS 

As mentioned above, stem cell therapy provides intriguing 

treatment possibilities for many human diseases, including 

autism. However it is still in its immature stage. There are 

many barriers to overcome on the path to clinical feasibility 

and treatment success. First of all, stem cell therapy as a new 

renovation has a lot of technical complexities to be addressed 

when used in human body. Immuno-rejection of stem cell 

transplants is a great challenge in clinical treatment. There is 

a need to establish cell survival rates after immediate or 

subsequent immune-rejection, for example, or after graftversus-host 

disease. Individualized iPSC tissue offers the 

possibility of personalized stem cell therapy in which graft 

rejection would not occur, but achieving this on a large scale 

is problematic because of inefficient reprogramming 

techniques and high costs. The creation of stem cell banks 

comprising HLA-typed hESCs and iPSCs may help 

overcome the immunological barrier by providing HLAmatched 

(histocompatible) tissue for the target population. 52 

Immune modulation offers therapeutic benefit for immune 

rejection reactions. 53 Neural stem cells have unique 

characteristics that help them modulate the host 

immunological defense, but, under some conditions, may still 

trigger a rejection process. 54 

Interactions with surrounding tissue could also be 

complicated for surviving transplanted stem cells. MRI 

studies could track the grafted cell migration 55 and the 

surrounding tissue which may negatively affect graft survival 

or the functional recovery of the tissue. Kim et al 56 described 

procedures to direct the differentiation of human embryonic 

stem cells and human induced pluripotent stem cells into 

forebrain neurons that are capable of forming synaptic 

connections, and that are able to induce presynaptic 

differentiation in human induced pluripotent stem cellderived 

neurons. 

The risk of tumors is a significant safety issue and threat, as 

are viruses used in some therapies that can develop in 

recipient's bodies. This is of particular importance when 

using pluripotent cells 57,58 The pluripotent cell methods of 

greatest efficiency for reprogramming cells are currently 

retrovirus or lentivirus-based, and, therefore, run the risk of


mutagenesis by virtue of viral integration into the host 

genome. 59 Progress in reducing the number of gene products 

needed for reprogramming, and in the use of either nonintegrating 

viruses or small molecules to supplant retrovirusbased 

reprogramming, is ongoing. 60 These developments may 

mitigate the concerns about insertional mutagenesis, but will 

not entirely assuage concern for altered growth control of 

modified cells, particularly those with pluripotency. 

Generating the proper cell type from pluripotent cells 

remains a significant challenge for some cell types. Protocols 

have now been devised to create some neural cell types of 

clear clinical importance. 61 However, for other tissues, the 

cell types created most closely resemble embryonic blood 

cells and are not capable of engrafting the bone marrow 

without further and undesirable genetic manipulation. 62 

Achieving the right stage of differentiation is another 

consideration in development of the stem cell derived cell 

therapies. It may be most desirable to generate progenitors, 

rather than fully mature terminally differentiated cells in 

some tissues, so that the replaced cells do not quickly senesce 

and die. 

Furthermore, autism as a group of highly complicated 

neurological disorder is more genetically labile than others. 

For example, secondary malignancies (SMs) in Hodgkin 

lymphoma (HL) are thought to be related to exposure to 

chemotherapy and radiation therapy, and tend to occur a 

decade after initial therapy. Chandrakasan et al, for example, 

reported a 14 year old autistic male who developed malignant 

fibrous histiocytoma (MFH) two years after autologous stem 

cell transplantation for advanced stage HL. The MFH and 

post-surgical reactive tissues exhibited multiple clonal 

abnormalities. In addition, PHA-stimulated peripheral blood 

lymphocytes showed increased frequency of non-clonal 

chromosomal aberrations. The potential role of genomic 

instability in early onset of SM in this patient was 

discussed. 63 In light of likely etiological heterogeneity, it is 

possible that only some cases of autism will respond 

positively to stem cell therapy, such as those with evidence of 

hypoperfusion and immune dysfunction. 

It is needed to point out those stem cell technology based 

therapy protocols, we reviewed as promising as they are, are 

actually examples of a larger group of strategies (such 

as gene transfer, or using antibodies to induce 

endogenous stem cells to form blood vessels or neurons) that 

may one day help neurons ameliorate abnormalities that 

underlie autism. 

Lastly, social and ethical impacts are important 

considerations. As mentioned above, stem cell therapy is in 

its early stage and mostly not approved by FDA and can be 

only done outside of USA. The technology and protocol is 

not well established. It’s very costly, and not necessarily safe 

(e.g. stem cells may be contaminated with various 

pathogens). 

CONCLUSION 

Autistic Spectrum Disorders encompass a wide range of 

disorders or conditions that are not yet clearly defined or 

recognized. More work need to be known before the 

pathology is clear and treatment can be proposed. While the 

rationale for using stem cells to treat autism is indeed 

promising, stem cell medicine, or in general, regenerative 

medicine, is still in an immature and primary stage. In vitro 

and in vivo animal studies will need to be furthered to better 

understand the pathogenesis of autism and screen new 

medications, and clinical trials with sufficient patient 

numbers are needed to assess treatment efficacy. When 

patients and their families consider new treatments, the 

proposals need to be interpreted in a discerning manner that 

can be balanced with scientific evidence. We propose more 

effort involve improvement of technology, development of 

vivo animal models and development of protocols for clinical 

trials. We foresee a potential for significant progress in the 

next decade as stem cell research and regeneration medicine 

continue to mature. 

FINANCIAL DISCLOSURE 

Authors declare no financial interests related to this work. 

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Review 

Autism Disease: Neural Network Going Awry and 

Therapeutic Strategy Underlying Neural Plasticity 


ABSTRACT 

Autism is the major form of Autism Spectrum Disorders 

(ASD). Autism was first discovered in 1940s and has 

attracted enormous research and social activities recently. 

It is a disease currently defined only by behavior 

problems including impairments in communication, 

inability in social interactions, and stereotyped patterns 

of interest and behavior. Because of the complexity 

nature of the disease, there are many basic questions yet 

to be answered by scientific research. Autism is of great 

and increasing public health concern because the number 

of children receiving services is growing each year. In this 

commentary review, we will analyze recent studies on 

brain structure, genetics, and brain conditions and graph 

an overview of autism from these findings. Under the 

basis of synaptic plasticity, we believe the findings have 

led us to propose a hypothesis on therapeutic strategy, by 

which we may be able reshape the troubled neural 

network towards its normal networking function. 

[N A J Med Sci. 2011;4(3):139-150.] 

KEY WORDS: Autism Spectrum Disorders, DSM-V, Rett‟s 

Syndrome 

INTRODUCTION OF AUTISM AND AUTISM 

SPECTRUM DISORDERS 

Autism disorder is discovered and described with the same 

disease name independently by two physicians, the American 

psychiatrist Leo Kanner and Austrian pediatrician Hans 

Asperger. 1,2 The terminology is derived from the Greek word 

„autos‟ meaning „self‟. Intriguingly, the patients often reverse 

the normal use of pronouns, particularly using „you‟ instead 

of „I‟ or „me‟ when referring to themselves. 1 In 1943, Leo 

Kanner published the classic paper Autistic Disturbances of 

Affective Contact. In the paper, he described a group of 

patients with excellent rote memories (such as remembering 


Mei Zhang, MD 

Neurodegeneration Drug Discovery Programs 

Lead Discovery Technologies 

EMD Serono Research Institute 

Merck KGaA, Darmstadt 

45 Middlesex Turnpike, MA 01821 

Email: 

mei.zhang@emdserono.com, mei.zhang.m@gmail.com 

rhymes, lists, and numbers) but poor social and 

communication skills starting from infancy. In 1944, Hans 

Asperger published his original paper described a similar 

condition with similar social and communication difficulties 

similar to Kanner‟s autism but with relatively normal 

intelligence, now known as Asperger syndrome. 2 It was 

noticed that Asperger first created this terminology in his 

speech before both publications. 1 Largely based upon Kanner 

and Asperger‟s independent findings, we now define autism 

as a group of disease with shared characteristics including 

impaired social interactions, troubled inter-personal 

communications, restricted interests, and repetitive 

behaviors. i Most patients develop symptoms before the age 

of one year old, which might have been already emerging 

even at the time of birth, and all have onsets before age of 3. 

One of the major reasons for autism attracting public interest 

and medical attention is that this is a highly popular disease, 

highlighted by a world-wide prevalence of approximately 0.2 

percent. The other four subtypes of ASDs are either similarly 

common or less common than autism, including Pervasive 

Developmental Disorder Not Otherwise Specified (PDD- 

NOS or Atypical Autism) (0.15 percent prevalence), Rett‟s 

Syndrome (caused by MECP2 mutations or less commonly 

CDKL5 or FOXG1 mutations) (0.006 percent prevalence), 

Asperger‟s Disorder (ASP; a similar condition that is not 

associated with language delay or general intellectual 

impairments) (0.025 percent prevalence) and Childhood 

Disintegrative Disorder (CDD; usually a normal development 

followed by an abrupt recession of brain functions) (0.001 

percent prevalence). 7 The estimated prevalence of ASD in the 

US is 1 in 110. 8 It is noteworthy that in 2000 US Centers for 

Disease Control and Prevention (CDC) have built a group of 

programs named the Autism and Developmental Disabilities 

Monitoring (ADDM) Network to track the prevalence and 

characteristics of ASDs in the country. 9 The prevalence of 

autism in the US has kept increasing each year after the 

initial discovery of the disorder. 

Autism spectrum disorders and autism are now classified 

under the category of Neuordevelopmental Disorders in the 

revising fifth edition of Diagnostic and Statistical Manual of 

Mental Disorders (DSM-V) (in development, expected 

publication after July 15, 2011) by the American Psychiatric 

Association. 10 In DSM-IV it has been classified under the 

category of Pervasive Developmental Disorders (PDD). 

According to DSM-V, a person must have all four 

characteristics below for the diagnosis of ASD; therefore, 

diagnosis of autism must also meet all of the parameters of


the following four aspects in DSM-V (with minor corrections 

for typo and punctuation for consistency by the author): 

A. Persistent deficits in social communication and social 

interaction across contexts, not accounted for by general 

developmental delays, and manifest by all 3 of the 

following: 

1. Deficits in social-emotional reciprocity; ranging from 

abnormal social approach and failure of normal 

back and forth conversation through reduced 

sharing of interests, emotions, and affect and 

response, to total lack of initiation of social 

interaction. 

2. Deficits in nonverbal communicative behaviors used 

for social interaction; ranging from poorly 

integrated- verbal and nonverbal communication, 

through abnormalities in eye contact and bodylanguage, 

or deficits in understanding and use of 

nonverbal communication, to total lack of facial 

expression or gestures. 

3. Deficits in developing and maintaining relationships 

appropriate to developmental level (beyond those 

with caregivers); ranging from difficulties 

adjusting behavior to suit different social contexts 

through difficulties in sharing imaginative play 

and in making friends, to an apparent absence of 

interest in people. 

B. Restricted, repetitive patterns of behavior, interests, or 

activities as manifested by at least 2 of the following: 

1. Stereotyped or repetitive speech, motor movements, 

or use of objects; (such as simple motor 

stereotypes, echolalia, repetitive use of objects, or 

idiosyncratic phrases). 

2. Excessive adherence to routines, ritualized patterns of 

verbal or nonverbal behavior, or excessive 

resistance to change; (such as motoric rituals, 

insistence on same route or food, repetitive 

questioning or extreme distress at small changes). 

3. Highly restricted, fixated interests that are abnormal 

in intensity or focus; (such as strong attachment to 

or preoccupation with unusual objects, excessively 

circumscribed or perseverative interests). 

4. Hyper-or hypo-reactivity to sensory input or unusual 

interest in sensory aspects of environment; (such 

as apparent indifference to pain/heat/cold, adverse 

response to specific sounds or textures, excessive 

smelling or touching of objects, fascination with 

lights or spinning objects). 

C. Symptoms must be present in early childhood (but may 

not become fully manifest until social demands exceed 

limited capacities). 

D. Symptoms together limit and impair everyday functioning. 

Currently autism is largely regarded and cared as a social 

problem for physically normal patients. Many of them 

have received public support such as from professional 

and public societies as well as commercial trainings. A 

significant proportion of patients have complications 

including epilepsy and anxiety that are associated with 

the disease. These patients are frequently under drug 

treatment to control symptoms. A collection of drugs for 

officially (FDA) recognized indications to autism, as well 

as off-label treatment (a much larger proportion), are 

listed below. 

In the rest part of the review, we will focus on autism (rather 

than ASD) for its abnormal brain features, genetic defect 

profiles, oxidative stress related physical conditions, and the 

concept of neural plasticity, and from these analyses, we 

hope to depict an overall picture towards the hypothesis for 

neuroplasticity based therapy for autism patients. 

Table 1. Drug for treating symptoms and complications in autism patients. (From source that is updated in 2011 11 ) 

Part 1: US Food and Drug Administration (FDA) approved drugs for autism: 

Name 

Abilify 

Risperdal 

Generic 

Name 

aripiprazole 

risperidone 

Description 

This antidepressant was recently approved by the FDA in the United States for the treatment of 

irritability associated with autistic disorder in pediatric patients 6 to 17 years of age. 

This oral psychotropic medication is used to treat aggression, irritability, and severe behavior problems 

in autistic children 5-16 years old.


Part 2: Off label treatment for autism: Drugs below approved for psychological disorders may also have therapeutic effects on 

autism that, however, are off-labeled. Clinicians can administer these drugs to autism patients for releasing related symptoms and 

improving social behaviors. 

Name Generic Name Description 

Actos 

Actoplus Met 

pioglitazone 

hydrocloride 

pioglitazone 

hydrocloride and 

metformin 

hydrochloride 

Both Actos and Actoplus Met are being tested in people with neurological 

disorders, including autism, because it can also be anti-inflammatory in glial 

cells in the brain. Preliminary studies showed improvements in behavior in 

children with autism. 

Adderall amphetamine Adderall is a central nervous system stimulant that affects chemicals in the brain 

and in nerves. These brain chemicals (neurotransmitters) regulate activity and 

impulse control. Adderall may be prescribed off-label for people with autism. 

Caution: amphetamines have a high potential for abuse and addiction. 

Anafranil 

Aricept 

clomipramine 

hydrocloride 

donepezil 

hydrochloride 

Anafranil is an antidepressant that may be prescribed off-label for children 

with autism to help decrease repetitive movements and improve social contacts 

Aricept enhances cholinergic function in the brain by reducing the activity of 

the enzyme acetyl cholinesterase. In people with autism, Aricept may help 

improve attention, learning, and memory. Possible benefits of Aricept are being 

tested in children and adults with autism, as well as ADHD and schizophrenia. 

Ativan lorazepam Ativan is an anti-anxiety medication that may be prescribed for people 

with autism to help reduce anxiety, and to help reduce symptoms 

of catatonia(rigid and insensitive muscles). Ativan is indicated 

for treatment of anxiety disorders. 

Bethanechol bethanechol chloride Bethanechol is prescribed for triggering urination and emptying of the bladder 

when urine is being retained in autism patients. 

Buspar 

Carbatrol - 

Equetro -Tegretol 

buspirone 

hydrochloride 

carbamazepine 

Buspar is an antianxiety medication that is indicated for 

generalized anxiety disorder. Buspar may be prescribed off-label for people 

with autism to help reduce anxiety and aggression and to help improve 

behaviors. Buspar has helped improve behaviors in some people with autism. 

This medication is currently being tested in children and adults with autism. 

Carbamazepine is the generic for three brand name drugs, Carbatrol, Equetro, 

and Tegretol. 

Tegretol is an anticonvulsant medication used to 

help control seizures. Tegretol may be prescribed for people with autism who 

have seizures, and can also help soften mood swings. 

Carbatrol may be prescribed for people with autism who have seizures, and can 

also help reduce aggression. 

Equetro is an extended-release formulation of carbamazepine. It is indicated for 

the treatment of mania in bipolar disorder. Equetro can have serious side 

effects that include agranulocytosis and other changes in blood cells, so the 

person taking this medication should be monitored with regular blood tests. 

Note: Carbamazepine can have serious side effects with a 

certain genetic background. 

Clozaril -FazaClo clozapine This is an antipsychotic medication that may be prescribed off-label for children 

with autism to help reduce hyperactivity, fidgeting, 

and aggression. Clozaril® lowers binding of dopamine to most types 

of dopamine receptorsand other types of receptors on cells in the nervous 

system.


Concerta 

methylphenidate 

hydrochloride 

Some children with autism also have ADHD and this drug may be helpful in 

treating the symptoms of ADHD. 

Depakene valproic acid Depakene affects the way that cells get signals to turn on and off in the nervous 

system. People with autism who also have seizures might be prescribed this 

medication. 

Depakote divalproex sodium Depakote is an anticonvulsant used to treat epilepsy. People with autism who 

also have seizures might be prescribed this medication. 

Dexedrine - 

Dexedrine 

Spansule 

dextroamphetamine 

sulfate 

Dexedrine may be prescribed off-label for hyperactivity in children with autism. 

Dextroamphetamine sulfate is an amphetamine that stimulates the brain 

and nervous system. Caution: Amphetamines have a high potential for abuse and 

may lead to drug dependence. 

Diastat diazepam Diastat may be prescribed for people with autism who also have epilepsy, and 

would usually be administered as short term treatment during the seizure. 

Diflucan fluconazole Diflucan is an anti-fungal antibiotic that is prescribed to treat fungus infections 

in any part of the body. Diflucan may be prescribed off-label for children 

with autism to help relieve their autism symptoms, based on the idea that autism 

symptoms may be related to fungus infections in children. 

Dilantin phenytoin sodium Dilantin is an antiepileptic drug that is indicated for helping 

to control seizures in children and adults with autism. 

Endrate edetate disodium Endrate is administered I.V., and recommended only for severe cases of metal 

poisoning and prescribed for emergency treatment of hypercalcemia as chelation 

therapy in children with autism. 

Eskalith lithium carbonate Eskalith (lithium carbonate): Eskalith® is anantidepressant that may be 

prescribed off-label for children with autism. 

The safety andeffectiveness of Eskalith in children with autismhas not been 

proven but it may be helpful for some of them. 

Fortamet - 

Glumetza 

metformin 

hydrochloride 

Metformin works by decreasing liver glucose production, and increasing 

sensitivity to insulin in muscle and fat tissue. In people with autism, 

taking metformin with antipsychotic medications such as risperidone may help 

reduce weight gain that often occurs as a side effect of 

the antipsychoticmedication. 

Geodon ziprasidone Geodon is an antipsychotic medication that may be prescribed for people 

with autism to help reducehyperactivity, aggression, self-abusive behavior, 

temper tantrums, lability (mood swings), social withdrawal, and repetitive 

behaviors. Geodon is currently in clinical trials to test effectiveness in children 

with autism. Some children have improved with treatment. Geodon works as 

adopamine and serotonin type 2 antagonist, and has other effects on the nervous 

system. 

Haldol haloperidol Haldol is an antipsychotic medication that may be prescribed for some people 

with autism to help control aggression. 

Inderal 

propranolol 

hydrochloride 

Known as a beta-blocker, Inderal being studied as a treatmentfor 

severe aggression in children with autism. 

Klonopin clonazepam Clonazepam is indicated for use to treat seizure disorders and panic disorder. It 

may also be prescribed off-label for other conditions. 

Invega paliperidone Paliperidone is indicated for treatment ofschizophrenia in adults. It may be 

prescribed off-label for children with autism. Invega belongs to a class 

of drugs called atypical antipsychotics. 

Lamictal lamotrigine Lamictal is an anticonvulsant and mood stabilizer that may be prescribed off-


label for people withautism to help 

reduce lethargy (tiredness),irritability, hyperactivity. It may also 

improvelanguage, communication, and social skills. 

Luvox fluvoxamine maleate Luvox is an antidepressant that may be prescribedoff-label for people 

with autism to help decreaserepetitive movements and improve social contacts. 

Mycostatin nystatin Oral medication is Nystatin; cream form is Mycostatin. Mycostatin 

and Nystatin are prescribed to treat fungal infections of the skin, mouth, vagina, 

and intestinal (digestive) tract. 

Namenda 

memantine 

hydrochloride 

Namenda may be prescribed off-label for people with autism in an effort to help 

improve language, social behavior, and other behaviors. Namenda is 

a glutamatereceptor antagonist (inhibits glutamate binding to its receptors). 

Paxil paroxetine Paroxetine is an antidepressant that is a type ofselective serotonin reuptake 

inhibitor (SSRI). It works by restoring the balance of serotonin, 

aneurotransmitter in the brain, which helps to improve 

certain mood problems. Paxil® may also be prescribed for people with autism. 

Pepcid famotidine Pepcid is a type of histamine-2 blockers that decreases the amount of acid that 

the stomach produces. Pepcid® is used to treat and prevent ulcers in the stomach 

and intestines. It also treats other conditions in which the acid produced by the 

stomach is a problem, such as gastroesophageal reflux disease (GERD) and 

heartburn. 

Provigil modafinil Provigil promotes wakefulness. Off-label,modafinil is used by sleep deprived 

people to stay awake and to treat fatigue in autism. 

Prozac 

fluoxetine 

hydrochloride 

Prozac is an antidepressant that may be prescribed for people with autism to help 

decreaseaggression and depression. It can also help reduce repetitive behaviors, 

and improve languageand social interactions. 

Remeron mirtazapine Mirtazapine is an antidepressant that adjusts thebalance of neurotransmitters like 

norepinephrine and serotonin in the brain. Mirtazapinemay also be 

prescribed off-label for children withautism. 

Revia -Vivitrol naltrexone This medication may be prescribed for autistic children to help improve ability 

to socialize and make eye contact, and also to help reduce painsensitivity, selfinjury 

behaviors, and repetitive behaviors. This drug is an opioid antagonist, so 

it binds to opioid receptors and blocks the binding of alcohol or other drugs to 

thereceptors, thus blocking the opiates from having an effect so the person will 

stop their addiction. Some children with autism have higher than normal levels 

of beta-endorphins in their nervous system, and naltrexone can lower betaendorphin 

levels. 

Ritalin -Methylin 

methylphenidate 

hydrochloride 

Ritalin and Methylin are mild central nervous system stimulants that may be 

prescribed for people with autism to help reduce 

hyperactivity and repetitive movements. 

Rozerem ramelteon Ramelteon is an oral medication (tablets) fortreatment of insomnia (an inability 

to sleep well).Ramelteon stimulates melatonin receptors in thenervous system, 

thereby promoting sleepiness. Many children with autism have 

problems sleepingand ramelteon is currently being tested foreffectiveness in 

children with autism. 

Sarafem 

fluoxetine 

hydrochloride 

Sarafem is an antidepressant that may be prescribed for people with autism to 

help decreaseaggression and depression. It can also help reduce repetitive 

behaviors, and improve languageand social interactions. 

Sporanox itraconazole Sporanox is prescribed to treat serious fungal infections which may invade any 

part of the body including mouth, throat, lungs, or nails.


Stablon -Coaxil - 

Tatinol 

Strattera 

Symbyax 

tianeptine 

atomoxetine 

hydrochloride 

fluoxetine 

hydrochloride and 

olanzapine 

Tianeptine is a serotonin reuptake enhancer. This mechanism of action differs 

from manyantidepressants that are serotonin reuptake inhibitors. 

Strattera may be prescribed off-label for people with autism to help 

with hyperactivity, obsessions, and other behavior problems. Stratteraworks by 

changing the ways some neurons are turned on and off. 

Symbyax contains an antidepressant (fluoxetine) and 

an antipsychotic (olanzapine). Symbyax may be prescribed for people 

with autism to decreaseanger, aggression, and repetitive movements; and to 

improve social interactions. 

Tenex -Intuniv guanfacine Tenex or Intuniv (extended release form) stimulates certain receptors in the 

brain and nervous system. Guanfacine is indicated for lowering 

blood pressure and may also be prescribed off-label for sleep disorders, posttraumatic 

stress disorder, anti-social behaviors, oppositional disorder, and 

Tourette‟s disorder. 

Thorazine - 

Thorazine 

Spansule 

Tofranil 

chlorpromazine 

imipramine 

hydrochloride 

Thorazine may be prescribed for the treatment of severe behavioral 

problems such as combativeness and/or explosive hyperexcitable behavior. 

Tofranil is a tricyclic antidepressant that is usually prescribed for depression, 

and for childhood enuresis (bed-wetting). 

Topamax topiramate Topamax is an anticonvulsant that may be prescribed for people with autism to 

help reduceirritability and self-injuring behaviors. 

Trileptal oxcarbazepine This anti-seizure medication affects the way neurons are turned on and off. 

People with autism who also have seizures might be prescribed this medication. 

Valium -Diastat diazepam Valium is a sedative that may be prescribed for people with autism to help 

reduce aggression and anxiety, or for seizures. 

Versenate 

edetate calcium 

disodium 

Versenate chelates or strongly binds to divalent and trivalent metals 

including lead, zinc, cadmium, manganese, iron, and mercury. Versenate may 

be used in children with autism to reduce heavy metals in their body in an effort 

to improve behaviors. 

Xanax alprazolam Alprazolam helps restore chemical balance in the brain when there are 

imbalances that may cause anxiety. It may also be prescribed off-label for 

people withautism. Caution: alprazolam may be habit-forming. 

Zoloft 

sertraline 

hydrochloride 

Zoloft is an antidepressant that may be prescribed to help 

reduce anxiety and repetitive behaviors in people 

with autism. This medication is aserotonin reuptake inhibitor (SSRI). 

Zyprexa olanzapine Zyprexa is a psychotropic medication that may be prescribed off-label for people 

with autism to reduce disruptive and repetitive behaviors. Zyprexa works as 

a dopamineand serotonin type 2 antagonist, and has other effects on the nervous 

system. 

NEUROIMAGING ABNORMALITY OF AUTISM IS 

CHARACTERIZED BY PAN-BRAIN INVOLVEMENT 

Three types of techniques have been utilized to identify brain 

abnormalities in autism. These include head circumference 

measurement, postmortem anatomy, and neuroimaging. 

Neuroimaging has been the most promising technique to 

unravel the structural and functional changes of autism brain. 

To explore the significance of neurobiology findings on 

autism, it would be necessary to summarize the application of 

in vivo imaging technology and the progress in human brain 

mapping. 

Mapping human brain has been mainly benefited from 

advanced neuroimaging technologies. Positron emission 

tomography (PET), magnetic resonance imaging (MRI), 

functional MRI (fMRI) and neurospectroscopy have been 

applied to autism research. 12 PET detects gamma rays from 

pulsed radioactive material (a blood sugar analog) to track 

brain blood flow. Based upon the high fidelity correlation


between brain activity and blood supply, PET produces threedimensional 

images and records changes of brain blood flow. 

Modern PET scanners acquire the images with the aid of 

computerized tomography scan (CT scan), namely PET/CT 

scan. PET based technology is a specific and sensitive 

method for brain function analysis. This technology has 

serious limitations due to the use of on-site generated radiotracers. 

13 MRI, which wins the Nobel Prize in 1980, 

revolutionarily contributed to medical and neural imaging 

field. MRI utilized magnitude field to realign the brain water 

protons and detect the diffusion of water molecule during 

magnitude releasing. A several minute scan can provide more 

than 100 pictures of tissue slices visualizing the entire brain. 

Detail and accurate structures of only 1mm in size can be 

identified for the most part of brain. 14 MRI technology is 

non-invasive, non-radioactive, and has been proved safe from 

more than 30 years of use. MRI is the most powerful in vivo 

technique to characterize live brain structures. The further 

developed MRI, fMRI, combines MRI with blood flow 

detection technique to accurately examine activated brain 

area. fMRI is the major technology to localize and map the 

functionality of the brain. Neurospectroscopy (MRspectroscopy, 

or MRS) is a newly developed imaging 

technology which records protons from various tissue 

chemicals other than water (unlike MRI), such as intrinsic 

phosphorus containing metabolites, sodium, potassium, 

carbon, nitrogen, and fluorine. MRS provides the possibility 

to record human and animal brain biochemistry in vivo. The 

combination of MRS with PET or MRI may create a 

powerful platform for mapping human brain in normal and 

pathophysiological conditions such as autism. 15 

Neuroimaging-based studies on brain mapping highlight the 

integrity and interactions between cortex and limbic system, 

between left and right hemispheres, and between the alreadybuilt 

structure and the neural plasticity of human brain. A 

functionally efficient human brain is depend upon the well 

developed cerebral cortex and sub-cortical structures, 

coordination between both hemispheres, and modifiability of 

developed, matured brain. Functional brain mapping suggests 

that human brain is constantly under dynamic reconstruction 

adjusting from the change of environment. Although infants 

already have approximately 100 billion neurons at birth that 

is the similar amount to adults, the neurons are largely 

separated from each other and not well myelinated. 16 They 

are relatively inactive in communication and work separately 

as single cellular units. In the early period of life, the most 

important activity is the maturation process by establishing 

neuronal networking across the brain. The first two years of 

life is the most critical stage for establishing the network 

towards a highly functional system. 6 The maturation process 

is largely dependent upon the genetic programming that is 

adapted to personal development of human being. Recent 

study of human brain has suggested that this system is altered 

in genetic psychological disorders including autism. 17,18 

The first finding on autism brain abnormality is probably the 

enlarged brain size. This finding has provided important clue 

to autism‟s underlying pathology. Kanner first noticed autism 

patients had relatively large head size in his clinics (Kanner 

1943). 1 Other early reports also suggested that children with 

autism had enlarged brain size. 19 Clinical analysis has 

confirmed this disease feature in broad population. 

Systematic clinical examination, post-mortem and MRI 

studies have revealed that increased head circumference 

(macrocephaly), brain weight. 20,21 and brain volume. 22,23,24 

were a gross anatomic feature of autism. The finding of brain 

enlargement in autism appears to be widely noticed. These 

abnormalities could be resulted from several problematic 

developmental processes that cause increased neurogenesis, 

enhanced myelination and decreased neuronal elimination. 25 

Researchers have examined available data from literature on 

the entire developmental course of brain enlargement in 

autism. They found that the enlargement is time-delimited to 

the first 2-4 years of life. There are three stages of the size 

change during autism childhood life - a reduced or normal 

brain size at birth, an early rapid rate of brain growth before 

year 2, and an abrupt cessation of growth by years 2-4. 26 

Acceleration of brain growth in early age followed by a 

dramatic deceleration is a consistent finding in autism. This 

early cessation of growth results in a 2-4 year old autistic 

brain size that is similar to a normal adolescent or adult in 

majority of cases. At the age of 3-4, the period of 

pathological growth and arrest has likely already passed. 

Since autism pathology might develop mainly in the first 

years of life which is typically prior to the clinical diagnosis, 

by the time of diagnosis, clinicians and researchers often face 

a structure-wise “permanent” outcome. 27 

Further studies by neuroimaging seemed to have achieved 

very limited focuses on autism brain pathology. Despite 

growing number of quantitative MRI studies, only few robust 

findings have been observed. Some consistent findings from 

the main stream of research suggest the existence of 

morphometric abnormalities in several substructures in 

autism brain. Besides the total brain volume change, the 

structural abnormalities also involve the cerebellum, 

hippocampus, amygdala, corpus callosum, parieto-temporal 

lobe, and limbic- forebrain structures. The results have been 

noticed from well-designed MRI reports with satisfactory 

methodology. Among them, the size of corpus callosum may 

be reduced and amygdale may be increased. 25 While some of 

the structural changes are not yet of indicative about clinical 

manifestations, these two structures are highly interesting 

regarding the autism clinical characteristics. Amygdala is 

involved in emotional processing and therefore important in 

social interaction and cognitive functioning including of 

facial expression recognition, ability to gaze and 

interpretation of gaze, motion mimicking, visual alertness of 

potential threatening and hostile approaches. 5 There has been 

developed a proposal of an “amygdale theory of autism”. 29 

Lack of the related function might contribute to the social 

behavior and social intelligence deficits. Corpus callosum 

size reduction may diminish inter-hemispheric connectivity 

between relevant functional nuclei. The combination of both 

deficits may be involved in pathophysiology of the cognitive 

impairments of autism. It is still in debate about whether


frontal lobes are anatomically abnormal in autism, however 

considerable evidences from several controlled functional 

reports support that the pathophysiology likely exist due to 

cognitive impairment of autism. 30,31,32 

In summary, it is difficult to pinpoint the structural 

abnormalities but apparently easy to notice the overall 

change of autism brain - the abnormalities are rather 

generalized instead of localized, involving regions covering 

from the cortex, limbic system, to cerebellum, strongly 

suggest a troublesome brain system as a whole organ. It is 

now commonly accepted that autism has disturbed neural 

network involving cortical and subcortical areas, including 

temporo-parietal cortex, limbic system, cerebella, and 

prefrontal regions. 

It is noteworthy that some well controlled MRI studies have 

showed negative findings in the size of certain brain 

structures including cerebellar vermis, brainstem, basal 

ganglia, and 4 th ventricle, suggesting that these structures 

may be anatomically preserved but still deserve further 

investigation with advanced imaging technologies. 25 The 

quality of MRI-based neuroimaging investigations has 

steadily improved over recent years; still, many MRI studies 

seemed to be suffered from considerable methodological 

limitations, restricting the generalization of their findings. 

Longitudinal studies employing MRI would be preferential to 

tracking formation of abnormality of brain development to 

understand the neurobiology of autism. Future high quality 

quantitative MRI studies will need to be further carried out, 

with a focus on identifying possible morphological brain 

markers to further clarify the neural networks sustaining the 

pathophysiology of autism. Novel neuroimaging technologies 

such as voxel-based morphometry, 33 magnetization-transfer 

imaging, 25 and diffusion tensor MR imaging 34 are expected 

for further investigating the relative contributions of brain 

sub-structures for mapping and characterizing the neural 

networks of autism. 

GENETIC PROFILE OF AUTISM IS CONTRIBUTED 

BY COMPLEX GENE VARIATIONS 

Autism is currently recognized as a genetic disease, most 

likely resulted from multiplex genetics factors with or 

without the influence of before or after birth environments. 3 6 

It is recognized that autism is one of the highest heritable 

disorders among psychiatric disease. Around 80% of 

monozygotic twins suffer from the same disease if acquired, 

compared to only 10% of sharing in dizygotic twins. 37,38 It 

affects predominately males with a male-to-female ratio of 

approximately 4.3:1, which might indicate an association 

with sex chromosomes. 39 

The genetic architecture of autism is not yet known. Autism 

is very likely a genetic disorder that results from 

simultaneous genetic variations related to multiple genes. 

Studies showed that although certain form of ASD may be 

transmitted in a Mendelian fashion within a single individual 

or family, for autism itself, common genetic variations in the 

population may contribute in a far more common and 

complex manner than Mendelian. 40,41,42 Large-scale genetic 

studies have been conducted in the last decade and shown 

clearly that the disease is not simply a Mendelian disorder. 43 

Despite various gene candidates have been proposed, none 

has been assigned to autism as disease-causing gene. Rare 

mutations have been identified in several synaptic genes, 

including neuroligin (NLGN3 and NLGN4X), 44 neurexin 

(NRXN1), 45 contactin (CNTN4) 46,47 and SH3 and multiple 

ankyrin repeat domain 3 (SHANK3). 42 Other candidate genes 

have been thought to be promising: GABA receptor, 

serotonin transporter genes, engrailed 2, MeCP2, Wnt2, and 

BDNF. Some of the genes encode neuronal cell-adhesion 

molecules that may be related to autism pathology. Some 

candidate genes have functions in synapse organization and 

are regulated by the trans-synaptic cell adhesion complex 

comprising the neurexins and neuroligins, both of which have 

been implicated in autism. 48 Genetic analysis has also 

observed a low functioning system featured with melatonin 

deficiency in a small number of autism population. Children 

with autism have been observed to show pineal gland 

hypofunction, with low melatonin production and cooccurrence 

of sleep disturbances and altered circadian 

rhythms. 49 Mutations in splicing or promoter region in the 

ASMT gene were detected in autism. 50 ASMT encodes for 

the last enzyme in melatonin synthesis and the altered ASMT 

gene can cause low expression or function of ASMT 

resulting in decreased level of melatonin. 49 Multiple small 

studies have demonstrated that 2 to 10 mg of melatonin may 

benefit autism patients with improved sleep. 52,52,53 Future 

study will need to identify melatonin‟s long term therapeutic 

effect on autism for the improvement of communication and 

language deficiency. 

Copy number variations (CNVs) (in contrast to amino acid 

coding region mutations in single genes) are indications of 

genomic alteration in a general fashion rather than restricted. 

CNVs were found enriched in ASD cases compared to 

controls. CNVs of both deletion and duplication were 

recurrently observed in 5-10% of ASD cases in several 

chromosomes. Genomic regions with heritable CNVs may 

carry substantial risk for ASD including autism as reported 

recently in several studies. 54,55 Some CNV studies have 

revealed clustering of genes in multiple signaling pathways 

in autism. For example, CNVs within or surrounding genes 

related to ubiquitin pathways, were found in autism. 56 The 

affected genes include UBE3A, PARK2, RFWD2 and 

FBXO40. Since these targeted genes are involved in neuronal 

cell-adhesion or ubiquitin degradation, both important gene 

networks may contribute to the susceptibility of ASD. 

Furthermore, the consequence of genetic modifications on 

the gene products might have restructured those important 

pathways and ultimately the delicate function of the brain. 

Overall, genetic alterations are multiplexed and in a 

complicated fashion in autism. Pathway involvement rather 

than single gene change has been found in independent 

autism research centers worldwide. This might have served 

as a biological basis for the etiology and pathophysiology of 

autism discussed in later paragraphs.


PHYSICAL CONDITIONS OF AUTISM ARE 

GENERALLY ASSOCIATED WITH ANXIETY AND 

OXIDATIVE STRESS 

Numerous studies have been conducted to unravel the 

etiology of autism but the precise cause of autism remains 

largely elusive. Up to date, autism can be only considered a 

multi-factorial disorder that may involve biological factors 

from genetics as well as additional environmental 

contributors. Recently, systemic studies have been 

demonstrating that autism patients may have increased 

vulnerability to oxidative stress which may link genetics and 

environment together for integrative consideration. 57 

Oxidative stress is an emergent or chronic condition caused 

by the imbalance between the production of active free 

radicals (reactive oxygen species or ROS) and the repair of 

ROS-caused damage. 58 Although it is essential for human 

body to maintain certain level of ROS production for immune 

protection 60 and cell signaling, 59 excessive normal oxidative 

state is harmful to tissues and can cause toxic effects through 

the reaction of the free radicals with cellular components. 

Because of the non-specific biochemical redox reaction, ROS 

is able to damage any component of the cell, including 

proteins, lipids, DNA and numerous other small molecules. 61 

Oxidative stress is involved in many human diseases, 

especially neuro-psychological diseases (or related 

conditions) including schizophrenia, bipolar disorder, fragile 

X syndrome, chronic fatigue syndrome, Alzheimer's disease, 

Parkinson‟s disease, and myocardial and heart disease. 57 

It is known that children have low level of glutathione from 

conception through infancy. 62,63 Due to the lack of 

glutathione-producing capacity by neurons, the brain has a 

limited capacity to detoxify ROS. Antioxidants such as 

glutathione are required for neuronal survival during the 

early critical period, 64 however as a metabolically active 

organ, the child brain is vulnerable to oxidative stress due to 

its limited antioxidant capacity, higher energy requirement, 

and higher amounts of lipids and iron which usually serves as 

redox catalytic agent. 65 The brain makes up about 2% of 

body mass but consumes 20% of total oxygen and the vast 

majority of oxygen consumption is used by the neurons. 13 

Neurons apparently are the most susceptible to oxidative 

stress damaging when excessive ROS is generated, especially 

in children. 

As indicated by recently conducted genetic studies, autism 

patients may have altered neuronal adhesion proteins and 

ubiquitin pathways that might have been modified by 

genomic regions associated with NLGN1, ASTN2, UBE3A, 

PARK2, RFWD2 and FBXO40 genes. The related pathways 

are associated with cellular stress and ROS production in 

pathological conditions. 67,68,69 Evidence began to accumulate 

that oxidative stress influence autism disease status since 

oxidative stress markers and abnormal DNA methylation 

have been found in patient‟s samples. Oxidative 

protein/DNA damage and DNA hypomethylation (epigenetic 

alteration) have been found in patients. 70 The oxidative stress 

related metabolic profile of unaffected siblings differed 

significantly from affected case siblings but not from normal 

controls. These data indicate autism has deficit in antioxidant 

and methylation capacity, which might lead to cellular 

damage and altered epigenetic gene expression. 

It is implicated that there might be a shared mechanism from 

the role of oxidative stress in the pathogenesis of 

neuropsychiatric diseases including autism. 71,72 Oxidative 

stress may play a role as a mechanism linking the risk factors 

and pathological pathways described above. Results from 

clinical trials with antioxidant N-Acetyl Cysteine (NAC) are 

anticipated to give important clues and links to the hypothesis 

in the near future. 73 

In fact, it is commonly recognized that autism and anxiety go 

hand-in-hand. 74 Anxiety as well as depression is always 

accompanying people with autism (and their relatives). 75 

These issues have been additional burdens for individuals to 

bear and are impacting heavily on their daily functioning. 76 

Autism affects patients‟ ability to communicate with others 

and understand the surrounding world. This is often bound to 

cause anxiety or panic situations. Anxiety overload becomes 

even more burdened when changes in daily life happen to 

alter child‟s routine and subsequently increase anxiety and 

aggressive behaviors. 77 For anxiety condition that affects 

child and family‟s life seriously, many parents choose to use 

anti-anxiety drugs for their autistic children (see Table 

above). These treatments may reduce autism children‟s 

aggression behavior but often cause sedation and 

neuromuscular dysfunction. 78 Epidemiological surveys have 

revealed that between 15% and 30% of people with autism 

also suffer from certain degree of epilepsy 79 and need 

treatment (see Table above). Autism neurons might undergo 

high activity causing often, long and constant firing during 

early neurogenesis developmental window which then causes 

permanent damage and even epilepsy. 80 40% of people with 

autism also have electrical discharges on EEG recordings, as 

opposed to just 2% in a normal population, also suggesting 

an oversaturated brain activity. 81 

Anxiety and oxidative stress may also happen one after 

another or simultaneously in autism brain. 82 Animal 

modeling study reveals the presence of oxidative stress in the 

central and peripheral systems linked to anxiety. These 

findings suggest the redox system in anxious condition may 

play a role in brain damage. 83,84 Interestingly, a study carried 

out in University of Granada‟s Institute of Biotechnology 

shows that melatonin administration to mice could neutralize 

oxidative damage and delays the neurodegenerative process 

of aging. Researchers believe this mechanism of action might 

contributed to melatonin‟s therapeutic effect in human autism 

considering that melatonin itself is also a powerful 

antioxidant that is able to penetrate and work in brain. 49 

Melatonin administration in ASD was associated with 

improved sleep parameters, better daytime behavior, and 

minimal side effects. This might have been achieved by its 

potent antioxidant role described previously in addition to the 

improvement of sleep and reduced anxiety level in autism. 

Another example of anti-oxidant therapy is from a recent 

completed clinical trial of treatment of autism with


minocycline conducted by the NIH, National Institute of 

Mental Health (NIMH). The mechanism of minocycline 

delays neurodegeneration is based upon the anti-inflamation, 

antioxidative stress and apoptosis preventing effects of the 

drug. It would be very interesting to learn the trial results in 

the near future. 85,86 

NEUROPLASTICITY AS THERAPEUTIC BASIS IS 

HIGHLY INDICATED BY THE DISEASE FEATURES 

OF AUTISM 

The most distinctive feature of human brain is that it is a 

highly adaptive system, especially cerebral cortex. 87 human 

brain is able to perform self-changing function under proper 

external support. In normal condition, human mental capacity 

is able to process broadly varied information and complex 

new experiences. The brain‟s ability to rebuilt itself and to 

act and react in ever-changing environment is known as 

multiple term including neuroplasticity, brain plasticity, 

neural plasticity, or central nervous system plasticity, 88,89,90 

which at the electron microscopic level, is achieved at the 

inter-neuron level by the synaptic plasticity. 91 Normally, at 

birth, neuroplasticity (synaptic plasticity) allows the 

estimated 80-100 billion neurons to continually form brainwide 

neural network for the inter-neuronal communication 

with 10,000 synapses from each neurons. Neuroplasticity is 

best demonstrated in the process of brain development in the 

first two years of life. Neuron numbers decline when entering 

into adulthood and the ineffective or rarely used connections 

are eliminated with certain well used synapses remaining in 

brain. 93,94 Recent studies on adult brain also demonstrated 

that human neural connections do not ever reach a fixed 

pattern but rather they can undergo remodeling in certain 

areas of brain. 95 For example, study from primates suggest 

that even a few months training with specific targeting of 

functional lobules of brain could change the structure of brain 

map. Under the stimulation, the corresponding brain area 

grew significantly with enlarged size. This probably achieved 

by generating new synapses from existing neurons or 

regenerating entirely from neural stem cells into new 

neurons. ii While this neural regeneration was long believed to 

be impossible after age 3 or 4, research now shows that new 

neurons can develop late into the life span, even into late 

stage of approximately year 60. 97 These findings suggest 

human brain possess adaptive flexibility, regenerative 

capacity, and remarkable efficiency throughout life. 

Neuroplasticity holds the key to the development of many 

new and more effective treatments for brain damage or 

degenerative diseases. 98,99 Neuroplasticity also offers hope to 

people suffering from cognitive disabilities or disease 

including autism. The potential of the brain‟s plasticity is 

expected to take advantage of basic research advancement in 

human biology. 

It is now widely hypothesized that a disturbed neural network 

including the temporo-parietal cortex, limbic system, 

cerebellum, prefrontal cortex, and corpus callosum is 

involved in pathophysiology of autism. Considering the 

broad pathological involvement, it is not surprising that 

autism might not have mutated single protein but rather have 

an imbalanced brain of retarded total efficiency (with less 

common cases of Asperger Syndrome which might turn the 

imbalanced system into a beneficial aspect on certain 

functions such as remembering rote and rigid structures while 

lack of certain brain functions. 100 The hypothesized 

imbalance could have been the result of undesired change of 

multiple biological pathways. This is particularly important 

because most of the structures have been established in the 

early life of patients and it‟s with hope that early alteration 

would be largely beneficial to autism children. It would be 

the key to efficiently deal with this imbalance at very early 

childhood. As discussed in previous context, so far the time 

of autism diagnosis has been at the end stage of neurogenesis 

in childhood. Study on adult neuroplasticity has provide 

sound evidence that late stage of childhood brain is able to 

undergo remodeling with potential and power of 

neuroplasticity even if they have passed the previously 

described the “critical” developing stage. Progress in the field 

of neuroplasticity and its ultimate application in clinical 

medicine or social training would hold enormous potential 

contributing to autism therapy. 101 

Two drugs, haloperidol as well as arguably olanzapine, have 

been shown in psychological disorders to effect in modifying 

whole brain grey matters. This longitudinal, tightly controlled 

study followed patients up for nearly 100 weeks with 

magnetic resonance imaging (MRI) assessments and 

neurocognitive outcome evaluation in 14 academic medical 

centers (United States, 11; Canada, 1; Netherlands, 1; 

England, 1). a conventional antipsychotic, haloperidol (2-20 

mg/d), or an atypical antipsychotic, olanzapine (5-20 mg/d). 

The author concluded that the differential treatment effects 

on brain morphology could be due to haloperidol-associated 

toxicity or greater therapeutic effects of olanzapine. However 

this conclusion has been chllenged from another angle which 

hypothesizes that olanzapine might also involve 

neuroplasticity for autism. 102,103 

CONCLUDING REMARKS 

It is believed that autism patients undergo synaptic 

connection deficiency in early life, which might be associated 

with anxiety, stress, and the damaging effect of excessive 

ROS production. It would be important to track the status of 

ROS system in autism patient body and keep this dangerous 

system in balance during neurogenesis and brain functioning. 

Combining genetic profiling, biological pathway analysis, 

and brain mapping with neuroimaging technologies, 

neuroplasticity may hold the key for autism therapy for the 

regeneration of functional synapses. Based upon systemic 

neuroimaging and brain mapping with novel technologies 

towards localized and specified brain training, we may be 

able to optimize the autism pathological brain structure and 

neuronal network towards social and communication benefits. 

It can also be anticipated to combine small molecule drug 

treatment on autism to aid the neural regeneration efforts. 

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Review 

Effective Treatments for Auditory Sensitivities in Autism 


ABSTRACT 

Hypersensitivity to sound is a frequent symptom of 

autism spectrum disorders and can be difficult to 

manage. Because an individual with sound 

hypersensitivity may display disruptive behaviors for 

significant periods of time in response to the sound, the 

condition demands treatment. Behavioral and 

desensitization therapies, which employ some of the 

techniques of cognitive behavioral therapy, appear to be 

promising, efficient, and effective types of treatment for 

these symptoms. 

[N A J Med Sci. 2011;4(3):151-157.] 

KEY WORDS: CLL/SLL, ZAP-70, CD38 

INTRODUCTION 

Autism is a clinically-diagnosed developmental disorder 

characterized by qualitative impairment in social 

communication (Filipek et al. 1999) and communication, as 

well as by the presence of restricted repetitive behaviors and 

stereotypies (American Psychiatric Association, 2000). It is 

common for children on the autism spectrum to also display 

unusual reactions to sensory stimuli, in terms of both 

underarousal and overarousal. Kanner (1943) noted in his 

seminal paper that some children with autism showed an 

“aversion” to certain sounds. More recently, Rimland and 

Edelson (1995) claimed that approximately 40% of children 

with autism show some symptoms of auditory 

hypersensitivity, according to parent reports. Other figures 

for aversion to noises range from 30% to 53% of children 

with autism (Baranek et al. 1997, Volkmar et al. 1986, 

respectively). However, these figures generally apply to 

younger children under the care of parents or teachers. 

Figures for older children or adults with autism or other 

developmental disabilities are lacking. Likewise, research 

attempting to identify the specific etiology of auditory 

hypersensitivity in the context of auditory processing 

disorders has been inconclusive. 

In individuals who suffer from auditory hypersensitivity, the 

reaction to sounds can be so severe that it results in extreme 

behavioral disturbance or even self-injury, though hearing 

Received 6/14/2011; Revised 7/23/2011, Accepted 7/23/2011 


Department of Speech, Language, and Hearing Sciences 

Boston University, Boston, MA 

Email: karenc@s-t-a-r-corp.com 

thresholds are on average not different from normal in the 

autistic population or in the population of 

> those with auditory hypersensitivities. These behaviors are 

especially difficult for a family to tolerate when the reaction 

is to a common household sound, such as the sound of the 

toilet flushing. Regardless of the cause of these symptoms, 

parents and clinicians of children with autism search for ways 

to help these children tolerate the auditory world better. This 

paper will describe two recent approaches to reducing 

symptoms of hypersensitivity to sound and evaluate the 

literature in terms of its clinical relevance and effectiveness. 

SYMPTOMS OF AUDITORY HYPERSENSITIVITY IN 

AUTISM 

A hyper-reaction to certain sounds is not unusual for children 

on the autism spectrum. This reaction can take the form of 

placing hands over the ears, screaming, crying, or running 

away when the sound is detected. Some children with autism 

become so averse to the sounds that they react to the sight of 

the object that makes the sound even if that object is silent at 

the moment. It is a severe disruption in family routines 

when, for instance, a parent is unable to vacuum the house 

for fear of a serious reaction from her child, or when a child 

is so averse to the sound of a toilet flushing that she will not 

use the bathroom at school and instead has accidents (Koegel 

et al., 2004). It is also upsetting for parents to see their child 

in such extreme distress. 

There are two main methods used by some occupational 

therapists, speech-language pathologists, educators, and 

audiologists to treat auditory hypersensitivities. The more 

prevalent is Auditory Integration Training (AIT), a form of 

sensory integration therapy, though the best-controlled 

studies of it have repeatedly shown no clinical effect. A 

comprehensive review of the clinical literature on AIT is not 

included here, but one can be found in Sinha et al. (2004). 

The other is by the use of systematic desensitization 

paradigms, also used in cognitive behavioral therapy to treat 

anxiety disorders. Systematic desensitization paradigms are 

generally credited to Mowrer (1960), who theorized that 

through structured exposure to a feared stimulus, the fear 

response can be extinguished and the individual can habituate 

to the stimulus. 

AUDITORY INTEGRATION THERAPY FOR 

AUDITORY HYPERSENSITIVITY 

AIT was developed in the 1950s by a French 

otorhinolaryngologist named Alfred Tomatis. In the Tomatis 

method, “the stimuli include specially created compact discs


of Mozart music and Gregorian chants. The acoustical signal 

modulation equipment attenuates low frequency sounds and 

amplifies higher frequencies (300-800 Hz).” (Corbett & 

Constantine 2006, p. 37). The treatment is hypothesized to 

“enhance auditory perception by stimulating middle ear hair 

cells” and the frequency modulation “allows the child to 

gradually focus listening on language frequencies” (Corbett 

& Constantine, 2006). These hypotheses represent 

fundamental misunderstandings in basic audiology and 

acoustics. 

Today, most versions of AIT are commercially available 

products based on Tomatis’ methods. They use digitally 

filtered music or speech as the active ingredient in their 

therapies. After initial testing to set filtering frequencies and 

levels, the individual would then be assigned some number of 

listening sessions, during which she listens over headphones. 

Traditionally, the sound level of the stimulus has been quite 

high and potentially damaging to the hearing mechanism, but 

in the past two decades practitioners have paid more attention 

to safe listening levels, keeping the average level at or below 

80 dB SPL, or dB sound pressure level, which is a measure 

of absolute sound pressure level. 80 dB SPL is 

approximately the level of a loud alarm clock within arms’ 

reach (American Speech-Language-Hearing Association, 

2009). 

Dr. Guy Berard, a student of Dr. Tomatis, went on to develop 

his own version of AIT, which he used to treat a young 

autistic girl who later showed great improvement (Stehli, 

1997). Both methods use audiometric data to locate 

frequency bands to which a child is “sensitive”. These are 

defined as frequencies in the audiogram where a child’s 

threshold is 5 dB lower than to the frequencies on either side. 

Music is then band-pass filtered at the “sensitive” frequencies 

to increase the relative amplitude of the signal in those 

frequency regions. For example, if a child’s audiogram 

showed a dip in threshold of 5 dB (a sensitivity) at 2000 Hz 

as compared to the thresholds at 1000 Hz and 4000 Hz, then 

music played to the child would be amplified in the region of 

2000 Hz. However, many commercial audiometers can only 

be calibrated to within ± 3dB and the intensity level can only 

be changed in increments of ±5 dB. 

The goal of Berard-style AIT is to achieve an audiogram that 

shows lower sensitivity for high-frequency (> 4 kHz) and 

low-frequency (< 1 kHz) sounds relative to mid-frequency 

(2-3 kHz) sounds. However, normal audiograms take many 

shapes and represent a point at which a response is elicited a 

specified percentage of the time, rather than an absolute 

boundary. 

Berard-style AIT uses any type of music, always delivered 

through one of two proprietary devices, called the Earducator 

or the Audiokinetron. Both devices contain filters that 

change center frequency and attenuation level randomly. The 

goal of the therapy is ostensibly retraining of the stapedius 

muscle in order to normalize hearing. Again, this represents 

a misunderstanding of accepted audiological findings. The 

function of the stapedius muscle is to dampen the vibration of 

the stapes (stirrup), one of the middle ear bones. The 

stapedius, which is under reflex control only, stiffens the 

ossicular chain and effectively reduces the amplitude of 

sound reaching the cochlea. While it is possible for the 

stapedius to become paralyzed, as by Bell’s Palsy (a 

dysfunction of cranial nerve VII, the facial nerve), it is not 

possible to remediate the condition by “exercising” the 

stapedius muscle because the muscle has become denervated. 

Both Berard and Tomatis listening sessions typically last for 

twenty minutes to one hour at a time, daily for a period up to 

twenty weeks. During the sessions, the child is monitored by 

a therapist who either engages the child in other enjoyable 

activities and encourages the child to keep the headphones 

on, or simply keeps the child quiet and calm. 

A detailed review of the clinical literature on AIT can be 

found in Sinha et al. (2004). These authors report that the 

largest studies of AIT showed no difference on outcome 

measures between treatment and control conditions, while 

smaller trials reported clinically insignificant improvements 

in the total score of the Aberrant Behavior Checklist, which 

“is not, according to the instrument’s developer, a clinically 

meaningful outcome.” (p. 8) 

TREATMENTS OTHER THAN AIT FOR AUDITORY 

HYPERSENSITIVITY 

A. Desensitization Paradigm for Auditory 

Hypersensitivity 

The non-AIT research on auditory hypersensitivities in 

autism takes a very different view of their causes and, thus, 

the treatment. In the view of Koegel et al. (2004) the 

problem of hypersensitivity to sounds in children with autism 

is that “the child’s extreme aversion to these stimuli may 

relate to an irrational fear of the stimulus rather than to pain 

associated with the stimulus” (p. 123); that is, a child with 

hypersensitivities may have a phobia. Koegel et al. therefore 

implemented a systematic desensitization program with three 

children with autism who displayed auditory 

hypersensitivities, to see if these children could become 

comfortable in the presence of the sounds. By the end of the 

study, all three children showed no reaction to the presence 

of either the sound or the object that made the sound. 

The children in the Koegel et al. (2004) study presented with 

both autism, diagnosed according to DSM-IV criteria 

(American Psychiatric Association, 1994) and “apparently 

severe hypersensitivity to auditory stimuli”. Diagnoses of 

severe hypersensitivity to sound were made on the basis of 

parental report and clinical observation, and each child’s 

reactions to the particular sounds they found noxious were 

documented in the baseline condition. Sounds that caused 

distress included a toilet flushing (Child 1); animal sounds 

from toys (Child 2); and vacuum, blender, and hand mixer 

sounds (Child 3). Subjects were referred to the clinic where 

the authors work, for treatment of auditory hypersensitivity


and other symptoms of autism; no randomization was used in 

this study because it was a repeated single-subject design. 

The behavior of all three children in response either to the 

noxious sound or the object associated with that sound was 

assessed at baseline, as a matter of course during the study, 

and at a follow-up session after treatment. The structure of 

the baseline and follow-up sessions was identical and 

consisted of videotaped visits to the locations (home, school, 

stores) where the children encountered the noises that caused 

them discomfort. During these visits, an interval recording 

system was used, in which raters rated the behavior of the 

child in continuous 10-second intervals. Behavior was 

classified as “comfortable” (score of 0), “mild anxiety” (1), 

“high anxiety” (2), or “intolerable reaction” (3). The authors 

define each of these categories operationally and rated each 

child’s behavior every ten seconds. Behavior rating scores 

were averaged every three minutes to obtain mean anxiety 

scores for the sessions, and a hierarchical step was deemed 

completed if the child’s behavior averaged “comfortable” for 

two to four consecutive three-minute intervals. Agreement 

was defined as the two raters giving the child’s behavior the 

same label for the interval. Inter-rater agreement was 

assessed and ranged from 83% to 100%, with a mean across 

all sessions of 96.8%. Two raters of the child’s behavior 

were involved in coding, one of whom was blind to the 

treatment portion of the paradigm. The blinded rater scored 

the child’s behavior from videotapes presented in random 

order. The high mean inter-rater reliability suggests that the 

lack of blinding for one rater did not introduce measurable 

bias into the scores. 

The dependent measures used in this study were the number 

of hierarchical steps per week where the child’s anxiety level 

was judged as “comfortable” and the mean anxiety level 

during a session. Follow-up probes were conducted 

approximately three weeks after the end of treatment (i.e., 

after the child had experienced at least one session in the 

presence of the sound, during which the mean level of 

anxiety was “comfortable” in conditions identical to 

baseline). At both baseline and follow-up, the child was in 

the same room with the stimulus sound and its source, and 

mean anxiety levels were rated. As the anxiety levels were 

reduced until they reached and remained at a certain 

criterion, tests of statistical significance are not relevant and 

were not employed in the analysis. 

The only negative effects alluded to in the study were that the 

children would be put in a position to show anxiety during 

the baseline condition. However, the criterion for advancing 

a child from one step in the desensitization hierarchy to the 

next was fairly conservative: a step was deemed completed if 

the child spent two to four consecutive three-minute intervals 

of time at a “comfortable” level of anxiety. This meant that 

the child showed no anxiety relating to the stimulus and 

appeared to be relaxed, playing happily, and unaffected by 

the sight or sound of the stimulus for six to twelve minutes at 

a time. 

B. Behavioral Modification Paradigm for Auditory 

Hypersensitivity 

In contrast with Koegel et al., who considered the auditory 

hypersensitivity to be a phobia, Devlin et al. (2008) treat the 

issue of hypersensitivity to sound in children with autism as a 

purely behavioral problem. Specifically, the child who was 

studied in their paper “emitted problem behaviors such as 

feet stomping, aggravated delayed echolalia, and covering his 

ears when exposed to various selections of music.” (p. 673). 

Devlin et al. investigate the effectiveness of a DNRO, or 

“differential negative reinforcement procedure”, to reduce the 

problem behavior. 

The sole participant in this single-subject study was a sixyear-old 

boy with diagnoses of Autism Spectrum Disorder 

and Learning Disability. The authors do not specify who 

made the diagnosis or according to which criteria. Neither is 

the method of finding the subject and entering him into the 

study described, and no blinding methods were mentioned. 

A control condition was used in which the participant had 

free access to preferred toys in the absence of musical 

stimuli. 

Pre-and post-baseline measures consisted of identifying 

“disruptive behavior”. This was defined as covering ears, 

displaying aggravated delayed echolalia, agitated finger 

spelling, or foot-stamping. Agreement statistics on 

identification of the behavior averaged 97% over two raters 

and ranged from 91% to 100%. Mean levels of disruptive 

behavior were plotted for all stimuli for all sessions, until a 

total of 16 or 17 sessions, comprising approximately five 

minutes of therapy. No negative side effects were discussed, 

except for the need to expose the child to the music in 

response to which he was displaying disruptive behavior. 

The DNRO procedure consisted of exposing the child to 

music for short, gradually-increasing intervals. If the child 

refrained from showing the behavior for, say, five seconds 

while the stimulus was present, the music only lasted 30 

more seconds, after which the teacher turned it off. If the 

child did display the behavior during that five-second 

interval, the music was left on and the interval restarted. The 

length of the interval increased from five seconds to two 

minutes, over seven non-equal steps. Devlin and colleagues 

used four types of music and three playback sources (CD, 

iPod, and a capella from one of five singers; Disney songs, 

pop tunes, TV theme songs, and classical music), randomly 

selected for each interval, yielding 12 conditions. The 

number of 10-second intervals in one-minute sessions during 

which the child displayed the behaviors was assessed before 

and after treatment. All lessons lasted for five minutes total 

and were conducted three to six times per day at the child’s 

school. A control condition was also monitored for the same 

problem behaviors which consisted of a five-minute block of 

free play, during which the child had free access to favorite 

toys, with no music present. At baseline, over all music 

type/playback device conditions, the mean number of 10-


second intervals with problem behavior per minute of music 

was 4.5 (out of six; i.e., six 10-second intervals per minute). 

Mean number of intervals per minute with disruptions with 

no music was 0.8. After an average of 10.2 lessons over all 

playback/music types, the average number of intervals per 

minute with disruptions while music was present was 0.2. 

The authors report that “no incidents of problem behavior 

were recorded for each of the {listening} conditions 

following treatment session 6.” (p. 676). The authors state 

that “treating individuals with developmental disabilities to 

tolerate multiple forms of auditory stimulation is important 

because this may act as a form of desensitization to auditory 

sounds that occur readily in the natural environment.” (p. 

679) 

PERCENTAGE OF NON-OVERLAPPING DATA 

ANALYSIS 

A “percentage of non-overlapping data” (PND) analysis can 

be used to quantitatively evaluate treatment effectiveness in 

studies using single-subject designs such as the Koegel and 

Devlin studies. Scruggs et al. (1987) define PND as “the 

percentage of data points during the treatment phase that 

exceed the most extreme data point in the baseline phase.” 

A PND analysis can be interpreted as a treatment effect, 

according to Mastropieri & Scruggs (2001): greater than 

90% PND indicates a very effective treatment, 70%-90% 

PND indicates an effective treatment, 50%-70% PND 

indicates a questionable treatment, and less than 50% PND 

an ineffective treatment. For example, imagine that the 

number of coughs per minute for ten consecutive minutes 

was used as an evaluation of the effectiveness of an 

antitussive drug. If, while the antitussive was not being 

used, the number of coughs per minute for ten minutes was 

always between five and ten; but while the antitussive was 

present, only one 1-minute interval in ten minutes contained 

more than four coughs, the PND value would be (20-1)/20, or 

95%. 

PNDs for both the Koegel and Devlin studies were 

calculated. In the Koegel study, the baseline level of anxiety 

each child showed in response to their feared stimulus was 

“intolerable” (3). Therefore, the number of treatment 

intervals, or steps in the desensitization hierarchy, during 

which a child showed an anxiety level of (0), (1), or (2) was 

counted. The number of steps at 0, 1, or 2 was then divided 

by the total number of hierarchical steps to yield the PND 

value. In fact, every child’s anxiety level was rated as 

“comfortable” (0) during the treatment phase in Koegel’s 

study, since the goal was for the child not to experience 

anxiety in the increasingly close presence of the feared noise. 

For Devlin’s study, during the baseline condition, the child 

showed disruptions during one 10-second interval. For each 

playback (treatment) condition, the number of intervals 

during which the subject showed more than one interval with 

disruptions was tallied and divided by the total number of 

treatment intervals to yield the PND percentage. Then, the 

results were combined across all playback conditions for a 

total for this subject. All of these figures are tabulated in 

Table 1. 

Table 1. PND Analysis for Behavioral Studies. 

Study Child/Condition Tx 

Intervals 

> Baseline 

Koegel et 

al. 

Devlin et 

al. 

Total 

Tx 

Inter 

vals 

For the Koegel study, for Child 1 and toilet flushing noises, 

16 of the 18 hierarchical steps were completed with the 

child’s behavior rated as “comfortable” (this includes three 

follow-up sessions at the last step in the hierarchy). Only 

during the two first sessions was the child’s behavior rated as 

anything but “comfortable”. Child 2 completed 17 of 20 

hierarchical steps with “comfortable” behavior in the 

presence of an animal noise toy, again including follow-up 

sessions after treatment was finished. Child 3 had a more 

complex case. With vacuum noise, 17 of 20 steps were 

completed at the “comfortable” level. With blender noise, 22 

of 25 steps were completed comfortably, including sessions 

with the same stimulus at a novel location. If that treatment 

sequence were broken into two sections, those conducted at 

home and those conducted at the alternate location, the 

figures would be 16/18 “comfortable” at home (89%) and 7/8 

“comfortable” at the alternate location (87.5%) instead of 

22/25 sessions overall at “comfortable” (88%). On first 

analysis, the outlier appears to be the hierarchical steps with 

% 

Child 1, toilet 16 18 89% 

Child 2, animal 17 20 85% 

noises 

Child 3, vacuum 17 20 85% 

Child 3, blender 22 25 88% 

Child 3, mixer 3 4 75% 

All conditions 75 87 86% 

CD + TV themes 5 5 100% 

CD + pop tunes 1 3 30% 

a capella + Disney 5 5 100% 

a capella + pop 5 5 100% 

tunes 

a capella + TV 5 5 100% 

themes 

iPod + TV themes 5 5 100% 

iPod + pop tunes 0 4 0 

TV + Disney 5 5 100% 

TV + pop tunes 5 5 100% 

TV + TV themes 5 5 100% 

All conditions 41 48 85.4%


mixer noise. However, it is important to remember that 

Child 3 independently generalized to this condition. Once he 

had shown habituation to the sound of the mixer, therapy was 

discontinued, even though more sessions at which his 

behavior in the presence of the mixer sound could have been 

rated “comfortable” would have improved the PND score. 

Thus, the number of steps during which Child 3’s behavior in 

the presence of mixer noise could have been rated 

“comfortable” was, in essence, artificially low. The first 

session with mixer noise was the baseline condition, and the 

last three were essentially follow-up sessions, conducted 30 

weeks after the baseline condition with the mixer. 

In any case, the PND values for the Koegel study all fall 

within the “effective” range. Remembering that the goal of 

the treatment was to extinguish symptoms of distress in the 

presence of the feared sounds, that each child was kept at a 

comfortable level during all hierarchical steps, and that no 

child demonstrated any symptoms of anxiety in the presence 

of the sounds after treatment, it appears that the treatment 

was indeed successful. 

In the Devlin et al. study, the control/no-treatment condition 

was effectively the opposite of that in Koegel et al. (2004). 

In Koegel et al., the children’s behavior during treatment was 

compared to the level of distress shown during the baseline 

condition with the feared stimulus. In the Devlin et al. 

article, the child’s behavior was compared to a free-play 

condition when no music (i.e., the feared stimulus) was 

present. This illuminates a great difference between the two 

studies. In the Koegel et al. study, the aim was to keep the 

child comfortable throughout the therapy. In the Devlin et al. 

study, no attempt was made to keep the child comfortable, 

but instead to teach the child not to display certain behaviors. 

Presumably, by the end of the therapy, the child in the Devlin 

study also became desensitized to the previously feared 

stimulus, but the Koegel et al. approach seems much more 

humane to implement because the child is always kept in a 

calm state. On the other hand, one can imagine Devlin’s 

methods as being more amenable to the teaching of coping 

strategies. 

In the Devlin study, all conditions except for pop tunes 

played on an iPod and or CD showed no overlap, meaning 

that the child showed more intervals of distress during 

treatment than during free play (control). Most interesting 

are the pop tunes conditions. While pop tunes were playing, 

whether from CD, iPod, or a capella recordings, the child 

showed the lowest number of intervals with disruption – 

similar numbers to the free-play condition. This would 

suggest that the pop tunes bothered the child least of all the 

types of music. Over all conditions, the average PND for the 

Devlin study was approximately 85%, again well within the 

“effective” range. 

TREATMENT EFFICIENCY ESTIMATES 

This section examines the amount of time required to achieve 

the results demonstrated in the literature, as an indication of 

how efficiently the treatment delivered the effects it 

promises. 

The shortest amount of time that complete desensitization 

took Child 1 in the Koegel et al. study was approximately 

two and a half hours, over five days. For Child 2, the course 

of therapy lasted approximately one week from baseline to 

follow-up, or a total of approximately two hours of therapy 

over seven days. Therapy for Child 3, who had three sounds 

needing treatment, was conducted in one-hour sessions, once 

per week for 34 weeks. This included five weeks of baseline 

to sounds 1 and 2, four weeks of follow-up to sound 1, three 

weeks of follow-up to sound 3, and an additional five weeks 

of extra therapy designed to desensitize the child to sound 2 

in a different environment. Excluding the follow-up 

sessions, this child required a total of 22 weeks of therapy for 

three sounds in two different locations. At follow-up, all 

children were judged by both raters to be comfortable with 

the sound playing and the object that made the sound present 

and in view. 

It is more difficult to ascertain the amount of treatment time 

used in the Devlin study. The child in question was given 

therapy during the school day, for five minutes at a time, 

three to six times per day. Twelve combinations of playback 

source and music were employed, so it would seem that 

twelve therapy sessions were used and that the total number 

of days of therapy was approximately ten. 

For both the Koegel et al. and Devlin et al. studies, requiring 

five to 34 treatment sessions to completely eliminate the 

problem behaviors associated with auditory hypersensitivity 

in all four subjects, to all sounds, objects, and environments 

contrasts sharply with the mixed clinical results from AIT, 

which according to Sinha et al. (2004) show little to no 

clinical effect. The spontaneous generalization that Koegel’s 

Child 3 showed to the final sound in his hierarchy also 

indicates that he internalized an important lesson and learned 

some sort of coping strategy. In the studies reporting on AIT, 

by contrast, 10 to 100 hours of therapy were required, despite 

clinically insignificant improvements in aberrant behaviors. 

(Most published studies use a 10-hour course of therapy, 

given twice per day in 30-minute blocks). Madell (Madell & 

Rose 1994, Madell 1999), a proponent of AIT, states clearly 

that “the goal of the therapy is to reduce auditory symptoms 

that that may be interfering with a child’s auditory 

functioning,” (1999, p. 372) and that “{AIT} is a treatment 

(not a cure) for auditory symptoms.” (1994, p. 16) In 

addition, another proponent of the therapy cautions readers 

that “typically only 60% of children with autism respond” to 

auditory integration training (Neysmith-Roy 2001). 

It is clear that Devlin’s (2008) and Koegel’s (2004) methods 

provide much better efficiency than AIT. Neither required 

specialized training or equipment and therefore resulted in no 

extra cost to the clinician; yet both completely eliminated the 

disruptive behavior they were designed to treat. A drawback 

of the Devlin approach is that it appears to be punitive and is


less child-centered than Koegel’s desensitization therapy, in 

which the child is kept comfortable at all steps in the 

hierarchy. On the other hand, allowing a child to experience 

discomfort in a safe, controlled situation where coping 

strategies can be explicitly taught is more educational than 

avoiding discomfort. By contrast, AIT therapy, childcentered 

or not, generally yielded no results and cost the 

clinicians money for equipment and training (and, thus, lost 

therapy hours). 

DISCUSSION 

Hypersensitivity to sounds is a difficult symptom of autism 

or other developmental disorders. This is especially true 

when a child’s reaction is extreme, prolonged, or involves 

injury to himself or others. It causes significant disruption in 

family life and creates a tremendous amount of extra stress 

on families who already have many concerns. 

Hyposensitivity to auditory stimuli, perhaps a more 

complicated condition, can also cause great sadness for 

parents who wish to engage with a child who does not 

respond to his or her name. It is therefore vitally important to 

find effective treatments for both conditions. Auditory 

integration training is a popular therapy, offered by many 

therapists, but behavioral or desensitization therapies are 

another option. 

Because there are so few peer-reviewed studies on behavioral 

treatment for auditory hypersensitivity, a variety of criteria 

must be considered when evaluating the literature. Thus, this 

paper examined the effectiveness of behavioral therapies 

according to a “percentage of non-overlapping data” (PND) 

analysis, an estimate of treatment efficiency in terms of timeto-completion 

and proportion of symptoms remitted, and an 

estimate of the burden to the clinician for different types of 

therapy. 

According to a PND analysis, the behavioral studies’ 

treatment paradigms were both in the “effective” range. 

Behavioral methods took approximately five hours, but all 

children who received this type of therapy showed complete 

extinguishment of symptoms after treatment, in contrast to 

the approximately 60% of individuals in whom symptoms of 

auditory hypersensitivity are reduced (Madell 1999). AIT 

therapies impose a significant financial and training time 

burden on the clinician who wishes to employ them, while 

behavioral therapies do not. 

The two behavioral studies cited in this paper describe a 

version of their therapy given to nonverbal or minimally 

verbal children, but is not difficult to imagine how to modify 

the therapy for children with better communication skills. 

Devlin et al. comment, “Alternative forms of treatment (e.g., 

teaching one to walk away from sources of aversive auditory 

stimulation) could have been considered for the participant in 

this study. In addition, when circumstances allow the 

termination of music, the strengthening of a communicative 

response presents as an attractive alternative to the 

intervention used in the present investigation.” (p. 679) In 

other words, combining behavioral or desensitization 

methods with child-initiated requests, verbal reinforcers, 

positive self-talk, or other methods from cognitive behavioral 

therapy would be appropriate for more verbal children and 

could enhance the effects by explicitly teaching a child 

effective coping skills. At the same time, cognitive 

behavioral techniques can improve self-awareness, 

communication skills, and adaptive behavior. 

Regardless of the theoretical implications of the clinical 

results, Koegel et al. point out that “the children’s ability to 

become comfortable with stimuli that were judged to be 

intolerable is socially significant… Following intervention, 

they were able to participate in all settings and the families 

did not need to avoid specific settings or alter their lifestyles 

because of possible negative effects they may have had on 

their child.” (p. 133.) Reducing parents’ stress helps not 

only the parent, but also the child with a disability and any 

siblings as well. 

ACKNOWLEDGEMENTS 

The author wishes to thank Dr. Helen Tager-Flusberg, Dr. 

Ann Dix, Dr. Melanie Matthies, Dr. Gael Orsmond, and two 

anonymous reviewers for extremely helpful comments on 

previous versions of this paper. All errors are the 

responsibility of the author alone. 

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Review 

Behavioral Treatment for Children with Autism 


ABSTRACT 

Autism is a complex neurodevelopmental disorder 

representing a heterogeneous group of individuals with 

similar symptomatologies and multiple biologic etiologies. 

More children will be diagnosed with autism this year 

than with AIDS, diabetes & cancer combined. 

Government statistics suggest the prevalence rate of 

Autism is increasing, around 10-17 percent annually. 

Autism costs the nation over $35 billion per year, a figure 

that is expected to increase significantly in the next 

decade. In efforts to remedy this devastating epidemic, 

many treatments and interventions are being developed. 

Among these interventions, Applied Behavioral Analysis 

(ABA) is probably the best-known and best-researched 

treatment available for autism spectrum disorders. This 

article will very briefly describe the ABA behavioral 

treatment process for children with autism, and review 

several key studies on its effectiveness. Due to the 

complexity of ABA principles, techniques, and their 

application, this article is not intended to be a detailed or 

definitive explanation on the subject. 

[N A J Med Sci. 2011;4(3):158-163.] 

Key Words: Autism, neurodevelopmental disorder, ABA 

INTRODUCTION TO AUTISM AND APPLIED 

BEHAVIORAL ANALYSIS 

Autism is characterized by abnormalities in social 

interaction, communication, and restricted repertoire of 

activities and interests. Moderate to severe behavioral 

problems such as irritability, aggressiveness, noncompliance, 

and self-injurious behavior are often present. 

According to the Mayo Clinic, symptoms of autism set in 

before the age of three. For reasons currently unknown, the 



Paulina Peng-Wilford, PhD 

Executive Director of Multicultural Neurobehavioral 

Rehabilitation Center and Global Alliance for Healthcare, 

146 Martin Street, Carlisle, MA 01741 


Department of Medicine, Beth Israel Deaconess Medical 

Center, Harvard Medical School, Boston, MA 

incidence of autism appears to be rising. Once thought to be 

very rare, autism spectrum disorders are estimated to occur in 

as many as 1:110 (one in every 110 people). 1 

Currently, the exact causes of Autism are unknown, and 

physicians have no cure for autism; however, with 

appropriate treatment and education, many children with the 

disorder can learn and develop. Specially, early interventions 

often can reduce challenges associated with the disorder, 

lessen disruptive behavior, provide some degree of 

independence, and improve the quality of life for children 

with autism. According to Dr. Rogers’ conclusion in 

"Evidence-Based Comprehensive Treatments for Early 

Autism": early intervention programs are indeed beneficial 

for children with autism, often improving developmental 

functioning and decreasing maladaptive behaviors and 

symptom severity at the level of group analysis. 2 

Although there is no single treatment protocol for all children 

with autism, among the many methods available for 

treatment and education of people with autism, applied 

behavior analysis (ABA) has become widely accepted as an 

effective treatment option. The National Institute of Child 

Health and Human Development lists Applied Behavior 

Analysis among the recommended treatment methods for 

autism spectrum disorders. A Report of the Surgeon General 

states, “Thirty years of research demonstrated the efficacy of 

applied behavioral methods in reducing inappropriate 

behavior and in increasing communication, learning, and 

appropriate social behavior in people with Autism”. 3 

Applied behavior analysis, according to Drs. Baer Wolf and 

Risley, is the process of systematically applying interventions 

based upon the principles of learning theory to improve 

socially significant behaviors to a meaningful degree, and to 

demonstrate that the interventions employed are responsible 

for the improvement in behavior. 4 

Applied behavior analysis is one of the three major branches 

of behavioral analysis (the other two branches are 

behaviorism and the experimental analysis of behavior). 

Behavior analysis can be traced back to John B. Watson and 

what became known as Watsonian behaviorism or stimulusresponse 

psychology. B.F. Skinner is credited, though, as 

being the founder of the experimental analysis of behavior. 

The science of behavior analysis focuses on principles about 

how behavior works, or how learning takes place. For 

example, one principle of behavior analysis is positive


reinforcement. When a behavior is followed by something 

that is valued (a "reward"), that behavior is likely to be 

repeated. Through decades of research, the field of behavior 

analysis has developed many techniques for increasing useful 

behaviors and reducing those that may be harmful or that 

interfere with learning. Applied behavior analysis (ABA) is 

the use of those techniques and principles to address socially 

important problems, and to bring about meaningful behavior 

change. 5 

The field of applied behavior analysis grew in the 1950s and 

1960s as researchers began to apply methods of experimental 

analysis of behavior to determine if principles of behavior 

demonstrated in laboratory settings with nonhumans could be 

replicated with humans in naturalistic settings. Applied 

behavior analysis as it is now known can be traced to the 

work of Ayllon and Michael in 1959. 6 The field began to 

expand and two significant events in 1968 marked the formal 

beginning of contemporary applied behavior analysis: (1) the 

publication of the Journal of Applied Behavior Analysis and 

(2) the publication of “Some Current Dimensions of Applied 

Behavior Analysis,” by Baer, Wolf, and Risley. 7 

Baer provided recommendations for applied behavior 

analysis which later became the field’s defining 

characteristics. These defining characteristics state that 

applied behavior analysis should be applied, behavioral, 

analytic, technological, conceptual, effective, and capable of 

generalized outcomes. As the field of applied behavior 

analysis continues to grow and is applied to a wide variety of 

problems additional characteristics have been suggested, but 

the original defining characteristics as proposed by Baer et al. 

remain the standard. 8 

Dr. Ivar Lovaas first applied Behavioral Analysis techniques 

to autism patients at the Psychology Department of UCLA . 

His idea was that social and behavioral skills could be taught, 

even to profoundly autistic children, through the ABA 

method. 8 Since that time, a wide variety of ABA techniques 

have been developed for learners with autism in building 

useful skills in communication, social, academic, and 

community living skills, and adaptive living skills 

including gross and fine motor skills, personal self-care, 

home and community orientation and work skills. 

FUNCTIONAL BEHAVIORAL ANALYSIS OF 

AUTISM 

Due to difficulties with communication skills, social skills, 

and narrow interests, children with autism often exhibit 

challenging behaviors including noncompliance, aggression, 

and repetitive actions that interfere with daily life. These 

behaviors, which appear meaningless, unproductive, or even 

dangerous, can be stopped or modified. 

How does ABA intervention effectively stop or modify these 

maladaptive or dangerous behaviors 

All behaviors serve a purpose for an individual, and 

problematic behaviors can serve such purposes or functions 

as: 

To gain attention from someone in the environment. 

To gain a tangible consequence: a treat, a token, money, 

a favorite toy or video. 

To gain a sensory consequence: to get warmer if one is 

cold, or cooler if hot, to gain some tactile, auditory, 

visual, proprioceptive, or vestibular consequence. 

To self-regulate one's emotions: to calm down if 

agitated, to raise one's arousal level if it is depressed. 

To escape from or avoid an undesirable situation. 

Typically these behaviors are in response to or 

anticipation of requests to work, play, or communicate, 

or a means to avoid environments which may have 

uncomfortable stimuli. 

Modification of the problematic behaviors is most effective if 

the purpose or motivation behind the behaviors can be 

determined, because, once that motivation is known, once the 

need that the child is trying to fill is ascertained, a 

replacement behavior can be taught to meet that need more 

effectively and appropriately. 

Thus, ABA program first starts with a functional behavioral 

assessment, a well-established behavioral assessment tool 

that uses a variety of methods to define a target behavior and 

determine the underlying causes of it. 9 

The assessment is conducted by a trained therapist and the 

process starts with carefully observing and precisely 

describing the behavior that the child is exhibiting and the 

events and stimuli in the environment both before and after 

that behavior. Often, this process is referred to as identifying 

the ABCs of a particular behavior: 

Antecedent - the stimulus or stimuli to which the child 

responds, for example, a directive or request for the child 

to perform an action. 

Behavior - the behavior that we see exhibited by the 

child, for example, a response from the child - successful 

performance, noncompliance, or no response. 

Consequence - the stimulus or stimuli that the child 

receives as a result of his behavior, the consequence is 

defined as the reaction from the therapist, which can 

range from strong positive reinforcement (ie. a special 

treat, verbal praise) to a strong negative response, “No!” 

The therapist will observe and describe the behavior across a 

broad sample of environments and occasions. The data that 

are collected from these observations will be analyzed; the 

therapist will look for trends in the occurrences of that 

behavior, for stimuli that may be evoking it or the needs that 

the child is attempting to fill by exhibiting this behavior. The 

therapist then forms hypotheses about the motivation or 

purpose that maintains the occurrence of problem behavior,


and finally formulates a treatment plan and recommends 

intervention options to modify the problem behavior. 

ABA BEHAVIORAL INTERVENTION METHODO- 

LOGY 

Functional behavioral assessment yields useful information 

for designing intervention strategies or techniques that are 

likely to be effective. Many techniques are used for 

behavioral intervention in an ABA program; however, the 

most common and distinguishing type of intervention is 

Discrete Trial Teaching (DTT). It is what people most often 

think of when you say "ABA" or "Lovaas Method”. 10 

Discrete Trial Teaching is a specific ABA teaching technique 

used to maximize learning and enables the learner to acquire 

complex skills by first mastering the subcomponents of the 

targeted skill. 

DTT breaks down skills into small sub-skills and teaches 

each sub-skill intensely, one at a time. It involves repeated 

practice with prompting and fading of prompts to insure the 

child’s success. DTT then uses reinforcement to help shape 

and maintain positive behaviors and skills. 

Specifically, DTT is a procedure, or a single cycle of a 

behaviorally-based instruction routine. A particular trial may 

be repeated several times in succession, several times a day, 

over several days (or even longer) until the skill is mastered. 

There are four parts, and an optional fifth, to a discrete trial: 

•the discriminative stimulus (SD)-- the instruction or 

environmental cue to which the teacher would like the child 

to respond 

• the prompting stimulus (SP) - a prompt or cue from the 

teacher to help the child respond correctly (optional) 

• the response (R) - the skill or behavior that is the target 

of the instruction, or a portion thereof 

• the reinforcing stimulus (SR) - a reward designed to 

motivate the child to respond and respond correctly 

• the inter-trial interval (ITI) - a brief pause between 

consecutive trials 

These parts of the discrete trial are often represented 

symbolically like the following: 

SD --> SP---> R --> SR --> ITI 

This illustrates the order of a discrete trial teaching. First 

comes the teacher's instruction (SD). If the teacher thinks the 

child may need some help to respond correctly, she will give 

him a little prompt, cue, or model to help him out (SP). Then, 

either with help or without, the child gives some response to 

the instruction (R). If the child responds incorrectly she 

might correct him, and then give him another chance. If he 

responds correctly, or close to correctly, the teacher will give 

him some reward or praise to encourage him (SR). After that 

is completed, the teacher might want to pause for a bit before 

continuing, to let the child know that they have completed 

one set and have moved on to the next (ITI). 

This procedure is effective in teaching a variety of simple 

and complex skills. Children with autism often face many 

deficits and difficulties in learning. Discrete-trial training 

can help them to compensate for these difficulties and gain 

the skills needed to overcome their disorder. 11 

For example: 

• Attention - Many children with autism begin a program 

with rather short attention spans. In DTT, tasks are 

broken down into short, simple trials. At the start of a 

program, interactions may only be a few seconds in 

length. As the child's attention span increases, the length 

of the interactions increases accordingly. 

• Motivation - Children with autism may not be as 

motivated to work as other children might be. DTT 

attempts to build this motivation by rewarding 

performance of desired behaviors and completion of 

tasks with tangible or external reinforcement (food, toys, 

time to play, etc.). That external reinforcement is paired 

with social praise with the hope that eventually praise 

will become as reinforcing as the treats, etc. 

• Stimulus control - Discriminating between stimuli which 

we would like to think of as important -- teacher/parent 

requests, invitations from peers, important 

environmental cues (school bells, alarms, weather, etc.) - 

- and all the other "background" stimuli is often difficult 

for children with autism. In DTT the presented stimuli 

(typically instructions from a teacher or parent) are clear 

and relatively consistent. The child is given rewards only 

for behaviors in response to those stimuli so that 

eventually he comes to understand that certain stimuli 

are probably more deserving of his attention than others. 

• Generalization or transferring - Generalization, the 

application of a behavior or skill across a number of 

environments or to a number of related behaviors, is 

typically quite difficult for children with autism. 

Consequently, the instructions in DTT programs are 

designed to change over time, in content (the verbiage of 

the instruction) and context (who is giving the 

instruction, where and when it is being given) gradually 

and carefully. 

• Cause-effect learning and observational learning - 

Children with autism typically have a great deal of 

difficulty in "picking things up" from their 

environments. To compensate then, DTT teaches skills 

and behaviors explicitly, without relying on these areas 

of difficulty. 

• Communication - Often in children with autism, both 

expressive and receptive language are deficient. 

Teaching that relies on a great deal of verbiage from the 

teacher, then, is often too difficult for these children. The 

instructions given in discrete trials are simple, concrete, 

and clearly provide only the most salient information, 

especially at first. As the child progresses, and his 

receptive language becomes stronger, these instructions 

can become more complex. 

• Perspective taking and understanding of social and 

behavioral expectations - While there is little built into


the DTT structure to directly address deficits in social 

cognition and perspective taking, they are designed to 

avoid reliance on these deficient skills. Discrete trials 

can be designed to teach those deficient skills explicitly 

as well. 

Initially, ABA programs for children with Autism utilized 

only DTT, however, ABA programs continue to evolve, 

placing greater emphasis on the generalization and 

spontaneity of skills learned. As children progress and 

develop more complex skills, the strict DTT approach is 

often combined with other teaching strategies based on the 

ABA principles, such as Natural Environment Training 

(NET) to address more complex skills training needs. NET 

specifically emphasizes that all skills are taught in a more 

natural environment in a more "playful manner." Moreover, 

the reinforcers used to increase appropriate responding are 

always directly related to the task, not the subcomponent of 

the task. Some other ABA based interventions, such as RBI, 

VBI, CBT, and other educational programs, such as 

TEACCH, SIT, and RDI, are all proven to be beneficial to 

children with autism. 12 

EFFECTIVENESS OF ABA INTERVENTION 

The use of ABA principles and techniques to help persons 

with autism live happy and productive lives has come into 

widespread use in 1990s. Thousands of published studies 

have shown that ABA techniques can help individuals with 

autism to learn specific skills, such as how to communicate, 

develop relationships, play, care for themselves, succeed in 

school and at work, and participate fully and productively in 

family and community activities. Documentation of the 

efficacy of ABA-based interventions for people with autism 

emerged in the 1960s, with comprehensive evaluations 

beginning in the early 1970s. 

Hingtgen & Bryson in 1972 reviewed over 400 research 

articles pertinent to the field of autism that were published 

between 1964 and 1970. They concluded that behaviorally 

based interventions demonstrated the most consistent 

results. 13 

In a follow-up study, DeMeyer, Hingtgen & Jackson 

reviewed over 1,100 additional studies that appeared in the 

1970s. They examined studies that included behaviorally 

based interventions as well as interventions based upon a 

wide range of theoretical foundations. Following a 

comprehensive review of these studies, DeMeyer, Hingtgen 

& Jackson (1982) concluded ". . .the overwhelming evidence 

strongly suggest that the treatment of choice for maximal 

expansion of the autistic child's behavioral repertoire is a 

systematic behavioral education program, involving as many 

child contact hours as possible, and using therapists 

(including parents) who have been trained in the behavioral 

techniques". 14 

In 1987, Lovaas published his report of research 15 conducted 

with 38 autistic children using methods of applied behavior 

analysis 40 hours per week. Treatment occurred in the home 

and school setting. After the first two years, some of the 

children in the treatment group were able to enter 

kindergarten with assistance of only 10 hours of discrete trial 

training per week, and required only minimal assistance 

while completing first grade. Others, those who did not 

progress to independent school functioning early in 

treatment, continued in 40 hours per week of treatment for up 

to 6 years. 

All of the children in the study were re-evaluated between the 

ages of six and seven by independent evaluators who were 

blind as to whether the child had been in the treatment or 

control groups. There were several significant findings: 16 

In the treatment group, 47% passed "normal" first grade and 

scored average or above on IQ tests. Of the control groups, 

only one child had a normal first grade placement and 

average IQ. 

Eight of the remaining children in the treatment group 

were successful in a language-disordered classroom and 

scored a mean IQ of 70 (range = 56-95). Of the control 

groups, 18 students were in a language-disordered class 

(mean IQ = 70). 

Two students in the treatment group were in a class for 

autistic or retarded children and scored in the profound 

MR range. By comparison, 21 of the control students 

were in autistic/MR classes, with a mean IQ of 40. 

In contrast to the treatment group, which showed 

significant gains in tested IQ, the control groups’ mean 

IQ, did not improve. The mean post-treatment IQ was 

83.3 for the treatment group, while only 53.3 for the 

control groups. 

Subsequent to the work of Lovaas and his associates, a 

number of investigators have addressed outcomes from 

intensive intervention programs for children with autism. For 

example, the May Institute reported outcomes on 14 children 

with autism who received 15 - 20 hours of discrete trial 

training. 17 While results were not as striking as those 

reported by Lovaas, significant gains were reported which 

exceeded those obtained in more traditional treatment 

paradigms. 

A 2005 California study found that early intensive behavior 

analytic treatment, a form of ABA, was substantially more 

effective for preschool children with autism than the mixture 

of methods provided in many programs. 18 

A 2007 clinical report of the American Academy of 

Pediatrics concluded that the benefit of ABA-based 

interventions in autism spectrum disorders (ASDs) "has been 

well documented" and that "children who receive early 

intensive behavioral treatment have been shown to make 

substantial, sustained gains in IQ, language, academic 

performance, and adaptive behavior as well as some 

improvement of social behavior. 19


Researchers from the MIND Institute (Medical Investigation 

of Neurodevelopmental Disorders in UC, Davis) published 

an evidence-based review of comprehensive treatment 

approaches in 2008. On the basis of "the strength of the 

findings from the four best-designed, controlled studies," 

they were of the opinion that one ABA-based approach (the 

Lovaas technique created by Ole Ivar Lovaas) is "wellestablished" 

for improving intellectual performance of young 

children with ASD. 20 

A 2009 review of psycho-educational interventions for 

children with autism whose mean age was six years or less at 

intake found that five high-quality ("Level 1" or "Level 2") 

studies assessed ABA-based treatments. On the basis of these 

and other studies, the author concluded that ABA is "wellestablished" 

and is "demonstrated effective in enhancing 

global functioning in pre-school children with autism when 

treatment is intensive and carried out by trained therapists." 21 

This list can go on and on, however, the report of the 

MADSEC (Maine Administrators of Services for Children 

with Disabilities) Autism Task Force provided a succinct 

description, put together by an independent body of experts: 

Over the past 40 years, several thousand published research 

studies have documented the effectiveness of ABA across a 

wide range of: populations (children and adults with mental 

illness, developmental disabilities and learning disorders), 

interventionists (parents, teachers and staff), settings 

(schools, homes, institutions, group homes, hospitals and 

business offices), and, behaviors (language; social, 

academic, leisure and functional life skills; aggression, selfinjury, 

oppositional and stereotyped behaviors). 22 

ABA is now considered to be at the forefront of therapeutic 

and educational interventions for children with autism. The 

large amount of scientific evidence supporting ABA 

treatments for children with autism have led a number of 

other independent bodies to endorse the effectiveness of 

ABA, including the U.S. Surgeon General, 23 the New York 

State Department of Health, 24 the National Academy of 

Sciences, 25 and the American Academy of Pediatrics. 26 

However, despite the vast empirical support, ABA behavioral 

intervention has faced many challenges and criticism. A 2009 

systematic review and meta-analysis by Spreckley and Boyd 

of four 2000–2007 studies (involving a total of 76 children) 

came to different conclusions than the aforementioned 

reviews. Spreckley and Boyd reported that applied behavior 

intervention, did not significantly improve outcomes 

compared with standard care of preschool children with 

autism in the areas of cognitive outcome, expressive 

language, receptive language, and adaptive behavior. They 

stated that large multi-site randomized trials are needed to 

improve the understanding of ABA's efficacy in autism. 27 

Others questioned whether Lovaas used a representative 

sample of children with autism and overstated the 

effectiveness of ABA intervention. It is also suggested that 

Applied Behavior Analysis and discrete trial techniques are 

less effective for improving language than naturalized 

teaching. 28 

CONCLUSION 

There is a wealth of validated and peer-reviewed studies 

supporting the efficacy of ABA interventions to improve and 

sustain socially significant behaviors in every domain, in 

individuals with autism. Importantly, results reported include 

"meaningful" outcomes such as increased social skills, 

communication skills, academic performance, and overall 

cognitive functioning. These reflect clinically significant 

quality of life improvements. While studies vary as to the 

magnitude of gains, all have demonstrated long-term 

retention of gains made. 

Additionally, according to a cost/benefit analysis conducted 

by Jacobson, Mulick & Green 29 competently-delivered, early, 

intensive behavioral intervention can offer the hope of 

significant gains for both children and taxpayers: estimated 

savings per child to age 22 are about $200,000; to age 55, 

$1,000,000. 

However, ABA behavioral intervention is not without 

controversy. While that debate continues, researchers should 

continue to vigorously investigate behavioral intervention as 

a promising area of research and treatment benefiting 

individuals with autism. Practitioners should leverage ABA 

techniques with the proven efficacy of other effective 

interventions such as RBI, VBI, CBI, TEACCH, SIT, RDI, 

etc., and “broaden their collaboration with psych iatrical 

specialists for optimal outcome and long-term benefit for 

children with autism”, as suggested by Dr. Granpeesheh and 

his colleagues. 30 

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MMWR Surveill Summ. 2009;58(10):1-20. 

2. Rogers SJ, Vismara LA. Evidence-based comprehensive treatments for 

early autism. J Clin Child Adolesc Psychol. 2008;37(1): 8-38. 

3. Mental Health: A Report of the Surgeon General: Other Mental 

Disorders in Children and Adolescents P.6-8. 

www.surgeongeneral.gov. 7/30/2011. 

4. Baer DM, Wolf, MM, Risley TR. Some current dimensions of applied 

behavior analysis. J Appl Behav Anal. 1968;1(1):91-97. 

5. Baer, DM, Wolf MM. Some still-current dimensions of applied 


6. Ayllon T, Michael J. The psychiatric nurse as a behavioral engineer. J 

Exp Anal Behav. 1959;3:324-334. 

7. Lovaas OI. Behavioral treatment and normal educational and 

intellectual functioning in young autistic children. J Consult Clin 

Psychol. 1987;55(1):3-9. 

8 Baer DM, Wolf, MM, Risley TR. Some current dimensions of applied 


9. Umbreit J, Ferro JB, Liaupsin CJ, Lane KL. Functional Behavioral 

Assessment and Function-Based Intervention. Prentice Hall Mar. 31st, 

2006, ISBN-10: 013114989X 

12. Myers SM, Johnson CP, Council on Children with Disabilities. 

Management of children with autism spectrum disorders. Pediatrics. 

2007;120 (5):1162-1182.


13. Hingtgen JN, Bryson CQ. Recent developments in the study of early 

childhood psychoses: Infantile autism, childhood schizophrenia, and 

related disorders. Schizophrenia Bulletin. 1972;5:8-54. 

14. DeMyer MK, Hingtgen JN, Jackson RK. Infantile autism reviewed: A 

decade of research. Schizophrenia Bulletin. 1981;7:388-451. 

16. Lovaas OI. Behavioral treatment and normal educational and 

intellectual functioning in young autistic children. J Consult Clin 

Psychol. 1987;55(1):3-9. 

17. Anderson SR, Avery DL, Dipietro EK., Edwards GL, Christian WP.. 

Intensive home-based early intervention with autistic children. 

Education and Treatment of Children. 1987;10:352-366. 

18. Howard JS, Sparkman CR, Cohen HG, Green G, Stanislaw H. A 

comparison of intensive behavior analytic and eclectic treatments for 

young children with autism. Res Dev Disabil. 2005;26(4):359-383. 

19. Myers SM, Johnson CP, Council on Children with Disabilities. 

Management of children with autism spectrum disorders. Pediatrics 

2007;120 (5): 1162-1182. 

20. Rogers SJ, Vismara LA. Evidence-based comprehensive treatments for 

early autism. J Clin Child Adolesc Psychol. 2008;37(1):8-38. 

21. Eikeseth S.. Outcome of comprehensive psycho-educational 

interventions for young children with autism. Res Dev Disabil. 

2009;30(1):158-178. 

22. Maine Administrators of Services for Children with Disabilities 

(MADSEC). Report of the MADSEC Autism Task Force. 2000. 

23. Mental Health: A Report of the Surgeon General: Other Mental 

Disorders in Children and Adolescents P6-8. www.surgeongeneral.gov. 

7/30/2011. 

24. New York State Department of Health, Early Intervention Program. 

Clinical practice guideline: Autism/ pervasive developmental disorders, 

assessment and intervention for young children (Age 0-3 Years). 

Albany, NY: 1999. 

25. Lord C, McGee JP, editors. Educating Children with Autism. 

Washington, DC: National Academies. 2001. 217-221. 

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Disabilities. The pediatrician’s role in the diagnosis and management 

of autistic spectrum disorder in children. Pediatrics. 2001;107(5):1221- 

1226. 

27. Spreckley M, Boyd R. Efficacy of applied behavioral intervention in 

preschool children with autism for improving cognitive, language, and 

adaptive behavior: a systematic review and meta-analysis. J Pediatr. 

2009;154(3):338-344. 

28. McPheeters ML, Warren Z, Sathe N, Bruzek JL, Krishnaswami S, 

Jerome RN, Veenstra-Vanderweele J. A systematic review of medical 

treatments for children with autism spectrum disorders. Pediatrics. 

2011;127(5): e1312-1321. 

29. Jacobson, JW, Mulick JA, Green G. Cost-benefit estimates for early 

intensive behavioral intervention with young children with autismgeneral 

model and single state case. Behav Intervent. 1998;13;201-226. 

30. Granpeesheh D, Tarbox J, Dixon DR. Applied behavior analytic 

interventions for children with autism : a description and review of 

treatment research. Ann Clin Psychiatry. 2009;21(3):162-173.


Review 

Autism Treatment from Acupuncture Perspective 

Jing Liu, MD, PhD, Zeng Xiaoqing, MD, Ping Yao, MD 

ABSTRACT 

Although acupuncture has been used in the treatment of 

autism for many years, almost no formal clinical trials 

have been devoted to confirm the effectiveness of the 

acupuncture for the disease in the western countries, 

where a big population of children and family have been 

suffering from the shortage of effective therapy. This 

review is to summarize the reports from about 20 clinical 

trials of acupuncture for autism in the last decade in 

China. The results of these reports suggested that 

acupuncture may be a potentially valuable approach in 

treating autism. Around 80% symptom improvements 

were stated in most of the studies. The reports also 

demonstrated that acupuncture may enhance the 

efficacies of conventional therapies for autism, such as 

behavior rehabilitation therapy. It was suggested that the 

effects of acupuncture for autism may be partially related 

with its effects on anti-inflammation and on the 

modulation of the brain signal conductivity, supported by 

the research including fMRI. A concept of transcranial 

electrical acupuncture stimulation (TEAS) is proposed. 

Compared with the conventional acupuncture technique, 

TEAS is hypothesized to target directly on the brain 

lesions of autism through modulating hyperpolarized or 

depolarized neurons of the brain, in order to improve the 

pathological status of autism. Clinical trials are needed to 

approve the proposal in the future. 

[N A J Med Sci. 2011;4(3):164-166.] 

Key Words: Autistic spectrum disorder, acupuncture 

The Centers for Disease Control and Prevention have called 

autism a national public health crisis. Due to shortage of 

effective therapeutic options in conventional medicine, many 

interests have shifted to the alternative remedies. Growing 

evidences support that acupuncture may be a potential 

effective approach in treating autism. This commentary will 

briefly review the update information of acupuncture on 

autism and open the discussions on the clinical study of 

acupuncture for the disease in the future. 


Jing Liu, MD, PhD, 1 Zeng Xiaoqing, MD, 2 Ping Yao, MD 1 

1. The Marino Center for Integrative Health, Cambridge, MA 

2. Cheng Du University of Traditional Chinese Medicine, 

Cheng Du, China 


Jing Liu, MD, PhD 

Email: ahl_health@yahoo.com 

Although no clinical trials worldwide have presented 

conclusive results on the effectiveness of acupuncture in the 

treatment of autism, some clues can be obtained from the 

clinical studies in the past decade. Reviewing the reports 

from about 20 clinical trials published in the last 15 years, 

with at least 30 cases in each study, the effective rates of 

autism treatment with acupuncture were around 80%. 

However, only a few of them were randomized controlled 

studies. No obvious side effects or safety concerns have been 

stated in these studies. 1,2,3 Here are a few examples. A 202 

case controlled study with autism showed that the effective 

rate of the symptom improvement by acupuncture was 

92.3%. Of the 78 and 58 severe patients, there were 92.3% 

and 40.5% improvements in the acupuncture treatment and 

control group respectively. 4 Reported from a 50 case of 

randomized controlled clinical trials, significant 

improvements were observed in language comprehension, 

self-care caregiver assistance, social initiation, receptive 

language, motor skills, coordination, and attention span, 

evaluated by the tests of Functional Independence Measure 

for Children (WeeFIM), Pediatric Evaluation of Disability 

Inventory (PEDI, Clinical Global Impression-Improvement 

(CGI-I) scale, Aberrant Behavior Checklist (ABC), and 

Reynell Developmental Language Scale (RDLS). In this 

study, acupuncture induced. significant improvements in the 

language comprehension domain of WeeFIM (p=0.02), selfcare 

caregiver assistant domain of PEDI (p=0.028), and CGI- 

I (p=0.003) in the electrical acupuncture group compared to 

the sham control group. 5 In a case of controlled study, 30 

sessions of treatments were applied on 32 autism children to 

test the effects of a acupuncture technique of Seven-star 

Needle Stimulation for over 6 weeks. The results showed that 

the acupuncture treatment induced significant improvement 

in language and social interaction, but not in stereotyped 

behavior or motor function, monitored by EEG (qEEG) with 

the quantitative behavior measurement. 6 

The effectiveness of acupuncture was also evaluated in 

comparison with other conventional medical approach. In a 

clinical study of 40 cases, including those with severe autism, 

acupuncture group using JIN's 3-needling technique 

presented significant better results than that of the behavior 

intervention. 7 A report from a four month clinical trial 

revealed that acupuncture, compared to piracetam treatment, 

showed a more significant improvement on the language 

comprehension. 8 Acupuncture may be also potentially a 

valuable adjuvant therapy to certain conventional treatments. 

It was documented that forty autistic children received 

rehabilitation training programs of ABA, Conductive 

Education Approach and the sensory integration. Twenty of 

those also received acupuncture treatment by end of the 

rehabilitation training. There was a 55.0% markedly effective


rate in the group using additional acupuncture, compared 

with a rate 15.0% in the group with rehabilitation alone. 9 The 

studies above all selected some of internationally recognized 

questionnaires to evaluate the changes of psycho-behaviorneural 

symptoms and the effectiveness rate of acupuncture 

treatment. Those questionnaires include Aberrant Behavior 

Checklist(ABC), Autism treatment evaluation checklist 

(ATEC), Functional Independence Measure for Children 

(WeeFIM), Pediatric Evaluation of Disability Inventory 

(PEDI, Clinical Global Impression-Improvement (CGI-I) 

scale, , and Reynell Developmental Language Scale (RDLS). 

Overall, there is shortage of well designed randomized 

controlled clinical trails to evaluate the true values of 

acupuncture treatment for the autism. However, the 

information obtained should be enough to encourage further 

investigations. 

The selections of acupuncture points have been various in the 

above clinical studies. In general, the acupuncture points 

were selected mostly based on the meridian theory in Chinese 

medicine. Some of those points are thought act by “waking 

up the brain and opening the orifice” in the theory. On the 

other hand, the relatively newly developed scalp acupuncture 

based on the brain anatomy has been commonly used in 

almost every group of clinical studies of autism. The most 

frequently used points of scalp acupuncture include: (1) 

Three Acupoints of the Temple: GB 8, l cun anterior and 

posterior to GB 8; (2) Three Wisdom Acupoints: GV l 2, 

bilateral GB 1 3,GV 20; (3) Three Acupoints of Brain: GV 

17, 1.3 cun left and right to GV 1 7; (4) Four Acupoints of 

the Mind: Ex-HN 1(Si Shen Cong); (5) three points on the 

occipital area: GVl5,GB20,GBl2. 10 A few years ago, a 

randomized controlled 50 case clinical trial of tongue 

acupuncture was first reported being effective for autism. A 

significant improvement in the treatment as compared to the 

control group was seen in self-care and cognition domains of 

the Functional Independence Measure for children. The 

authors applied acupuncture on the tongue including points 

of Ex•HN 1 2,Ex-HN l , and CV23. 11 

Quite a few new technologies have been developed in 

evaluating the effectiveness of acupuncture in treating 

autism, in addition to the subjective psycho-behavior tests. 

One of the impressive works was from Dr. Jia Shaowei. His 

group reported at 2008 that electrical acupuncture 

significantly improved SPECT brain image of 78.95% in a 34 

case clinical study, a result corresponding the clinical 

behavior improvement. They suspected that the increased 

blood flow and enhanced function in the prefrontal cortex, 

broca and wernicke region could partially contribute such 

changes. 12 fMRI has been one of the most promising tool in 

assessing the functional and structural changes of autism. For 

example, growing evidences support that autism is an 

inflammatory disorder of brain, evidenced by the fMRI 

finding that the total volume of brain, cerebella and caudate 

nucleus enlarged. The area of corpus callosum is reduced. 13 

The inflammation may involve in the changes of the 

neurophysiology of autism, characterized by a disturbance of 

the signal conductivities, particularly, the exaggeration of the 

excitatory signals and deficit of the inhibitory signals during 

information processing. Such abnormal balance mostly exist 

in the prefrontal and temporal cortex as well as deep nucleis 

such corpus callosum. 14 In fact, the anti-inflammatory 

effects of acupuncture were explored in many studies. 15,16 

Acupuncture may down-regulate exaggerated neural activity 

and generate a tranquilizing effect by enhancing GABAergic 

enhancing efficacy. 17 The results from Dr. Kathleen Hui’s 

fMRI studies further suggested that acupuncture may 

modulate the conductivity of cortico – limbic-subcortical 

network. 18 

Another new technique used in the autism study was based 

on the discovery that the activity of the sympathetic 

autonomic nervous system is significantly altered in children 

with autism. The authors measured 48 acupuncture points on 

fingertips by using a biometric device capable of gas 

discharge visualization (GDV). They found that the psychoemotional 

and physiological functional states of autism were 

correlated with the enhanced activities of the autonomic 

nervous system. 19 

So far, it seems that acupuncture is a potential approach to 

benefit the children with autism. However, it is clear that the 

ongoing knowledge and techniques of acupuncture need to be 

further studied and improved. For instance, no autism 

research of acupuncture has focused on the digestive system, 

although the inflammation in gut system may play an 

important role in the development of autism. 20,21,22 

Furthermore, acupuncture alone is not a complete solution for 

autism, although many clinical studies suggested potent 

benefits. We hypothesize that acupuncture may mostly affect 

on the aspect of functional activities, probably including 

neural conductivity ignition and signal transduction, which 

may be similar to the concept of “Qi” effect of acupuncture 

in the view of traditional Chinese medicine. Considering that 

autism children have not only functional psycho-behavior 

symptoms but also significant abnormalities in nutritional 

abnormalities, such as essential fatty acid and phospholipids 

metabolism, which may accompany with the inflammation 

process and even the genetic disturbances. 23,24 So, it is 

reasonable to suggest that integration of acupuncture with 

proper nutritional therapy based on the individual needs is 

necessary. 

The acupuncture technique itself needs to be upgraded based 

on scientific evidences. fMRI found that the superior 

temporal sulcus (STS) region is an important component of 

the network of brain regions that support various aspects of 

social cognition and social perception. 25 Excessive signaling 

may lead to hyperexcitable behavior as a result of shortage of 

GABAergic functions in the area. The superior temporal 

sulcus function may underlie many of the social and language 

abnormalities seen in autism. 26 Therefore, one of the major 

targets of autism treatment should be on the prefrontal and 

temporal-limbic region functions. From this point of view, 

conventional acupuncture may not provide enough impact in


these areas, because the acupuncture stimuli are usually 

distant from the pathological lesions of the brain. Here, 

transcranial electrical acupuncture stimulation (TEAS) is 

proposed by Dr. Jing Liu based on the information review 

and the preliminary clinical experiences. 

The idea of TEAS is supported by the evidence of 

transcranial direct current stimulation (tDCS). tDCS 

involves placing metal electrodes on the scalp and applying a 

small and harmless electrical current across the cranium. The 

current can hyperpolarize or depolarize neurons in the path of 

the current. 27 It was shown that tDCS over frontal cortex 

enhanced retention of word learning. 28 Stimuli of 1 mA 

tDCS can induce a slight change in the resting potential of 

the brain cells, resulting improvement of the information 

process through modulating the depolarization thresholds of 

neurons. 29 Hence, we predict that TEAS may bring the 

electrical current across the targeted regions of brain as tDCS 

do, instead of the surface to surface stimulation of the scalp 

acupuncture. Both traditional acupoints and the neural 

anatomy should be considered when the acupoints of TEAS 

are selected. Another advantage of TEAS found from the 

previous clinical practice may be that the application is 

painless and easier accepted by children than that of 

traditional acupuncture. So far, we have little knowledge on 

how such electrical current can affect the brain function of 

those with autism. However, we predict that the targeted 

treatment of the TEAS can be well measured and evaluated 

by using modern techniques such as fMRI or EEG, 

considering that the prefrontal and temporal gyrus are located 

in the relative superior areas of the brain. Further 

investigations are needed to confirm the hypothesis. 

Together, acupuncture seems a therapeutic approach which 

may be beneficial to children with autism. However, more 

qualified clinical trials are needed to approve the 

effectiveness of acupuncture on the disease. TEAS, a new 

technique of acupuncture is proposed to improve the efficacy 

of acupuncture on autism treatment. 

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Proceedings 

Current Status of Autism Spectrum Disorder in China 

- Summary on the 369th Xiangshan Science Conferences 

Bai-Lin Wu, PhD, Zhenyu Zhang, PhD 

EDITORIAL 

On March 31st and April 1 st , the 369 th session of the 

Xiangshan Science Conferences was convened in Beijing, 

China under the theme of “Status Quo and Frontiers of ASD 

Studies”. Wu Ying, Investigator of Northwest University and 

distinguished professor of the Institute of Biophysics, 

Chinese Academy of Science; Yu Xin, professor and director 

of the Institute of Mental Health, the Sixth Hospital of 

Beijing University; Wei Liping, professor of Center for 

Bioinformatics, College of Life Science, Beijing University; 

and Wu Bailin, Investigator of Children’s Hospital Boston, 

Harvard Medical School and distinguished professor of 

Fudan University; acted as conference co-chairs. Almost 40 

specialists and scholars from multi-disciplinary fields were 

invited to attend the meeting within whom extensive 

exchange and intensive discussion were unfolded. They are 

selected from more than 20 organizations nation-widely. In 

the conference, 15 experts including 4 international experts 

were invited to give reports on their specific researches and 

clinical experiences, while focusing on three central topics: 

(1) Current progress and future prospects of ASD studies in 

the world; (2) Current situations and future prospects of ASD 

studies in China; and (3) Genetic/genomic and 

neurobiological studies of ASD. 

[N A J Med Sci. 2011;4(3):167-172.] 

Key Words: Autism, neurobiological disorder 

BACKGROUND 

Autism, generally known as autism spectrum disorders 

(ASD), in some cases is inclusively termed as pervasive 

developmental disorder. It is a serious neurobiological and 

developmental disability usually starting during infancy or 



Bai-Lin Wu, PhD 

Departments of Laboratory Medicine and Pathology, 

Children's Hospital Boston, Harvard Medical School, Boston, 

MA 02115 

Email: bai-lin.wu@childrens.harvard.edu 

Zhenyu Zhang, PhD 

60 Elm Ave, Coram, NY 11727 

childhood. The characteristics of autism are impairments in 

children are mentally retarded. After grown-up, 50%-70% of 

them still have exacerbate social adjustment, minimal selfsocial 

interaction, difficulties in verbal or non-verbal 

communication, and restricted, repetitive and stereotyped 

patterns of interests and behaviors. About 75% of the autistic 

care ability and requirement of lifetime support, placing 

enormous economic and psychological burdens on their 

families and the society. Historical epidemiological data 

suggested diagnosis of ASD among American children have 

been increasing dramatically, from 4 per 10,000 children in 

1970s to 10 for every 10,000 children in 1990s. In 2007, an 

investigation undertaken within 14 states of the United States 

showed that, about one child in 150 develops autism (for 

boys, the prevalence rate goes to 1 in 94). According to 

WHO statistics, there are about 600,000 to 1.8 million 

children with autism in China. In recent years, measures are 

taken to raise awareness and deep concerns about autism in 

developed countries. With large financial and human 

resources being invested, governments, foundations, 

universities, research institutes as well as general public are 

dedicating to the efforts of understanding and responding to 

autism. Compared with developed countries, in China, 

understandings and concerns in this regard are seriously 

retarded and inefficient, characterized as poor investment on 

related research, diagnosis and treatment. Urgent efforts 

should be made to raise the public awareness, increase 

funding supports to clinical and fundamental autism 

researches. It is also necessary to encourage the connection 

between researchers from clinical and fundamental studies, 

benefiting autistic patients and their families, therefore 

generating a more harmonious social atmosphere. 

MEETING REPORT 

Prof. Wu Ying delivered a keynote presentation “Current 

developments and frontiers of ASD studies both at home and 

abroad”. She reviewed several aspects of autism such as the 

pathogenesis mechanism of autism, current diagnostic criteria 

in China and abroad, etc. and she also gave a brief 

introduction of Autism Consortium China, a collaborative 

platform both for autism researches and clinical studies. She 

had an elaborative and systematic description of the etiology 

of autism, including both hereditary and environmental 

factors. She pointed out that, up to now, both twin studies 

and family studies have shown that autism has a genedominated 

basis; however it cannot be traced to a classical


Mendelian mutation. Existing studies show that on the level 

of complete human genomes, the number of autism-related 

genes is more than 300, only 10% of which follow 

monogenic inheritance; most of the autism still cannot be 

traced to definitive genetic/genomic mechanisms. In addition, 

she introduced the existing autism diagnostic criteria, both 

domestic and international, including the internationally 

recognized Diagnostic and Statistical Manual of Mental 

Disorders IV (DSM-IV) from the United States and Chinese 

Classification of Mental Disorders-third edition (CCMD-3). 

Because of the difference in language, culture background 

and fundamental realities, it is urgently necessary to establish 

and improve the diagnostic observation schedules which are 

according with the situations of China. Also, it needs to be 

clarified how to apply the early intervention at the earliest 

possibility after autism diagnosis. She also clearly realized 

the problems and challenges facing the autism research in 

China and pointed out the direction of future research. 

Prof. Wu Ying expatiated the mission of the Autism 

Consortium China (ACC). According to the Survey on 

Disability in 0-6 Year’s-Old Children in China, the 

prevalence of deformity within 0-6 year old children is 

persisting at a very high level. Autism, as one of the major 

triggers leading to their mental deficiency, brings an 

enormous burden both to their families and the society. Prof. 

Wu emphasized the necessity to awaken the attention to 

autism from various levels of the country and to catalyze the 

tight collaboration between the clinical specialists and 

researchers. In order to carry out the comprehensive autism 

studies in China as early as possible, and strengthen the 

domestic and international collaboration, Autism consortium 

China was initiated and launched in December, 2009. The 

founding board members of ACC consist of Wu Ying, Shen 

Yan, Wei Liping, Yu Xin, Liu Jin, Mao Meng, Lu Zuhong, 

Xu Qi, Xu Xiu and Wu Bailin. They assumed the mission to 

establish and provide a platform in China supporting 

collaboration among the community of research scientists 

and clinicians engaged in the studies or treatments of ASD. 

The major objectives of ACC include: 1) Spread and enhance 

understanding and knowledge of ASD within Chinese 

government and various levels of the society; 2) standardize 

the clinical diagnostic criteria and perform national 

epidemiological screening on ASD; 3) organize and 

implement inter-discipline, top-quality studies of ASD in 

China; 4) catalyze rapid advances on domestic and 

international academic exchange and scientific collaboration 

of ASD researches; and 5) ultimately, establish domestic and 

international early diagnosis criteria of ASD for 

comprehensive behavioral assessment as well as the 

molecular levels of analysis; along with safe, effective 

strategies from autism behavior intervention to medical 

treatments. With her heartfelt appealing, Prof. Wu Ying 

urged China’s fundamental scientific researchers and clinical 

specialists to work together as soon as possible, dedicating to 

the break-through on autism therapeutics. 

I. CURRENT PROGRESS AND FUTURE 

PROSPECTS OF ASD STUDIES IN THE WORLD 

Prof. Wu Bailin first introduced the successful experience 

from the Boston-based Autism Consortium in USA and 

analyzed challenges and opportunities for autism studies in 

China. He proposed a multi-institutional collaboration for the 

ASD studies and summarized the necessity to increase 

financial investment on ASD studies and the requirement to 

establish Chinese autism clinical sample database for such 

large-scale collaborative studies, as well as establishing 

diagnostic criteria suitable to Chinese situation and integrated 

with international standards. He urged his Chinese peers act 

in the spirit of globalization and put their efforts to be in line 

with the frontiers of international ASD studies. Prof. Wu Bailin 

further gave a specific report on the genome-wide 

association studies between the copy number variation 

(CNV) and the autism spectrum disorders. 

Dr. Persico from Università Campus Bio-Medico di Roma 

shared with Chinese peers about his 13 years’ experience in 

autism sample collection at Italian, elaborating on the 

application of diagnostic schedules, collection and 

preservation of samples, etc. He also introduced the present 

proceedings on family-based association study of ASD. He 

pointed out that it’s urgent for China to establish its own 

autism diagnostic observation schedules (ADOS), and 

introduced the difficulties and his invaluable experience 

while establishing ADOS in Italy. 

Dr. Mosconi, from University of Illinois at Chicago, 

emphasized the validity of early diagnosis and early 

intervention in autism therapy. According to previous studies, 

each autistic patient accrues about $3.75 million in costs over 

his or her lifetime, and it takes US government $35 billion 

every year to take care of the autistic patients. Thus it can be 

seen that ASD creates an extraordinary socio-economy 

burden. Several studies have shown that diagnosis/treatment 

at its early stages of ASD are very effective and can 

substantially reduce its socio-economic consumption. Thus, 

American Academy of Pediatrics (AAP) has urged that all 

children accept autism screening at their 18 month and/or 24 

month pediatrician visit. Regarding the prevalence of adult 

autistic patients in the US and Italy, Dr. Mosconi pointed out 

that, with early diagnosis and early intervention, ASD 

symptom of some of affected children will reduce or even 

disappear. If a child missed his or her best periods for 

diagnosis and intervention, it is seldom for the symptom to be 

mitigated. From Dr. Presico, in Italy, some of the adult 

autistic patients could be diagnosed as mental retardation, 

intellectual disability or other adult mental disorders. 

II. CURRENT SITUATIONS AND FUTURE 

PROSPECTS OF ASD STUDIES IN CHINA 

Prof. Liu Jing, chief physician from the Institute of Mental 

Health, Beijing University, gave a report entitled “Autism 

Diagnosis and Epidemiological Data in Beijing”. She 

reviewed the history of domestic research on autism in China 

since 1977, emphasizing that the epidemiological surveys of 

autism were not conducted in some places until 2000. As a


clinician, she witnessed an increasing of autism patients 

coming to seek treatment in recent years. Clinical data 

illustrated that the highest ratio of abnormality was found in 

children aged 25-36 months. Developmental language 

disorder proved the primary concern for the parents. The 

patients of initial diagnosis consisted mostly of children aged 

three years old, with the minimum age of 15 months. Dr Liu 

described that the current diagnostic criteria for domestic use 

include DSM-IV, ICD-10 and CCMD-3. And she also 

commented on the consistency rate of diagnoses made by 

using them. Speaking of the autism rating scales, she 

mentioned that the scales currently used in China are mostly 

for the purpose of intelligence and development assessments. 

According to her, these scales are by and large matching with 

international practice, whereas symptom rating scales are 

much less available, except for CABS, ABC, CHAT, CHAT- 

23, M-CHAT, and the autism screening scale. Only very few 

clinical diagnostic tools are put into use now, including 

merely the Childhood Autism Rating Scale (CARS), while 

the Autism Diagnostic Interview – Revised (ADI-R) and the 

Autism Diagnostic Observation Schedule (ADOS) are 

currently not yet widely applied to clinical practice. In terms 

of the rational use of scales, she laid emphasis on the 

significance of clinical diagnosis. Pointing out that the 

diagnosis of children can sometimes change with age since 

autism is a complex disease; she insisted clinicians should 

make clear the relationship between somatic diseases and 

symptoms when making diagnosis, in order to avoid 

misdiagnosing autism to be the attention deficit hyperactivity 

disorder or schizophrenia. In the end, she introduced the 

mental disability survey of 2-6 years old children in Beijing 

in 2004. 21,866 samples were collected. The findings showed 

that the typical autism patients in the autism spectrum 

accounted for 1.5‰, a percentage lower than that in the 

United States and Europe. This status, according to her, is 

largely due to the fact that physicians of autism diagnosis and 

treatment are very unevenly distributed, and those in rural 

and remote areas have little knowledge of or ability to 

identify autism. Taking the survey data for instance, she 

commented that in China parents obviously knew little about 

autism, with merely 13.6% of average awareness. The 

awareness in cities is relatively good, normally 76.3%, 

compared with only 2.3% in rural areas. Among people with 

higher education, the percentage reaches 75.7%, compared 

with simply 3.4% among people at lower education levels. 

Prof. Xu Xiu of Children’s Hospital at Fudan University 

reported the status of early screening, diagnosis and 

intervention for autism patients in Shanghai. Now Shanghai 

has five major hospitals capable of autism diagnosis and 

intervention. The scale of CHAT-23 was once adopted to 

screen 535 children aged 18-24 months, with the results 

revealing the good feasibility of this scale, while the scale of 

ASQ was suitable to be promoted in kindergartens. She 

suggested for the screening the name of “social skills and 

communication skills survey”, which was more acceptable to 

parents, rather than terms such as mental illness, autism, or 

other words of this sort. Considering high false positive rate, 

re-translation and amendments of the ASQ scale were 

recommended. Based on her experience in autism screening, 

she put forward suggestions as follows: 1) Make a clear 

distinction among screening scales, diagnostic scales, and 

diagnostic criteria. The screening scales are for screening 

purpose only; they should not be used as basis of diagnosis. 

2) The purpose of screening is to filter out children with 

ability deficit, in order that further professional diagnosis 

could be made. “Labeling” children prematurely should be 

avoided. 3) Parents are preferred to be survey respondents, 

because the answers from them are normally more reliable. 

4) Strengthen the popular science propaganda of autism. In 

terms of autism rehabilitation treatment, she introduced the 

current practice in rehab centers in Shanghai. Most of them, 

however, treat autism children and children with other 

disorders undifferentiatedly, so special trainers of autism 

rehabilitation are in urgent need. On the future model of 

rehabilitation interventions, it was recommended to establish 

a family-centered, community-based practice, with 

professionals providing guidance for early autism screening, 

diagnosis and intervention, and meanwhile to explore the 

practice with the integration of medical education and 

rehabilitation. Finally, Prof. Xu Xiu posed problems to be 

resolved in identifying autism at the early stage: how to 

single out one or two scales suitable for the early-stage 

screening of children in China; how to refer screeningpositive 

children to experts in specialized ASD/DD/ID clinics 

for further evaluation and diagnosis; and how to make it 

possible to provide a practical operation scheme for parents 

of high-risk children. 

Prof. Zhang Minglian of the Center of Mental Health in Wuxi 

presented the childhood autism epidemiological survey 

among children of 1-6 years old in Wuxi. In his report, he 

brought forward proposals as follows: 1) to increase parents’ 

and healthcare physicians’ knowledge of autism, in order to 

carry on early-stage diagnosis and intervention in a more 

efficient way; 2) to raise public’s awareness of autism by 

launching a propaganda among parents, in communities and 

throughout rural areas; 3)to strengthen the training of the 

first-line screening personnel and enhance their ability to 

identify autism; 4) to amend and improve those screening 

scales which have been maturely employed abroad for fitting 

them into domestic use; 5) to strengthen communication 

between psychiatrists and pediatricians on their differentials 

in understanding autism. 

Prof. Zou Xiaobing had founded Children’s Centre for 

Development and Behavior with the NO. 3 Hospital affiliated 

to Sun Yat-sen University in 1999. Since then he has 

organized 80 sessions of parent training courses, and has 

been holding long-term adherence to conducting continuing 

education courses for the medical staff. In his report “Current 

Situations of ASD Diagnosis and Treatment in Guangdong 

and Thoughts on the Etiology and Pathogenesis of ASD”, He 

introduced their diagnostic procedures and criteria. The 

simple S-CHAT scale was employed in the popular science 

propaganda of autism in kindergartens, elementary schools


and communities. He proposed M-CHAT, ABC, CARS, 

CBCS scales for use in the clinic, and suggested CARS scale 

and improved questionnaires based on ADI-R for collecting 

medical history. He meanwhile pointed out that no single 

scale should be used independently to diagnose autism. 

According to him, clinical experience plays a crucial role; 

diagnosis has to be made through all-scale medical history 

taking and intensive observation of patients’ behaviors. He 

also stated his thoughts on the etiology and pathogenesis of 

autism, saying that studies of pathogenic factors for autism 

must combine genetics, genomics, epigenetics, proteomics, 

psychology and neurobiology. In the end, he put forward the 

following suggestions: 1) to do the best in autism screening; 

2) to carry on a nationwide epidemiological survey, in order 

to improve studies and treatment efforts; 3) to conduct 

research on the reliable and effective interventions; 4) to 

attract more attention from the government to autism. 

In her report “Current Situation of Autism Diagnosis and 

Intervention in Shenyang”, Prof. Ma Hongwei summarized 

the autism diagnoses made by Shengjing Hospital affiliated 

to China Medical University in 2005, 2008 and 2009. He 

found that the clinic visit rate was increasing year by year, 

with the lowest rate of children under 18 months, the highest 

rate between 18 months and 3 years old, and the rising rate of 

4-5 years old. This progress might be facilitated by the 

enhanced awareness of parents. Unfortunately, children who 

were brought to clinic by parents were averagely too old to 

catch up the best time of early intervention. In addition, in 

terms of training attendance in rehab centers in Liaoning, the 

number of rural trainees was much less than that of urban 

ones, largely due to backward economic condition and lack 

of understanding of autism in rural areas. 

When sharing his experience in autism behavior analysis and 

treatment, Prof. Guo Yanqing of the Institute of Mental 

Health, Beijing University, pointed out that, in rural areas, it 

was hard to complete the questionnaire because of barriers in 

communication and understanding. Since parents are often 

not living with the children, questionnaires and interviews are 

usually done by grandparents, who have great difficulties in 

understanding the designed questions. In regard to behavior 

treatment, he commented that behavior training was actually 

an art. Having understood the basic principles, the trainer has 

to avoid rigidity in applying them into the training, and 

meanwhile employ proper and flexible training techniques. 

Improper training method may cause great impairment to 

children; therefore, training of trainers and parents must be 

well done beforehand. Guo sighed over existence 

environment and trainers conditions of domestic autism rehab 

centers. He further proposed avoiding the use of integrated, 

eclectic methods in institutional training. Meanwhile, he 

stressed that scientist should have a serving heart for patients 

while focusing on research. He also raised the question of 

how to render a better service to families with the autism 

child and how to follow parents’ training of the child at 

home. In answer to it, he suggested visiting parents at home 

after class, or requiring parents to record the training and then 

submit the video as feedback, as a supplement to class 

teaching of basic principles and methods. 

In the discussion, Prof. Zou Xiaobing explained that 

currently the data of epidemiological survey typically fall 

between 1-2‰, much lower than that in Western countries 

because of inconsistency in diagnostic criteria. He further 

pointed out that lack of professional teams to diagnose in the 

epidemiological survey might have led to inadvertently 

leaving out high-functioning autism and atypical autism, and 

therefore resulting in the inaccurate findings. He suggested 

that well-trained physicians would be crucial for a reliable 

epidemiological survey. Prof. Zhang Minglian attached 

importance to screening by saying that the reliability of 

epidemiological survey data would be conditioned by 

parents’ proper understanding, investigators’ enhanced 

awareness and accurate screening tools. Prof. Guo Yanqing 

insisted that conclusion should only be formed through strict 

screening and definite diagnosis. He suggested that there 

were no scales universally applicable to all diagnoses; only 

more contacts with patients and their parents. Prof. Wu Ying 

placed primary concern on clinic experience and training. 

Currently in China, there are too few practitioners in dealing 

with autism, and even less professionals in mental health, 

which have greatly restricted the development in this field. 

Prof. Jin Xingming, chief physician of Shanghai Children’s 

Medical Center stated that it is important to exercise a good 

training of professional teams prior to conducting the 

epidemiological survey, for now in China physicians who are 

able to diagnose autism are very limitedly numbered. Prof. 

Liu Jing and Prof. Jin Xingming both highlighted the 

importance of establishing the China’s own scales of 

diagnosing autism. 

III. GENETIC/GENOMIC AND NEUROBIOLOGI- 

CAL STUDIES OF ASD IN CHINA 

Prof. Wei Liping Prof. Wei introduced the method and 

progress in studying such complex diseases as autism by 

adopting genomics and bioinformatics technologies. She 

advanced proposals as follows: 1) to search for pathogenic 

genes by integrating and analyzing autism-related genes and 

protein data obtained through all various experimental 

methods. Considering autism is a complex multi-factorial 

disease, systematic integration should be employed as a 

proper strategy; 2) to construct autism-related molecular 

network by searching for the common molecular pathway of 

autism-related diseases; 3) to give particular attention to the 

regulatory SNP when analyzing autism-related SNP; 4) to 

standardize collecting clinical and genetic information of 

patients, in order to establish autism patients data base. 

Prof. Bao Xinhua of the Hospital of Beijing University 

shared her experiences of the clinic diagnosis and treatment 

of Rett syndrome. Rett syndrome is a severe neurodevelopmental 

disorder with girls, caused by MeCP2 genetic 

mutation. The incidence among girls is 1/10 000-1/15 000. A 

large proportion of Rett syndrome patients have autism 

spectrum disorders. Prof. Bao elaborated on characteristics


and classifications of Rett syndrome, and described their 

research methods and results of studies on genes which cause 

the disease. Prof. Liu Jia, from Beijing Normal University, 

presented a report “Relationship between Face Agnosia and 

Autism”. 

Prof. Xia Jun, from The Hong Kong University of Science & 

Technology, reported on the relationship between synaptic 

and autism. Prof. Xie Wei, from Southeast University, 

presented a report on the relationship between 

neurotransmitter delivery and autism, in which he described a 

new idea of studying autism by utilizing the drosophila 

model. 

IV. CONSENSUS AND RECOMMENDATIONS 

The participating experts had a warm, in-depth exchange of 

ideas and discussion on current problems and 

countermeasures in the field of autism studies, both clinical 

and research, in China. Executive chairwoman, Prof. Wu 

Ying, made it clear that autism studies in China lag far 

behind, and few Chinese experts’ voices can be heard in 

international conferences. In order to meet up with the 

international standard as early as possible, she proposed to 

establish a cooperative platform, on which cooperation can 

be realized for all the medical staff and scientific researchers 

in this field, and all clinical physicians and staff in the basic 

research can be assembled for information and resource 

sharing, so that Chinese experts can ultimately fit into the 

international exchange and cooperation via ACC. 

The experts unanimously agreed on Prof. Wu Ying’s 

proposal, making the decision to awaken attention at all 

social levels to autism via impact of ACC. It was decided to 

assemble all clinical experts and the basic research staff to 

enhance domestic studies on autism in China in many ways, 

and meanwhile to establish systems of early screening, early 

diagnosis, and early intervention, so as to alleviate the 

society’s and family’s economic and emotional burden, better 

promoting the harmonious development of society. The 

decision was also made to divide ACC into three working 

groups: the clinical group, the basic research group, and the 

patient & family support group. It was suggested to 

incorporate into ACC the scientific researchers (particularly 

those in western China) who are engaged in autism studies 

and clinical practice but not able to attend the conference, 

and also the disabled person’s federation at provincial level, 

as well as other related organizations. The three groups 

reached a consensus, determined to immediately undertake 

the tasks as follows: 

(1) Considering an extensive opinion solicitation is currently 

on the way for the revision of the U.S. Diagnostic and 

Statistical Manual of Mental Disorders, 5th edition (DSM-V), 

which will inevitable grow into a future international 

standard for mental illness including autism diagnosis, ACC 

is obliged to try to join in the revising as early as possible, so 

as to incorporate China’s conditions and cultural background, 

and thus to promote future research and clinical diagnosis in 

China. 

(2) To conduct screening and diagnosis in autism at three 

levels: initial screening, fine screening, and diagnosis. The 

experts all agreed that standardized scales are a necessity in 

initial screening, fine screening, and diagnosis, in order to 

realize the full potential in autism studies in China. The 

clinical group recommended popularizing knowledge of ASD 

on a social and mass level. It was also proposed to adopt 

simple infancy autism screening scales for early initial 

screening in ASD; to apply fine screening to children of one 

year old and up in the routine healthcare clinic, with the 

objective to bring earlier the age of ASD diagnosis; and to 

make childhood autism diagnosis in the divisions of 

pediatrics, pediatric healthcare, pediatric psychology, and 

developmental behavioral pediatrics with some major 

medical centers/top hospitals (including mental health 

hospitals, pediatric hospitals, and general hospitals). The 

clinical group of ACC recommended DSM-IV as diagnostic 

criteria, or alternatively ICD-10 and CCMD-3. In terms of 

diagnostic criteria, the clinical group laid importance on 

establishing China’s own diagnostic rating scales. They 

suggested issuing the recommendations manual on rating 

scales by ACC, introducing to clinicians the proper scales, 

the initial usage reports, the feasibility analysis, as well as the 

precautions, and then collecting feedbacks for the 

improvement of the manual, so that the final draft can be 

drawn for a nationwide promotion. 

(3) Recognizing the significance of the nationwide 

epidemiological survey, the experts decided to take the 

initiative in promoting the nationwide sample survey of 

childhood autism prevalence approved as a national project, 

aiming at drawing a precise picture of ASD in China, which 

could be used as a reference for policy making by relevant 

national authoritative departments. With respect to survey 

methods, the experts eagerly put forward their views one 

after another. It is important to point out that the current local 

epidemiological survey majorly focuses on prevalence in 

urban area, with little of rural statistics available; even if 

there is some, the rural prevalence is much lower than the 

urban one. 

(4) It was reiterated that the goal of studies is ultimately for 

the benefit of autism patients and their families. For this 

purpose, the experts suggested to initiate promoting 

applicable early intervention technologies in the maternal and 

child health system, as well as the disabled person’s 

rehabilitation system (including both state and private 

institutions); to promote and popularize, by taking full 

advantage of the ready-established child care network, the 

autism intervention system, characterized as communitycentered, 

family-participating and evaluation-based, which 

focuses on the individuals and combines comprehensive 

technologies of behavioral intervention, structure, and 

personal relationship. 

(5) To promote collaboration between the clinical group and 

the basic research group within ACC; to carry out the multicenter 

large sample randomized controlled trial of early


diagnosis and early intervention in ASD; to urge the 

multidisciplinary clinical research; to stimulate the 

translational medical research in multiple fields of genetics, 

genomics, epigenetics, proteomics, neurophysiology, 

neuropsychology, neuroimage, neural biochemics, 

neuroanatomy, as well as environmental risk factors, experts 

will try to obtain fund at all levels for such studies. 

(6) By general consensus, ACC annual conference will be 

held on the date earlier or later around World Autism 

Awareness Day, with the objectives to promote the exchange. 

It is also agreed to distribute knowledge of ASD by releasing 

papers in conference publications or in journals, and by 

organizing national continuing medical education classes; to 

regularly carry out public events and forums; to proceed with 

training among the public and professional staff; and to invite 

experts both from home and abroad to deliver lectures and 

share experience in various cities.

Editors-in-Chief 

Alexander Leaf, MD Harvard Medical School, Boston 

Xuejun Kong, MD Harvard Medical School, Boston editor@najms.net 

Associate Editors 

Mitchell Albert, PhD University of Massachusetts, Worcester 

Robit Arora, MD, FACC, FAHA, FSCAI, FACP The Chicago 

Medical School, North Chicago 

Frank Chen, MD, PhD State University of New York, Buffalo 

Jason Chen, PhD University of Massachusetts, Worcester 

Ke-Qin Hu, MD University of California, Irvine 

Edmond Kabagambe, DVM, PhD University of Alabama, 

Birmingham 

Tamara Kalir, MD, PhD Mount Sinai School of Medicine, 

New York 

David Lee, PhD Harvard Medical School, Boston 

Calvin Pan, MD Mount Sinai School of Medicine, New York 

Yiqing Song, MD, ScD Harvard Medical School, Boston 

George C.Tsokos, MD Harvard Medical School, Boston 

Specialty Editors 

Gastroenterology/Hepatology 

Victor Aroya, MD, FACG, AGAF 

Daryl Lau, MD, MS 

Hematology/Oncology 

Michael B. Lilly, MD 

Michelle Lau. MD 

Immunology/Rheumatology 

Marina Magrey, MD 

Cardiology 

Sheng-Zhong Duan, MD, PhD 

Neuropathology 

Rolf Pfannl, MD 

Endocrinology 

Zhao Liu, MD 

Psychology 

William Stone, PhD 

Publishing Staff 

Executive Editor 

Xiaochun Wang, PhD 

info@najms.net 

Managing Editors 

Frank Chen, MD, PhD 

Lanjing Zhang, MD, MS 

me@najms.net 

Executive Editorial Coordinator 

Jufang Shi, PhD, RPh 

editor@najms.net 

IT Consultants 

Philip Huang, MS 

Bo Gao, MS 

Xiaopei Chen, PhD 

Surgery 

Adam Landsman, DPM, PhD, 

FACFAS 

Hui-Chuan Sun, MD, PhD 

Anesthesiology and Pain management 

Lucy Chen, MD 

Ob & GYN 

Tamera Paczos, M.D. 

General Surgical Pathology 

Qin Huang, MD, PhD 

Hans Iwenofu, MD 

Organ Specific Pathology 

Thaer Koury, MD 

Lanjing Zhang, MD 

Clinical Pathology 

Jianlan Sun, MD, PhD 

Christopher A. D’Angelis, MD, PhD 

Manuscript Editors 

Rick Heller, MS 

Grace Perez-Lirio, MD 

Chirstine Bergstrom, MD 

Cindy Levine, MD 

Philip Treffletti, MD 

Director, Media Strategy 

Andy Thomas Ryan, BA 

Assistant Director, 

Media Communication 

John Cao, BA 

China Coordinator 

Rui Tan, MD, PhD 

Director, Publishing Service 

Xuemin Kong, MD 

Biochemistry 

William Shaw, PhD 

Pharmacology 

Chi-Hin Cho, B. Pharm, PhD 

ZhaoKui Wan, PhD 

Genetics 

Yiping Shen, PhD 

Bailin Wu, PhD 

Cancer Biology 

Jianyuan Luo, PhD 

Jiawen Han, MD, PhD 

Preventive Medicine/Healthcare 

Disparity 

Qi Zhang, PhD 

Jung Eun Lee, ScD 

Editing Staffs 

Zhenyu Zhang, PhD 

Jianbo Wan, PhD 

Assistant Editing Staffs 

Yawei Kong, PhD 

Boping Lai 

Legal Consultant 

Tina Tian, JD 

Marketing Consultant 

Raymond Liu, PhD 

Accounting Consultant 

Mike Minchello, CPA 

Senior Advisors 

Jing Liu, MD, PhD 

Calvin Pan, MD

North American Journal of Medicine and Science 

najms.net, najmed.org

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