Neuron, Vol.

28, 355363, November, 2000, Copyright 2000 by Cell Press

Autism Spectrum Disorders

Catherine Lord,* Edwin H. Cook,*

Bennett L. Leventhal,* and David G. Amaral
* Department of Psychiatry
The University of Chicago
5841 South Maryland Avenue
Chicago, Illinois 60637
Department of Psychiatry
Center for Neuroscience and
the M.I.N.D. Institute
University of California
Davis, California 95616

Autism is a neurodevelopmental syndrome that is defined by deficits in social reciprocity and communication, and by unusual restricted, repetitive behaviors
(American Psychiatric Association, 2000). Autism is a
disorder that usually begins in infancy, at the latest, in
the first three years of life. Parents often first become
concerned because their child is not using words to
communicate, even though he or she recites passages
from videotapes or says the alphabet. Though social
deficits may not be immediately obvious in early years,
they become gradually more evident as a child becomes
more mobile and as other children become more socially
sophisticated. Young children with autism often do not
seek out others when they are happy, show or point to
objects of interest, or call their parents by name. In
preschool years, repetitive behaviors, such as using peripheral vision to look at lines or wheels, or specific hand
and finger movements, begin to develop.
Autism is a heterogeneous condition; no two children
or adults with autism have exactly the same profile,
but difficulties fall into core domains that are reliably
measured and usually consistent across time, even
though specific behaviors may change with development. A child who may spend a great deal of time spinning objects and watching them out of the corner of her
eye at age four, may not show this behavior at all as a
teenager, but may be fascinated by sunroofs or bald
heads or World War I. A child whose primary method
of communicating requests at age two is to lead his
mother to whatever he wants, place her hand on it, or
use her hand to gesture toward it, may learn to ask for
what he wants quite clearly and persistently by the time
he is three or four, but continues to show difficulty carrying out back and forth conversations and coordinating
eye contact and gestures.
Because of its links to genetics and neural development and the severe abnormalities in social interaction
by which it is defined, autism offers the opportunity for
scientists to study the neurobiological origins of social
communication skills basic to human behavior. For example, even as infants, typically developing children
are more adept at catching the eye of other people,
To whom correspondence should be addressed (e-mail: cathy@

yoda.bsd.uchicago.edu).

Review

coordinating vocalizations with their intentions, and communicating all but the most extreme emotions with facial
expressions than are much older children or adults with
autism. Autism is a disorder of contrasts between
spared abilities and deficits in areas of social-communicative development that we take for granted: a child
with autism who can recite the alphabet and recognize
numbers may not turn to his name or follow a pointing
gesture. As adults, individuals with autism have a range
of outcomes from complete dependence to rare examples of successful employment. However, they almost
never marry and only rarely form ordinary, reciprocal
friendships. The possibility of identifying links between
the acquisition (or failure of acquisition) of basic social
behaviors and neurobiology has, in part, fostered the
recent surge of interest in the neuroscience of autism.
Issues in Diagnosis and Defining the Phenotype
Over the last 20 years, the conceptualization of a spectrum of autism-related disorders, including Childhood
Disintegrative Disorder, Aspergers Disorder, and Pervasive Developmental Disorder-Not Otherwise Specified
(PDD-NOS), which all include qualitative deficits in social
behavior and communication, has been supported by
longitudinal, epidemiological, and family studies (see
Filipek et al., 2000 for a general review). However, these
disorders vary in pervasiveness, severity, and onset. The
umbrella category is termed Pervasive Developmental
Disorder in the most common diagnostic systems
(American Psychiatric Association, 2000; World Health
Organization, 1992). Retts syndrome has been included
in the category of autism spectrum disorders within psychiatric systems because of the overlap in symptoms
in toddlers and preschool children but, because of its
different course (e.g., loss of purposeful hand use) and
neurological characteristics (e.g., deceleration in head
circumference), is a more differentiable group than the
other syndromes and so generally studied as a distinct
disorder. Clear distinctions among the other disorders
within the autism spectrum, as listed on Table 1, are
possible according to the degree of accompanying language deficit or general cognitive delay (American Psychiatric Association, 1994) or according to the severity
of social or behavioral symptoms (Lord et al., 2000).
Aspergers disorder involves the presence of autistic
social deficits and repetitive, circumscribed interests in
individuals who are verbally fluent. It has been of interest
to scientists because of the contrast, as discussed earlier, between relatively intact and often verbose qualities
of language and limited behaviors. Its prevalence is in
dispute because, in controlled studies, it has been difficult to reliably differentiate Aspergers syndrome from
autism without mental retardation or language delay,
except by neuropsychological profile (which may be tautological).
On the other hand, the appeal of the different categorizations is in part because there is such a range of abilities and patterns of deficits within the autism spectrum
that the possibility of finding subcategories related to

Qualitative impairment in social interaction,

as manifested by at least two of the
following:
a) marked impairment in the use of
multiple nonverbal behaviors, i.e.,
eye-to-eye gaze;
b) failure to develop peer relationships
appropriate to developmental level;
c) lack of spontaneous seeking to share
enjoyment with other people;
d) lack of social or emotional reciprocity.
Qualitative impairments of communication
as manifested by at least one of the following:
a) delay in, or total lack of, the development of spoken language;
b) marked impairment in initiating or
sustaining a conversation with others,
in individuals with adequate speech;
c) stereotyped and repetitive use of language or idiosyncratic language;
d) lack of varied, spontaneous makebelieve or imitative play.
Restricted, repetitive, and stereotyped
patterns of behavior, as manifested by one
of the following:
a) preoccupation with one or more
stereotyped or restricted patterns of interest;
b) adherence to nonfunctional routines
or rituals;
c) stereotyped and repetitive motor
mannerisms;
d) persistent preoccupation with parts
of objects.
Disturbance not better accounted for by
Retts or CDD.

Social
Interaction

Exclusions

Behavior

Communication

Delays or abnormal functioning in social

interaction, language, or play by age 3.

Age of Onset

Autistic Disorder

Loss of previously acquired purposeful hand movements;

appearance of poorly coordinated gait or trunk movements.

Severely impaired expressive and

receptive language development
and severe psychomotor retardation

Loss of social engagement

early in the course (although often
social interaction develops later).

Apparently normal prenatal

development; apparently normal
motor development for first 5
months; deceleration of head
growth between ages 5 and 48
months.

Retts Disorder

Table 1. DSM-IV/ICD-10 Diagnostic Criteria for Autism Spectrum Disorder

Disturbance not better accounted

for by another PDD or schizophrenia.

Same as Autistic Disorder, along

with loss of bowel or bladder
control, play, motor skills previously acquired.

Same as Autistic Disorder, along

with loss of expressive or receptive language previously
acquired.

Same as Autistic Disorder along

with loss of social skills (previously acquired).

Apparently normal development

for at least the first 2 years of
birth; clinically significant loss
of previously acquired skills
before age 10.

Childhood Disintegrative Disorder

Criteria are not met for

another PDD or Schizophrenia.

Same as Autistic Disorder.

No clinically significant delay

in language.

Same as Autistic Disorder.

No clinically significant delay

in language, cognitive
development, or development of age appropriate
self-help skills, adaptive
behavior, and environment
in childhood.

Aspergers Disorder
This category is to be
used in cases of
pervasive impairment
in social interaction
and communication
with presence of
stereotyped behaviors
of interests when
criteria are not met for
a specific disorder.

PDD-NOS

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Figure 1. Autism Prevalence in 29 Studies

Numbers indicate thousands in each target population.

etiology or pathophysiology continues to be enticing. In

addition, the range of services needed across the autism
spectrum is very broad, particularly once children reach
elementary school and into adulthood. For example, a
child with high functioning autism or Aspergers syndrome may do well academically in a fifth grade program
for children gifted in mathematics but need the support
of an assistant teacher in order to benefit from social
activities and help him as he begins to understand that
he is different from other children. Another child the
same age whose understanding of language and speech
is limited to single words and a few familiar phrases
may need continuing speech therapy on vocabulary as
well as benefit from the use of a picture system that
allows her to understand the schedule for the day and
communicate how she would like to spend her free time
at school and at home. The value of the spectrum diagnoses is to recognize that both of these children have
significant deficits that share similarities as well as differences.
In the last 10 years, standardized measures of autismrelated deficits have been developed that reliably measure history and present status, with relative independence from cooccurring language delays or mental
retardation. Standard diagnoses of autistic disorder,
Childhood Disintegrative Disorder, and PDD-NOS can
be made across a wide range of individuals of different
ages, language levels, and nonverbal abilities, including
young children. Severity of social and communication
deficits can be reliably quantified (see Filipek et al., 2000;
Lord et al., 2000). Experiments based on developmental
cognitive theories have identified increasingly specific
points in maturation when pivotal behaviors, such as
imitation, joint attention, and orienting to social stimuli,
fail to develop normally in autism (Osterling and Dawson,
1994). In addition, autism affects not only social behavior

and language but also many other aspects of functioning, including sensory responsiveness, play, and motor
activity. Approximately 30% of autistic patients also
have an associated seizure disorder.
As shown in Figure 1, adapted from Fombonne (1999),
epidemiological studies indicate an increasing prevalence for autism spectrum disorders in the last 15 years.
Much of the higher rates may be accounted for by more
complete ascertainment and the expansion of diagnostic frameworks to include milder forms of the disorder
(Fombonne, 1999). However, it is interesting to note that
the highest estimates of prevalence have all occurred
in the last 5 years, though in small samples in studies
where diagnoses were not always based on standard
clinical procedures. These findings and the increases in
the numbers of children with autism spectrum disorder
referred to school systems (see Baird et al., 2000) and
state programs have sparked the interest of many advocacy and scientific groups. The question of rising prevalence is particularly difficult to study because measures
and diagnostic systems to establish base rates have
changed greatly in the last 10 years, and, though available now, are expensive and time consuming (e.g., require a substantial parent interview and structured observation) if the milder forms of autism spectrum
disorder are to be identified.
Many, but not all, individuals with autism, have mental
retardation and almost all individuals with autism have
a history of language delay. However, there are autism
spectrum disorders (e.g., Aspergers disorder) in which
neither language delay nor mental retardation is present.
Families with children with moderate or mild mental retardation or normal intelligence with autism are no more
likely to have children with mental retardation without
autism than other families. Thus, the mental retardation
appears to be a part, but not a necessary part, of autistic

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disorders. There is some suggestion that lesser variants

of communication difficulties may be familial, not necessarily cooccurring with other features of autism (Folstein
et al., 1999). Language delay and milder communication
difficulties overlap with many other disorders, however.
The relationship between language impairment and autism is an important area of study that requires careful
selection of measures and comparison groups because
of the variability within normal development, frequent
associations with other disorders, and the need to measure the presence of specific social deficits across a
range of language levels (e.g., measuring social skills
is different in a nonverbal than verbal child). Another
approach has been based on the significant minority
of individuals with autism who have islets of ability,
usually in skills that require attention to detail, memory,
or computations (e.g., such as calendrical calculating
or perfect pitchsee Prior and Ozonoff, 1998). BaronCohen et al. (1995) have followed up on this notion to
suggest that the incidence of autism may be higher in
families where a parent has selected a field of interest
where imagination and social skills are less emphasized
and attention to detail and focus are particularly important, such as engineering or basic science. The question
of what are the broader phenotypes of autism and do
they extend into differences within the normal population is very complex and just beginning to be studied
systematically.
Genetics of Autism
The genetics of autism is an area that has stimulated
much recent research (see Cook, 1998, 2000 for recent
reviews). Possibly the most significant genetic finding
relevant to autism is the recent identification of the gene
responsible for Retts syndrome (Amir et al., 1999).
Retts syndrome is a neurodevelopmental disorder that
is associated with mental retardation, loss of communication skills, and autistic features that vary in prominence at different developmental stages. It has been,
somewhat controversially, placed within the diagnostic
category, pervasive developmental disorders, of which
autism is the exemplar. Retts syndrome is caused by
mutations in the methyl-CpG binding protein 2 gene
(MECP2). Decreased expression of MECP2 leads to the
failure to suppress expression of gene(s) regulated by
methylation. When the pathophysiology of MECP2 mutations is further elucidated, it is likely to add to an
understanding of autistic disorder.
Autism spectrum disorders are also seen in a substantial minority of patients with full mutations of the Fragile
X (FRAXA) gene FMR1. The reverse is not the case,
since full FMR1 mutations are seen in less than 1% of
recent samples of children with autism. More importantly, analysis of this single gene disorder will contribute to an understanding of the mechanisms by which
reduced FMR1 expression leads to mental retardation
and to social-communicative symptoms that overlap
with those seen in autistic disorders.
Autism is a paradigmatic complex genetic disorder,
similar to diabetes, asthma, schizophrenia, Alzheimers
disorder, and many others. The sibling recurrence risk
is approximately 4.5%, relative to a population incidence
and estimated prevalence of approximately 0.1%0.5%.

This relative risk to siblings (s) of 945 is one of the

highest for a complex genetic disorder and is higher than
the other disorders listed above. The most compelling
evidence for high heritability is the greater than 50%
concordance rate for monozygotic twins relative to an
3% concordance for dizygotic twins. This also suggests multiplicative genetic effects in which more than
one and probably more than 2 genes contribute in concert to the high risk for monozygotic twins.
The current focus in molecular genetics of autism is
on the identification of molecular genetic variation that
contributes to autism susceptibility. Candidate gene
findings of interest include a family-based association
and linkage finding between the serotonin transporter
promoter gene insertion/deletion polymorphism and autistic disorder. Of family-based, controlled studies, one
showed preferential transmission of the short arm of
the serotonin transporter promoter gene. Two showed
transmission of the long arm and two were not significant. Genetic or clinical heterogeneity or multiple tests
of candidate genes leading to false positives may have
led to this inconsistency. Another candidate gene finding has been one between a microsatellite near the alternative promoters and first 3 exons of the GABAA 3
subunit gene (GABRB3), but this has also not been found
in all samples.
The chromosomal disorder most frequently found
(0%3%) in recent large samples of autism has been
the finding of a maternal duplication of 15q11-q13. This
is the same region in which absent maternal gene expression (or mutation) of ubiquitin binding enzyme 3A
(UBE3A) leads to Angelman syndrome and in which the
absence of paternal chromosomal gene expression
leads to Prader-Willi syndrome, two other developmental disorders associated with mental retardation,
but that are associated with quite different phenotypes
than autistic disorder. Although there may be a convergence of the linkage disequilibrium findings for GABRB3
and the 15q11-q13 duplications, it is also possible that
the duplication of 15q11-q13 has distant effects, such
as the overexpression of UBE3A, leading to excessive
degradation of one or more of its targets.
Several genome-wide screens have been published
in autism in the past 3 years (reviewed in Cook, 2000)
and more are in progress. Much effort is now focused on
confirming the strongest finding from the first published
study, i.e., a linkage in a relatively large region (7q3235). Several other regions of interest have been identified
across different genome scans, including 2q, 16p, 19p
(e.g., see http://www.agre.org/bnews/scan.cfm).
Neurobiology of Autism
A fundamental goal of neurobiological approaches to
the study of autism is the definition of brain regions that
are most severely affected. Once affected brain regions
are identified and the types of alterations (structural
versus neurochemical; failure of development versus
degeneration) are better understood, strategies can be
developed for prevention, early diagnosis, and treatment. The neurobiology of autism has been hampered,
in part, by the heterogeneity inherent in the autism spectrum disorders. It is not currently clear whether autism
is a syndrome that varies in severity but nonetheless has

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a common neural basis or whether the autism spectrum

disorders have multiple etiologies and affect various
brain systems that nonetheless lead to the core deficits
of abnormal social behavior, impaired communication,
and stereotypical behavior. Clearly, in this as in every
other area of autism research, future progress will depend on better categorization of distinctive subsets of
autistic individuals using biochemical, genetic, neuroimaging, behavioral, and other diagnostic tools.
One approach to the neurobiology of autism, the neuropathological approach, employs both postmortem
analysis and noninvasive imaging techniques to determine the brain regions involved in autism. A second
approach attempts to understand the normal neural
substrates of functions, such as social cognition, that
are profoundly impaired in autistic disorders. It is a reasonable expectation that one or more components of
this system might be altered in autism. Thus, the neurobiology of normal social behavior can potentially narrow
the scope of suspect brain regions. A third, but currently
more poorly developed approach, is the development
of animal models. This effort has been hobbled by a
lack of knowledge concerning the etiology(ies) of autism
and a paucity of data, which is also highly variable, on
the characteristic neuropathology of autism, i.e., it is
not quite clear what a successful model of autism would
look like.
Neuropathology
Although autopsy studies of autism were begun in the
early 1980s, formal reports have only involved about 30
brains. There are a number of reports that the brains of
autistic individuals are larger than normal. Bailey et al.
(1998), for example, found that four of six postmortem
brains that they examined, from individuals ranging in
age from 4 to 24 years at time of death, were megalencephalic. Regional neuropathological studies have
pointed to possible alterations in the brainstem, cerebellum, and in a set of limbic structures, including the
hippocampal formation, amygdala, septal nuclei, and
anterior cingulate cortex. Cells in various portions of
the hippocampal formation, in the medial nuclei of the
amygdala, the medial septal nucleus, the mammillary
nuclei, and the cortex of the anterior cingulate gyrus
tend to be smaller and more densely packed than in
normal brains (Kemper and Bauman, 1998). Neurons
in the hippocampus of autistic individuals also have
reduced complexity of dendritic arbors. Some pathology
seems to be age dependent. In the basal forebrain nucleus of the vertical limb of the diagonal band of Broca,
for example, neurons were unusually large and numerous but otherwise normal looking in brains of autistic
children less than 12 years old but were small and reduced in number in brains of autistic adults older than 18
years. The Bailey et al. (1998) study confirmed qualitative
impressions that cell density was higher in the hippocampus of autistic individuals but morphometric analyses did not demonstrate significant differences. They
also noted abnormalities in the cytoarchitectonic organization and neuronal density of the superior frontal cortex
and superior temporal gyrus of some of their cases but
no quantitative differences were found.
Cerebellar abnormality has been a common finding.

Ritvo et al. (1986) noted that there was a loss of Purkinje

cells in the brains of four subjects with autism. Kemper
and Bauman have generally confirmed the loss of cerebellar Purkinje cells and reported changes in neurons
of the deep cerebellar nuclei. Bailey et al. (1998) also
observed loss of Purkinje cells but no apparent changes
in the number of granule cells or alterations of deep
cerebellar nuclei. It is important to note that the loss of
Purkinje cells is also a common correlate of seizure
disorders (Dam, 1992), and it is essential to determine
whether loss of this neuron class also occurs in autistic
subjects who are seizure free.
Rodier et al. (1996) found near complete absence of
the facial nucleus and superior olive in one postmortem
case. Bailey et al. (1998) also found brainstem abnormalities of the superior and inferior olives; however, the
organization of the facial nucleus was not evaluated.
Kemper and Bauman reported alterations in the portion
of the inferior olive that projects to the part of the cerebellar cortex with the most profound loss of Purkinje
cells.
The lack of a coherent description of the neuropathology of autism is undoubtedly due, in part, to the relatively
small number of brains that have been analyzed and to
the use of qualitative methods of assessment. Future
progress, both in neuropathological assessment of the
autistic brain and in studies of the molecular biology of
autism, will require the acquisition of high quality post
mortem tissue from well-characterized donors.
Structural Magnetic Resonance Imaging Findings
Given the relatively subtle and variable neuropathological changes that have been described in the autistic
brain, it is not surprising that structural magnetic resonance imaging studies have not found consistent
changes. Courchesne et al. (1988) reported selective
hypotrophy of vermal lobules VI and VII in the cerebellum
of autistic subjects. This has proven to be a controversial
finding and others have failed to consistently replicate
it. One explanation may be that not all subsets of the
autistic spectrum demonstrate cerebellar hypoplasia.
Holttum et al. (1992) found, for example, that cerebellar
hypoplasia does not appear to be associated with highfunctioning autism. Saitoh and Courchesne (1998) later
found that there were two subgroups of autistic subjects
that were characterized either by hypoplasia or hyperplasia of lobules VI and VII. Thus, depending on the
composition of a patient population, one might expect
to see hypoplasia, hyperplasia, or no change.
Abell et al. (1999) used a voxel-based whole brain
analysis and identified gray matter differences in the
amygdala and associated brain regions. Decreases of
gray matter were found in the right paracingulate sulcus
and the left inferior frontal gyrus, whereas increases
were found in the amygdaloid complex (particularly the
periamygdaloid cortex) the middle temporal and inferior
temporal gyrus, as well as in regions of the cerebellum.
It is not clear how these changes in MR signal characteristics relate to the increased density of smaller neurons
seen in many of these same areas. Aylward et al. (1999)
found that the volumes of both the amygdala and the
hippocampal formation were reduced in the autistic
brain, though neither Piven et al. (1998) nor Saitoh et al.

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(1995) observed changes in the hippocampus. Consistent with the neuropathological findings of Kemper and
Bauman, Haznedar et al. (1997) observed decreased
volume and decreased PET activity in the anterior cingulate gyrus of autistic subjects. Finally, there have been
no neuropathological findings in the basal ganglia of
autistic patients. However, Sears et al. (1999), using
structural MRI, observed an increased volume of the
caudate nuclei in autistic subjects that was proportional
to compulsions and rituals.
Neurobiology of Social Behavior
Regardless of whether an individual with an autism
spectrum disorder is mentally retarded or not and
whether the individual has language impairment or obvious stereotypical behaviors, all persons with autism
spectrum disorders have some disturbance of normal
social behavior. These deficits range from subtle abnormalities in social reciprocity, particularly with peers, to
much more obvious difficulties in the use of eye contact,
facial expression, and social motivation. A growing body
of literature indicates that important aspects of social
cognition, such as the salience or interpretation of facial
expressions or the appreciation of angle of gaze, are
markedly impaired in autistic subjects (Baron-Cohen et
al., 2000). Thus, an understanding of the brain systems
responsible for social cognition and for interpretation of
the social aspects of facial expression might be predictive of regions of brain dysfunction in autism.
Evidence from both human and animal studies indicates that certain brain regions are preferentially involved in social behavior. In the macaque monkey, these
would include the amygdala, orbitofrontal cortex, superior temporal gyrus, and temporal polar cortex. Damage
to any of these regions in macaque monkeys produces
a profound alteration of social behavior. Cortical areas,
such as the anterior cingulate gyrus, have also been
implicated in the production of species-specific vocalizations. Yet, other cortical regions, such as the inferior
temporal gyrus in monkeys and the fusiform gyrus in
humans, appear to be preferentially involved in the perception of faces. Neurons (face cells) that are highly
and selectively responsive to the image of faces have
been found in the inferior temporal gyrus of macaque
monkeys (Perrett et al., 1982). Neurons sensitive to the
angle of gaze have been found in the cortex of the
superior temporal sulcus (Perrett et al., 1985). Neurons
that are attuned to particular facial expressions have
also been found in the inferior and superior temporal
lobes of macaque monkeys (Hasselmo et al., 1989). Interestingly, cortical areas responsive to faces, facial expressions, and to angle of gaze send direct projections
to the primate amygdala (Stefanacci and Amaral, 2000).
These functional and neuroanatomical facts have raised
the prospect that the amygdala may be important for
components of social cognition such as the attention
to and interpretation of facial expressions. If this is the
case, the amygdala is a prime candidate for dysfunction
in autism.
A rare human disorder called Urbach-Wiethe syndrome
produces cystic calcifications of the medial temporal
lobe. In patient SM, these space-occupying lesions
mainly involve the amygdala bilaterally and she is mark-

edly impaired in her ability to judge facial expressions

of fear and anger (Adolphs et al., 1995). Even more germane to the pathology of autism, SM is unable to make
an accurate judgement of the trustworthiness of an individual from photographic images. Functional imaging studies have demonstrated activation of the
amygdala in normal subjects asked to make judgements
of facial expressions. Very recently, Baron-Cohen and
colleagues (1999) carried out a functional magnetic resonance imaging experiment using a test of judging from
the expressions of another persons eyes what that other
person might be thinking or feeling. In normal subjects,
this test resulted in activation in the superior temporal
gyrus and the amygdala with additional activations in
the frontal cortex. In the autistic population that they
studied, the task produced activations in the temporal
lobe and in the frontal cortex but not in the amygdala.
These interesting observations will need to be confirmed
and extended but raise the prospect that pathology of
some sort in the amygdala may play an important role
in the defects of social cognition observed in autism.
Schultz and colleagues (Schultz et al., 2000) compared
activation in the inferior temporal gyri (ITG) during face
and object processing in individuals with autism or
Aspergers disorder and those with typical development.
Individuals with autism spectrum disorders used ITG
significantly more during face processing than did normal controls, though the side of the effect varied across
an initial and a replication group. Thus, in this study,
individuals with autism used strategies typically used in
nonface object perception by normal adults in order
to discriminate faces. More work on relatively young,
homogeneous samples, which balance scientific rigor
with ethical restraints, are much needed (Rumsey and
Ernst, 2000).
Animal Models
The most successful animal model of autism produced
to date involves the bilateral removal of the medial temporal lobe of young macaque monkeys (Bachevalier,
1996). These animals show a variety of socioemotional
changes including social isolation and demonstrate
some other facets of autistic symptomatology such as
stereotypical behaviors. Clearly, the production of large
medial temporal lobe lesions does not closely mimic the
pathology observed in the autistic brain. It would be
interesting if more subtle and more focal dysregulation
could be produced in the developing nonhuman primate
brain that replicated the autistic behavioral pathology.
Other investigators have attempted to model the neuropathology observed in the brain stem using various
teratogens. This work has been motivated by the finding
that certain children exposed prenatally to thalidomide
developed some symptoms of autism. Rodier and colleagues (1996) have used maternal treatment with valproic acid in rats in an attempt to produce pathology
in cranial nerve nuclei (reviewed in Rodier, 2000). The
alterations that Rodier and colleagues observed in their
patient with autism involved mainly the facial nucleus
and the superior olive. In her valproate studies, Rodier
observed changes in motor nuclei of V and XII with
later treatments affecting the VIth and IIIrd cranial nerve
nuclei. None of her treatments affected the facial nu-

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cleus (unlike in the postmortem autistic brain). Morever,

Rodier et al. (1996) observed that there were no changes
of any other brain regions such as the cerebellum, hippocampus, or amygdala. Therefore, even based on the
minimal neuropathology available, the valproic acid
model would not appear to have much verisimilitude to
human autism.
Interventions, Families, and Needs for the Future
Given the limited information available on the etiology(ies) and biology of autism, therapies have generally
focused on educational and behavioral interventions.
There are increasing efforts to evaluate psychoactive
drugs for clinical benefit in autism. For example, a large
multisite study is in progress (McDougle et al., 2000) of
the effects of risperidone (a serotonin 5HT2A/dopamine
D2 receptor blocker), which showed some benefit in a
single double-blind placebo-controlled trial in terms of
reducing maladaptive behaviors without demonstration
of independent effects on core social and communication deficits.
Currently, intensive, structured education forms the
core of most treatment approaches, supplemented by
positively oriented behavior management, family support, and an emphasis on functional communication.
Children and adults with autism can clearly benefit from
direct teaching and exposure to developmentally appropriate experiences. Controversy remains, however, as
to whether it is possible to alter the trajectory of the
development of a child with autism or whether early
interventions primarily accelerate development in children who would make good progress in response to
many treatments or reduce secondary effects of social
isolation and lack of engagement. These issues have
been linked, so far without data, to larger questions of
neuroplasticity and the degree to which social engagement contributes to basic cognitive functions (Mundy
and Neal, 2000).
The variation in outcomes in autism spectrum disorders, from severe behavioral disturbance and profound
mental retardation, to uncommon cases of independent,
age appropriate functioning, and the limited success of
current therapies in completely diminishing the symptoms of autism, has resulted in some parents becoming
increasingly experimental in approaches to their childs
treatment. This makes parents vulnerable to new claims
of remarkable improvements, particularly in response
to highly publicized treatments, such as facilitated communication, auditory training, dietary manipulations,
and, recently, secretin (Volkmar, 1999). In the last case,
a serendipitous finding of behavioral improvement following the administration of secretin during endoscopy
(Horvath et al., 1998) led to widespread demand for this
treatment by parents. Since then, several double blind,
placebo-controlled clinical trials of secretin have found
it to have no positive effect on autism (e.g., Sandler et
al., 1999). Other clinicians and parents have promulgated the practice of controlling the diet of children with
autism. Most prominently, gluten-free and casein-free
diets have been purported to benefit young children
with autism, particularly. Recommendations for such
dietary restrictions are based on extremely limited scientific data (Lucarelli et al., 1995), though advocates of

such approaches counter that there is little evidence

(Sponheim, 1991) against them.
Another issue that has arisen recently is the proposal
that at least some cases of autism in which children
have had a few words and other social-communicative
behaviors that disappear in the second year of life may
be linked to vaccinations. This pattern of loss of words
often accompanied by increasingly obvious social deficits is described by parents as occurring in about onefifth of children with autism. The particular vaccinations
proposed as causal have varied, but currently the greatest focus has been on combination vaccines for measles, mumps, and rubella (Kawahima et al., 2000; Wakefield et al., 2000). This suggestion, based on research
carried out primarily by Wakefield and colleagues, has
been extraordinarily controversial. A number of epidemiological studies from countries with comprehensive
health registers have appeared not to support a link
between MMR vaccines and autism (Taylor et al., 1999;
Afzal et al., 2000). Here again, there is a chasm between
the visible increase in prevalence of autism as indicated
by the need for services, and empirical evidence for
the gradual broadening of criteria and improvements in
identification, which is felt by some not to be sufficient
to account for the increases. It is not surprising that
parents and some clinicians and researchers have attempted to account for this gap, with alternative theories.
Parents societies have traditionally been very important to the field of autism, from the founding of the first
autism societies in the US and UK many years ago, to
the current research support and advocacy provided
by a number of parent-founded, -led, and -supported
organizations. These organizations have already begun
to be influential in terms of research, especially in funding new investigators and attracting eminent scientists
from other fields into studying the disorder. The parents
organizations also have the potential to be extremely
helpful in dissemination of scientific information, particularly on the Internet, which, with the hundreds of
sources available, provides a tremendous but sometimes overwhelming amount of information.
Sometimes claims for extraordinary outcomes are unwittingly promulgated by scientists unfamiliar with the
range of behaviors and developmental course seen in
autism spectrum disorders and impatient with standard
clinical research procedures such as random assignment, double-blinding, and case-controls. On the other
hand, new ideas from diverse perspectives on treatment, prevention, and understanding of the pathophysiology of autism are urgently needed. One of the foremost
goals for the next decade will be greater communication
between basic scientists, clinical researchers, parents,
and persons with autism spectrum disorders so that
knowledge from neuroscience and other areas of biology can be more readily applied to autism in ways that
yield scientifically valid and effective results.
Acknowledgments
Supported by NIH K05 MH01196, P01 HD35482, K02 MH 01389,
R01 MH52223, MH41479, CAN, NAAR, and the M.I.N.D. Institute.

Neuron
362

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