Longitudinal Study of Amygdala Volume and Joint Attention in 2- to 4-Year-Old Children With Autism

Article (PDF Available)inArchives of general psychiatry 66(5):509-16 · June 2009with47 Reads
DOI: 10.1001/archgenpsychiatry.2009.19 · Source: PubMed
Cerebral cortical volume enlargement has been reported in 2- to 4-year-olds with autism. Little is known about the volume of subregions during this period of development. The amygdala is hypothesized to be abnormal in volume and related to core clinical features in autism. To examine amygdala volume at 2 years with follow-up at 4 years of age in children with autism and to explore the relationship between amygdala volume and selected behavioral features of autism. Longitudinal magnetic resonance imaging study. University medical setting. Fifty autistic and 33 control (11 developmentally delayed, 22 typically developing) children between 18 and 35 months (2 years) of age followed up at 42 to 59 months (4 years) of age. Amygdala volumes in relation to joint attention ability measured with a new observational coding system, the Social Orienting Continuum and Response Scale; group comparisons including total tissue volume, sex, IQ, and age as covariates. Amygdala enlargement was observed in subjects with autism at both 2 and 4 years of age. Significant change over time in volume was observed, although the rate of change did not differ between groups. Amygdala volume was associated with joint attention ability at age 4 years in subjects with autism. The amygdala is enlarged in autism relative to controls by age 2 years but shows no relative increase in magnitude between 2 and 4 years of age. A significant association between amygdala volume and joint attention suggests that alterations to this structure may be linked to a core deficit of autism.
Longitudinal Study of Amygdala Volume and Joint
Attention in 2- to 4-Year-Old Children With Autism
Matthew W. Mosconi, PhD; Heather Cody-Hazlett, PhD; Michele D. Poe, PhD;
Guido Gerig, PhD; Rachel Gimpel-Smith, BA; Joseph Piven, MD
Context: Cerebral cortical volume enlargement has been
reported in 2- to 4-year-olds with autism. Little is known
about the volume of subregions during this period of de-
velopment. The amygdala is hypothesized to be abnormal
in volume and related to core clinical features in autism.
Objectives: To examine amygdala volume at 2 years with
follow-up at 4 years of age in children with autism and
to explore the relationship between amygdala volume and
selected behavioral features of autism.
Design: Longitudinal magnetic resonance imaging study.
Setting: University medical setting.
Participants: Fifty autistic and 33 control (11 devel-
opmentally delayed, 22 typically developing) children be-
tween 18 and 35 months (2 years) of age followed up at
42 to 59 months (4 years) of age.
Main Outcome Measures: Amygdala volumes in re-
lation to joint attention ability measured with a new ob-
servational coding system, the Social Orienting Con-
tinuum and Response Scale; group comparisons including
total tissue volume, sex, IQ, and age as covariates.
Results: Amygdala enlargement was observed in sub-
jects with autism at both 2 and 4 years of age. Signifi-
cant change over time in volume was observed, al-
though the rate of change did not differ between groups.
Amygdala volume was associated with joint attention abil-
ity at age 4 years in subjects with autism.
Conclusions: The amygdala is enlarged in autism rela-
tive to controls by age 2 years but shows no relative in-
crease in magnitude between 2 and 4 years of age. A sig-
nificant association between amygdala volume and joint
attention suggests that alterations to this structure may
be linked to a core deficit of autism.
Arch Gen Psychiatry. 2009;66(5):509-516
rodevelopmental dis-
order likely involving
multiple brain systems.
Converging evidence from
magnetic resonance (MR) imaging, head
circumference, and postmortem studies
suggests that brain volume enlargement is
a characteristic feature of autism,
with its
onset most likely occurring in the latter
part of the first year of life.
On the basis
of functional MR imaging data identify-
ing decreased amygdala activity during
gaze processing,
Baron-Cohen et al
proposed that amygdala dysfunction may
account for core social characteristics of
autism. Neuropathological and struc-
tural MR imaging studies have also high-
lighted alterations within the amygdala.
Postmortem studies of individuals with au-
tism have noted immature-appearing and
densely packed cells
and fewer neu-
rons within the amygdala.
amygdala volumes have been observed
across multiple structural MR imaging
studies of adolescents and adults with au-
Altered amygdala activation in re-
sponse to facial and emotion processing
tasks also has been reported in func-
tional MR imaging studies of individuals
with autism.
Abnormal activation pat-
terns were not evident in functional neu-
roimaging studies of individuals with au-
tism presented with nonfacial social
processing paradigms.
Taken to-
gether, studies of the amygdala in autism
suggest that both the morphologic char-
acteristics and function of this structure
are abnormal and that amygdala dysfunc-
tion may be associated with social defi-
cits involving facial processing.
Adolphs et al
observed deficits in rec-
ognition of negative facial emotions among
patients with bilateral focal lesions of the
amygdala. The authors reported that these
deficits were the consequence of a failure
Author Affiliations: UNC
Neurodevelopmental Disorders
Research Center, The University
of North Carolina
at Chapel Hill.
©2009 American Medical Association. All rights reserved.
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to orient to the eye region when viewing faces. Sasson et
recently reported that, on an emotion recognition task
sensitive to deficits related to amygdala damage,
viduals with autism show decreased attention to face re-
gions relative to age- and IQ-matched healthy control sub-
jects and age-matched individuals with schizophrenia.
Individuals with autism in this study, in contrast to healthy
controls and individuals with schizophrenia, did not
modulate their attention to social scenes according to
whether faces were present or absent. Failure to orient
to faces and, more specifically, the eye region of the face
is inherent in multiple aspects of social impairment unique
to autism (eg, joint attention [JA], facial emotion pro-
cessing) and may be linked to amygdala abnormalities.
Multiple studies have identified JA deficits as the most
reliable marker of autism in the first 2 years of life
and thus suggest that the amygdala plays a key role in
neurodevelopmental alterations unique to autism.
Both increased
and decreased
amygdala vol-
umes have been noted in structural MR imaging studies
of individuals with autism. Schumann et al
first sug-
gested that inconsistencies across studies are the result
of age-dependent effects. Observing amygdala enlarge-
ment in school-aged (7
years) but not adoles-
cent (12
years) autistic children, the authors hy-
pothesized that enlargement of the amygdala in autism
is an early-occurring phenomenon. Consistent with this
report, Sparks et al
reported amygdala enlargement in
3- to 4-year-olds with autism, whereas studies of ado-
lescents and adults with autism have highlighted re-
duced amygdala volumes compared with typically de-
veloping individuals.
None of these studies has observed
individuals over time. Giedd et al
previously showed
that longitudinal studies are necessary for characteriz-
ing neuroanatomical development within the context of
interindividual variability and nonlinear growth. Stud-
ies of amygdala growth in young children with autism
observed over time are needed to map developmental pat-
terns and brain-behavior relationships unique to this dis-
Two recent studies reported that amygdala volume is
associated with social deficits in autism. Examining the
sample from the Sparks et al
study, Munson et al
ported that right amygdala enlargement at age 3 to 4 years
is associated with worse concomitant social functioning
and is predictive of worse social functioning at age 6 years.
However, that study did not specify the aspects of social
impairment in autism associated with amygdala vol-
ume. Nacewicz et al
reported that amygdala volumes were
reduced in a small group of adolescents with autism
(N=21) and that decreased amygdala volume was sig-
nificantly associated with decreased amount of time spent
fixating on the eye region of faces.
We examined amygdala volumes and growth in chil-
dren with autism at 2 years of age (the earliest age of gen-
erally accepted diagnosis) with follow-up at 4 years of
age. We developed an observational coding system to ex-
amine JA and its relationship to amygdala volume. Joint
attention was targeted because (1) it consistently has been
shown to be impaired in young children with autism
and (2) as measured herein, it requires attention to the
eye region of the face. Amygdala volumes were hypoth-
esized to be enlarged in autism and significantly associ-
ated with JA deficits that involve orienting to the eye re-
gion but would not be associated with other social
behaviors not involving orienting to the eye region (eg,
nonverbal gesture). Amygdala volumes were also exam-
ined in relation to nonsocial characteristic features of
children with autism, specifically restricted and repeti-
tive behaviors.
Fifty children with autism entered this MR imaging study at 2
years (18-35 months) of age, 31 of whom were followed up at
approximately 4 years of age (42-59 months of age;
Table 1).
Thirty-three control subjects (22 typically developing [TYP]
children and 11 nonautistic, developmentally delayed [DD] chil-
dren) entered the study at 2 years of age. The sample of con-
trol children was enriched with DD children to more closely
match the autism study group in terms of IQ. The TYP and DD
children were not analyzed separately because of the small
Table 1. Sample Characteristics
Subject Group, Mean (SD)
Total DD TYP
Time 1 (n = 50) (n = 33) (n = 11) (n = 22)
Age, y 2.68 (0.32) 2.58 (0.55) 2.83 (0.42) 2.46 (0.53)
Mullen composite IQ
53.78 (9.02) 89.21 (27.40) 56.58 (16.94) 105.82 (15.98)
Mullen AE/age 0.55 (0.17) 0.95 (0.31) 0.53 (0.27) 1.11 (0.22)
Sex, No. (%) male 43 (86) 24 (73) 10 (91) 16 (73)
Time 2 (n = 31) (n = 20) (n = 6) (n = 14)
Age, y 5.01 (0.42) 4.70 (0.47) 4.97 (0.49) 4.59 (0.53)
Mullen composite IQ
56.58 (16.94) 95.32 (28.40) 56.00 (6.77) 112.31 (12.34)
Mullen AE/age 0.53 (0.27) 0.94 (0.34) 0.61 (0.17) 1.10 (0.20)
Sex, No. (%) male 28 (90) 14 (70) 3 (50) 11 (79)
Abbreviations: AE, age equivalent; DD, developmentally delayed; TYP, typically developing.
Mullen Scales of Early Learning composite IQ standard score.
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sample sizes. Twenty control subjects (14 TYP, 6 DD) were fol-
lowed up at 4 years of age. Further details of subject ascertain-
ment are reported elsewhere.
In an earlier analysis of this sample
performed at age 2 years,
we observed a mean developmen-
tal quotient of approximately 54 for children with autism. We
hypothesized that our ascertainment of very young children with
autism may have been biased toward identifying individuals with
more severe presentations and/or lower IQ that led to their de-
tection at age 2 years. We therefore began to enrich this sample
with high-functioning autistic subjects at age 4 years. At the
time of the present analysis, 2 high-functioning autistic sub-
jects had been added to the sample, for a total of 52 autistic
subjects entering this study.
Subjects with autism were referred after receiving a clinical
diagnosis or while on a waiting list for a clinical evaluation of
autistic disorder. Subjects with DD were included only if they
had no identifiable cause for their delay (eg, prematurity, ge-
netic or neurologic disorder) and no evidence of a pervasive
developmental disorder after being screened with the Child-
hood Autism Rating Scale. The DD and TYP children were ex-
cluded if they had Childhood Autism Rating Scale scores of 30
or greater. Medical records were also reviewed and DD sub-
jects were excluded for evidence of autism, pervasive develop-
mental disorder not otherwise specified, or the previously men-
tioned medical conditions. A standardized neurodevelopmental
examination was administered to exclude subjects with any no-
table dysmorphologic characteristics, evidence of neurocuta-
neous abnormalities, or other significant neurologic abnor-
malities. Subjects were excluded if they had evidence of a medical
condition thought to be associated with autism,
including frag-
ile X syndrome or tuberous sclerosis. Cytogenetic or molecu-
lar testing was used to rule out fragile X syndrome in autistic
and DD subjects. Subjects also were excluded if they had evi-
dence of gross central nervous system injury (eg, cerebral palsy,
significant complications or perinatal/postnatal trauma, drug
exposure), seizures, or significant motor or sensory impair-
ment. Study approval was obtained from both the University
of North Carolina and Duke institutional review boards, and
written informed consent (from parents) was secured.
Children between 18 and 35 months of age (time 1) were eli-
gible for inclusion in this study. Medical records were re-
viewed. Diagnosis was confirmed by the Autism Diagnostic In-
Subjects were included in the autism group
if they met the interview’s algorithm criteria, had scores on the
Autism Diagnostic Observation Schedule (ADOS)
tent with autism, and met DSM-IV criteria for autistic disor-
der. The diagnosis was reassessed at age 42 to 59 months (time
2), and 3 subjects who no longer met criteria for autistic dis-
order based on the foregoing diagnostic criteria were not in-
cluded in the final analyses.
All subjects were assessed on the Mullen Scales of Early
and the Vineland Adaptive Behavior Scales.
Repetitive Behavior Scale–Revised
also was administered to
assess 6 domains of repetitive behaviors: stereotypical behav-
iors (ie, purposeless movements that are repeated in a similar
manner), self-injurious behaviors (ie, behaviors that cause physi-
cal self-harm and are repeated), compulsive behaviors (ie, be-
haviors that are repeated according to a rule), ritualistic be-
haviors (ie, activities of daily living repeated in a similar manner),
sameness behavior (ie, resistance to change), and restricted be-
havior (ie, limited range of focus, interest, or activity). The Re-
petitive Behavior Scale–Revised was examined in relation to
amygdala volume to assess the specificity of hypothesized re-
lationships between the amygdala and JA.
We developed a measure of social orienting, the Social Ori-
enting Continuum and Response Scale (SOC-RS),
that has been
previously validated and that incorporates both dimensional
and categorical response codes. The SOC-RS ratings are ap-
plied during observation of videotaped ADOS sessions. Rat-
ings are performed for social orienting and communication be-
haviors including initiating JA (IJA), responding to JA (RJA),
and nonverbal gestures.
After initial analyses of behavioral data, key items were se-
lected for analysis with the present MR imaging data. Joint at-
tention was examined in this study on the basis of its depen-
dence on attention to the eye region of the face. Joint attention
was defined as an event in which children either initiate di-
recting another person’s attention toward an object through the
use of eye gaze (ie, IJA) or follow someone else’s attention to-
ward an object by following a shift in eye gaze (ie, RJA). The
JA variables, therefore, assess children’s abilities when com-
municating attention by focusing on another individual’s eyes
or responding to cues specifically offered by eye movements
from others. In contrast to other behaviors scored within the
SOC-RS, JA requires that children attend to the eye region and
process shifts in eye gaze. An IJA is scored if children start a JA
and refer to the face of their social partner to monitor that per-
son’s attention (ie, if children point to an object but do not look
at the examiner, then the event is not scored). An RJA is scored
if children follow a shift in eye gaze by the examiner during
the scheduled JA press of the ADOS. Children were not in-
cluded in analyses of RJA if this activity was not observed on
camera. If children did not respond to one of 5 trials, then they
were scored as nonresponders. Although children were given
the opportunity to merely follow a pointing gesture by the ex-
aminer during the ADOS, only events in which children fol-
lowed a shift in eye gaze were scored because of our interest in
children’s ability to process information from the eyes. A JA
total (JAT) score was computed by assigning a score of 1 for
children who scored greater than 0 on either the IJA or RJA
variable. The rate of nonverbal communicative gestures not in-
volving attention to the eye region (pointing, clapping) was also
examined as a control variable to investigate the specificity of
relationships between amygdala volume and JA variables. Ges-
ture rate scores were calculated by dividing the frequency by
total observed time.
To eliminate bias from inadequate sampling, children were
not included in analyses if they were not observable on cam-
era for at least 10 minutes. This minimum time limit was set
to allow for a representative sample of behavior. Because final
analyses compared only rates (frequency/time) of behaviors and
responses that were presented to each individual over a fixed
number of trials, duration of observable behavior should not
affect results.
To establish reliability of SOC-RS items, raters indepen-
dently coded 15 videotaped ADOS sessions 2 times. Reliabil-
ity was calculated by means of intraclass correlation coeffi-
cients. After establishing an intrarater and interrater reliability
score of greater than 0.8 across these 15 cases, each rater in-
dependently coded cases for final analysis. Good interrater re-
liability was observed for IJA (0.80), RJA (0.86), and gestures
All subjects underwent imaging on a 1.5-T MR imaging scan-
ner (Signa; General Electric Co, Milwaukee, Wisconsin) at the
Duke–University of North Carolina Brain Imaging and Analy-
sis Center located at Duke University Medical Center. Image
acquisition was designed to maximize gray/white tissue con-
trast at age 2 to 4 years and included the following: (1) a coro-
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nal T1 inversion recovery prepared: inversion time, 300 mil-
liseconds; repetition time, 12 milliseconds; echo time, 5
milliseconds; 20° flip angle; 1.5-mm thickness with 1 excita-
tion; 20-cm field of view; and 256192 matrix and (2) a coro-
nal proton density/T2 two-dimensional multislice dual echo fast
spin echo: repetition time, 7200 milliseconds; echo time, 17/75
milliseconds; 3.0-mm thickness with 1 excitation; 20-cm field
of view; and 256160 matrix. A series of localizer images and
a set of phantoms were used to standardize assessments over
time and across individuals.
At both time points, in preparation for imaging, subjects with
autism and subjects with DD received moderate sedation (com-
bination of pentobarbital sodium and fentanyl citrate as per hos-
pital sedation protocol) administered by a nurse and under the
supervision of a pediatric anesthesiologist. A more detailed de-
scription appears elsewhere.
At age 2 years, TYP subjects un-
derwent imaging without sedation, in the evening, during natu-
ral sleep. At age 4 years, a subset of 5 TYP subjects were trained
to lie still in a practice scanner by means of behavioral tech-
niques, including desensitization and positive reinforcement; chil-
dren viewed videos of their choice and the video remained on while
children remained still.
Parents of TYP children identified whether
they wished their children to participate with or without the be-
havioral training. All images were reviewed by a pediatric neu-
roradiologist for significant clinical abnormalities. No evidence
of qualitative neuroanatomic abnormalities was observed for any
of the children included in the present study, on the basis of a
clinical review by a neuroradiologist.
A standardized tracing protocol was used for the amygdala and
briefly is described as follows. Reliability was obtained by 2 rat-
ers who made independent measurements on a set of 15 im-
ages, which included 5 images repeated 3 times (in random or-
der). The amygdala was manually traced on high-resolution T1
images aligned along the long axis of the hippocampus by means
of the ITK-SNAP tool
following a protocol developed by the
Center for Neuroscience and the M.I.N.D. Institute at the Uni-
versity of California, Davis.
We first established reliability with
the M.I.N.D. Institute group (average interrater reliability, 0.90)
on adult subjects. Subsequently, reliability was established on
images from our sample of 18- to 35-month-olds. Average in-
trarater reliability was r=0.93, and interrater reliability was
r=0.90. A single rater (r=0.90) performed all amygdala traces.
Figure 1 for an example of amygdala tracing.
Group differences were evaluated for age, sex, and developmen-
tal IQ. As expected, given the disproportionate rate of males with
autism, sex was unequally distributed across groups. Sex also is
known to be associated with brain volume and, therefore, was
included as a covariate in all analyses. An insufficient number of
females with autism was available to perform separate analyses
by sex. Given the variability of age across subjects (18-35 months),
age was also included as a covariate. The IQ of the autistic group
was significantly lower than that of the controls; therefore, IQ was
included in the analyses as a covariate.
The first set of analyses examined group differences in amyg-
dala volumes and growth rates. A series of mixed models with re-
peated measures of the amygdala volume domains (hemisphere,
time) were fit with amygdala volume as the dependent variable,
diagnostic group as the predictor of interest, and age, sex, and IQ
as covariates. This resulted in up to 4 observations per subject (left
and right amygdala, times 1 and 2). Diagnostic group was entered
as a 2-level categorical variable (autism, controls). Estimates for
the controls were created by using postestimation procedures to
combine the group estimates. Age, sex, IQ, and group were in-
cluded as predictors in each of the models, along with all 2- and
3-way interactions with hemisphere (right or left) and group. The
significance of the interactions with hemisphere was examined.
If none of these interactions was significant, then the effects were
reported as averages across the left and right amygdala. To evalu-
ate whether the group difference was proportional to that observed
in total tissue volume (TTV), a second model was fit that added
TTV and the 2-way interaction with age. The TTV included all
cortical, subcortical, and brainstem gray and white matter and was
selected rather than total brain volume because it provides a more
specific index of brain enlargement without inclusion of increases
due to ventricular enlargement. Results using total brain volume
were not different than those using TTV for the analyses.
Relationships between JA and amygdala volume were ex-
amined by adding the SOC-RS JA ratings and interaction terms
to the models described previously. The IJA, RJA, JAT, and ges-
tures were examined separately. Two-tailed tests were con-
ducted for the amygdala-behavioral analyses.
Because of insufficient image quality or artifact, we were
unable to adequately visualize the amygdala in 8 sub-
jects (5 with autism, 1 TYP, and 2 DD). The ratio of im-
ages that were of insufficient quality did not differ be-
tween diagnostic groups.
Significant hemisphere effects were observed across
groups for amygdala volumes (F
=3.14, P=.048). Right
amygdala volumes were larger than left amygdala vol-
umes. Therefore, analyses are reported separately for the
right and left amygdala.
Amygdala volume increased significantly over time in the
total sample of autistic and control subjects (=0.14,
SE=0.02, P.001) (
Figure 2). The slope of amygdala
Figure 1. Sample segmentation of right and left amygdala using ITK-SNAP
software. Visualization includes axial plane (A), volumetric representation
(B), coronal plane (C), and sagittal plane (D). Image is presented in
radiologic orientation with the right hemisphere visualized on the left side of
the image (green) and the left hemisphere on the right side (blue).
©2009 American Medical Association. All rights reserved.
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growth remained positive and significant after adjust-
ing for TTV (=0.07, SE=0.02, P=.002). Group com-
parisons of change in amygdala volume over time were
not significant before or after controlling for TTV.
Because no group differences were observed in rate
of amygdala volume change over time, amygdala vol-
umes at times 1 and 2 were averaged (
Table 2 and
Table 3). When average amygdala volumes were com-
pared, individuals with autism had significantly larger
right and left amygdala volumes than controls. After con-
trolling for TTV, only the right amygdala remained en-
larged in the autism group relative to the control group.
Results did not change when the 2 high-functioning chil-
dren with autism were excluded from analyses, nor did
they change when females were excluded.
Clinical correlates of amygdala volume were examined
for the autism group only; ADOS (and, consequently,
SOC-RS) data were not available for controls. At time 1,
8 of 39 children with autism (21%) initiated and/or re-
sponded to JA (ie, a JAT score of 1); 9 of 23 children (39%)
initiated and/or responded to JA at time 2. At time 1,
7 of the 39 autistic children (18%) initiated JA; 9 of 23
children (39%) initiated JA at time 2. At time 1, 7 of 39
children with autism (18%) responded to JA (ie, shifts
in eye gaze) bids from the examiner; at time 2, 4 of 21
children (19%) responded to JA initiated by the exam-
iner. At time 1, 19 of 39 children (49%) made at least 1
nonverbal communicative gesture; 16 of 24 (67%) ges-
tured at time 2.
The relationship between amygdala volume and JA
indexes did not differ when right and left amygdala vol-
ume were analyzed separately; therefore, right and left
volumes were averaged and combined for analysis. A sig-
nificant positive association was observed at age 4 years
between amygdala volume and JAT (
Figure 3; =0.25,
SE=0.07, P.001). This relationship was also signifi-
cant for amygdala volume and IJA (=6.04, SE=2.04,
Autism right
Autism left
Combined controls right
Combined controls left
1.0 2.0 3.0
1.5 2.5 3.5 4.54.0 5.0 5.5 6.0
Age, y
Volume, cm
Figure 2. Mean right and left amygdala growth trajectories for the autism
and control groups adjusted for age, IQ, and total tissue volume. Both
groups show significant growth, but the rate of change does not differ
between groups.
Table 2. Group Means and Differences in Amygdala Volume
Adjusted for Age, Sex, and IQ
Autism vs Controls
Difference, Mean
(SE), mm
P Value
Time 1
Total 0.324 (0.085) .03 20
Right 0.368 (0.086) .001 23
Left 0.279 (0.088) .001 18
Time 2
Total 0.249 (0.102) .02 13
Right 0.293 (0.105) .006 15
Left 0.204 (0.104) .05 11
Main effect
Total 0.295 (0.085) .001 17
Right 0.339 (0.087) .002 19
Left 0.250 (0.087) .005 15
Table 3. Group Means and Differences in Amygdala Volume
Adjusted for Age, Sex, IQ, and Total Tissue Volume
Autism vs Controls
Difference, Mean
(SE), mm
P Value
Time 1
Total 0.090 (0.073) .22 5
Right 0.135 (0.076) .08 7
Left 0.046 (0.076) .55 2
Time 2
Total 0.104 (0.084) .22 5
Right 0.149 (0.088) .10 7
Left 0.060 (0.084) .48 3
Main effect
Total 0.096 (0.065) .15 5
Right 0.140 (0.069) .045 7
Left 0.051 (0.067) .45 3
Response to
Volume, cm
Children Without JA
Children With JA
Figure 3. Mean and standard error of amygdala volumes (average of right
and left amygdala) contrasted for children with autism who did and did not
engage in joint attention (JA). Data are adjusted for age, IQ, and sex.
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P =.006), and between amygdala volume and RJA
( =0.19, SE=0.09, P = .04). The relationship between
amygdala volume and gestures was not significant for
either 2- or 4-year-olds with autism. The relationships
between amygdala volume and the 6 subscales of the Re-
petitive Behavior Scale–Revised were not significant at
age 2 or 4 years. Results did not change after exclusion
of females from the analyses.
Comparison of amygdala volume showed bilateral en-
largement in children with autism. Right amygdala vol-
ume was enlarged disproportionately to TTV increases,
and left amygdala was enlarged proportionately to TTV
increases. Consistent with previous research,
amygdala enlargement was found to be more robust than
left amygdala enlargement. Autistic subjects showed a 5%
increase in TTV at ages 2 to 4 years,
whereas observed
amygdala volumes were 16% larger than in the group of
2- to 4-year-old controls. Amygdala enlargement was pres-
ent by age 2 years. Growth trajectories between 2 and 4
years of age did not differ in autistic children and non-
autistic controls. These findings suggest that, consistent
with a previous report of head circumference growth rates
in autism
and studies of amygdala volume in child-
amygdala growth trajectories are acceler-
ated before age 2 years in autism and remain enlarged
during early childhood. Moreover, amygdala enlarge-
ment in 2-year-old children with autism is dispropor-
tionate to overall brain enlargement and remains dispro-
portionate at age 4 years.
Amygdala enlargement in autism was associated with
increased JA and, despite the findings that only the right
amygdala volume was increased relative to TTV enlarge-
ment, the strength of the relationship between JA and
amygdala volumes did not differ by hemisphere. It is im-
portant to note that the left amygdala is enlarged, but this
enlargement is not disproportionate to TTV. These re-
sults are consistent with both previous studies establish-
ing a significant association between amygdala volume
and social functioning in autism.
Amygdala enlargement was associated with JA abil-
ity at age 4 years but not with communicative gestures.
Analyses performed as part of a forthcoming detailed re-
port on basal ganglia and behavior in autism indicated
that the relationship between caudate nuclei volumes and
JA in this sample was not significant at either 2 or 4 years
of age, suggesting that the relationship between amyg-
dala volume and JA is specific (H.C.-H., Michael Graves,
BA, R.G.-S., M.W.M., M.D.P., G.G., and J.P., unpub-
lished data, 2008). Joint attention is distinct from other
social behaviors measured in the present study because
it involves social orienting and eye contact with others.
Adolphs et al
postulated that damage to the amygdala
limits individuals’ natural tendency to orient to the eye
region of faces. The observation that amygdala volume
is associated with JA and not other social behaviors sug-
gests that amygdala alterations in autism reflect dimin-
ished social orienting behavior and, more specifically, re-
duced tendency to coordinate eye contact. Reduced JA
engagement in autism precludes shared social experi-
ences and thus can have a cascade of developmental ef-
fects, including disrupted cognitive, communication, and
social cognitive growth.
The association between amyg-
dala volume abnormalities and attention to eyes has now
been established in 2 independent studies (the present
study and that of Nacewicz et al
), suggesting that this
association is evident from early childhood through
Nacewicz et al
reported decreased amygdala vol-
umes associated with reduced eye contact in adolescents
and adults with autism. The association between amyg-
dala enlargement and increased JA ability in autism ob-
served herein is consistent with these findings but also
suggests nonlinear growth patterns in autism.
Schumann and Amaral
and Nacewicz et al
esize an “allostatic overload” model to explain nonlin-
ear patterns of amygdala growth in autism. Within this
model, repeated exposure to a highly stimulating event
leads to a compensatory response (allostasis) within the
amygdala, including increased dendritic arborization and
consequent overgrowth. The compensatory response in-
volves excess production of corticotropins and gluco-
corticoids that, on surpassing a threshold concentration
(allostatic overload), result in cell death within the amyg-
dala. Initial amygdala hypertrophy in autism is thus fol-
lowed by reduced amygdala volume later in develop-
ment. The present results indicate that amygdala
enlargement emerges before age 2 years and persists, but
does not increase in magnitude, between 2 and 4 years
of age. This enlargement is associated with attention to
eyes and, although the mechanisms linking amygdala en-
largement and JA ability are not known, the present re-
sults are consistent with the hypothesis that an allo-
static process in which dendritic arborization and
overgrowth result from sensitivity to processing eyes is
evident in autism at approximately age 4 years.
The amygdala plays a critical role in early-stage pro-
cessing of facial expression
and in alerting cortical
areas to the emotional significance of an event.
amygdala, via afferent connections projecting from the
superior colliculus and pulvinar nucleus of the thala-
alerts upstream cortical regions, including the fu-
siform face area of the fusiform gyrus, orbitofrontal cor-
tex, and superior temporal sulcus, to the emotional
salience of stimuli such as faces. Damage to the primate
amygdala during adulthood has inconsistent effects on
social interactions but, if occurring during infant devel-
opment, leads to increased social fear within novel en-
Amygdala disturbances early in devel-
opment, therefore, disrupt the appropriate assignment
of emotional significance to faces and social interaction.
previously suggested that early amygdala al-
terations in autism during social processing contribute
to later deficits in face processing and higher-order so-
cial cognition. He hypothesized that experience with faces
in infancy corresponds with enhanced salience assigned
by the amygdala, which, in turn, leads to motivation to
preferentially allocate attentional resources to faces. Daw-
son et al
hypothesized that early social deprivation in
autism resulting from a lack of social attention (and con-
comitant failure to promote interaction through JA) dis-
©2009 American Medical Association. All rights reserved.
at University of Utah, on June 23, 2010 www.archgenpsychiatry.comDownloaded from
rupts normative trajectories of neural and behavioral de-
velopment. The association between amygdala
enlargement and JA ability observed herein thus sug-
gests that amygdala overgrowth in autism may contrib-
ute to subsequent cortical face processing system distur-
and core social and cognitive developments, as
are evident in autism.
The primary limitation within this study was that few
children with autism demonstrated JA abilities at age 2
or 4 years. The behavioral observations coded for the pres-
ent study target multiple social behaviors and provide only
a small number of presses for JA. Inclusion of additional
attempts to elicit JA across multiple contexts may in-
crease power to identify children with autism who en-
gage in JA at earlier ages. An additional limitation was
that the relationship between amygdala volume and JA
could not be investigated in control groups. Assessing
whether the pattern of amygdala-JA findings differs in
autistic and nonautistic children will be important for un-
derstanding brain-behavior associations unique to au-
tism. Last, the small number of females with autism in-
cluded in our study suggests that future investigation is
needed to determine whether amygdala enlargement and
the observed relationship between amygdala volume and
JA each are evident in females with autism.
We observed bilateral amygdala enlargement in a large
sample of 2-year-olds with autism that persisted through
4 years of age. This enlargement was disproportionate
to TTV enlargement for the right amygdala as well. Con-
tinued follow-up (now under way) of this sample will
be necessary to examine whether amygdala growth rates
in autism continue to parallel those seen in nonautistic
individuals, or whether a second period of accelerated
growth or period of volumetric atrophy occurs in au-
tism after age 4 years. Similarly, longitudinal MR imaging
studies of high-risk neonates will provide insights into
the onset of amygdala overgrowth in autism.
Submitted for Publication: April 25, 2008; final revi-
sion received September 5, 2008; accepted October 1,
Correspondence: Joseph Piven, MD, UNC Neurodevel-
opmental Disorders Research Center, University of North
Carolina, CB#3367, Chapel Hill, NC 27599-3367 (joe
Author Contributions: Dr Mosconi had full access to
all of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data
Financial Disclosure: None reported.
Funding/Support: This research was supported by Na-
tional Institutes of Health grants MH61696 (Dr Piven),
HD03110 (Dr Piven), and EB002779 (Dr Gerig).
Previous Presentation: This study was presented in part
at the 2007 International Meeting for Autism Research;
May 4, 2007; Seattle, Washington.
Additional Contributions: We appreciate the assis-
tance we received from the following: Neurodevelop-
mental Disorders Research Center Autism Subject Reg-
istry and the North Carolina Children’s Developmental
Services Agencies for assisting with recruitment; Chad
Chappell, MA, Nancy Garrett, BA, Michael Graves, BA,
Sarah Peterson, MA, and Matthieu Jomier, MA, for their
work on the imaging and behavioral data collection; David
Amaral, PhD, Cynthia Schumann, PhD, and Julia Ham-
stra, MS, for assisting with amygdala segmentation; and
participating families.
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    • "Intriguingly, it was also reported that the degree of amygdala enlargement in toddlers was positively correlated with the extent of their social interaction and communication deficits at 5 years of age. A number of other studies have shown incidences of increased amygdalar volume in early life (< 5 years of age) in autistic individuals (Munson et al. 2006; Mosconi et al. 2009). Schumann et al. (2004) previously found no evidence of amygdala enlargement in adolescents with ASD, suggesting that amygdalar size and cell number alterations in ASD are age-dependent. "
    [Show abstract] [Hide abstract] ABSTRACT: Autism Spectrum Disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders that are diagnosed solely on the basis of behaviour. A large body of work has reported neuroanatomical differences between individuals with ASD and neurotypical controls. Despite the huge clinical and genetic heterogeneity that typifies autism, some of these anatomical features appear to be either present in most cases or so dramatically altered in some that their presence is now reasonably well replicated in a number of studies. One such finding is the tendency towards overgrowth of the frontal cortex during the early postnatal period. Although these reports have been focused primarily on the presumed pathological anatomy, they are providing us with important insights into normal brain anatomy and are stimulating new ideas and hypotheses about the normal trajectory of brain development and the function of specific anatomical brain structures. The use of model systems that include genetic model organisms such as the mouse and, more recently, human induced pluripotent stem cell-derived brain organoids to model normal and pathological human cortical development, is proving particularly informative. Here we review some of the neuroanatomical alterations reported in autism, with a particular focus on well-validated findings and recent advances in the field, and ask what these observations can tell us about normal and abnormal brain development.
    Full-text · Article · Sep 2016
    • "This is believed to occur as a result of the reduced networking efficiency among widespread regions of the cortex, due to the increased long-distance connections (Lewis et al., 2013). Specifically, people with ASD show increased volumes of the amygdala (Mosconi et al., 2009; Murphy et al., 2012), which correlate with the severity of their social and communication impairments (Schumann et al., 2009). In the TD population, higher amygdala volumes are associated with poorer language abilities in infancy (Ortiz-Mantilla et al., 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: Autism spectrum disorders (ASD) are pervasive neurodevelopmental disorders entailing social and cognitive deficits, including marked problems with language. Numerous genes have been associated with ASD, but it is unclear how language deficits arise from gene mutation or dysregulation. It is also unclear why ASD shows such high prevalence within human populations. Interestingly, the emergence of a modern faculty of language has been hypothesized to be linked to changes in the human brain/skull, but also to the process of self-domestication of the human species. It is our intention to show that people with ASD exhibit less marked domesticated traits at the morphological, physiological, and behavioral levels. We also discuss many ASD candidates represented among the genes known to be involved in the “domestication syndrome” (the constellation of traits exhibited by domesticated mammals, which seemingly results from the hypofunction of the neural crest) and among the set of genes involved in language function closely connected to them. Moreover, many of these genes show altered expression profiles in the brain of autists. In addition, some candidates for domestication and language-readiness show the same expression profile in people with ASD and chimps in different brain areas involved in language processing. Similarities regarding the brain oscillatory behavior of these areas can be expected too. We conclude that ASD may represent an abnormal ontogenetic itinerary for the human faculty of language resulting in part from changes in genes important for the “domestication syndrome” and, ultimately, from the normal functioning of the neural crest.
    Full-text · Article · Aug 2016
    • "A careful review of the initial inconsistent volumetric findings of amygdala suggested that age of the sample examined may affect the results (Haar et al. 2014). This notion was supported by the reports of increased amygdala volume in toddlers and preschoolers which were related to later measures of joint attention (Mosconi et al. 2009). Beyond age, other potential sources of variability on volumetric findings of the amygdala, such as the role of comorbidity with anxiety disorders or alexithymia (Bird et al. 2010), have been suggested but have not been fully clarified. "
    [Show abstract] [Hide abstract] ABSTRACT: Recent advances in neuroimaging have offered a rich array of structural and functional markers to probe the organization of regional and large-scale brain networks. The current chapter provides a brief introduction into these techniques and overviews their contribution to the understanding of autism spectrum disorder (ASD), a neurodevelopmental condition associated with atypical social cognition, language function, and repetitive behaviors/interests. While it is generally recognized that ASD relates to structural and functional network anomalies, the extent and overall pattern of reported findings have been rather heterogeneous. Indeed, while several attempts have been made to label the main neuroimaging phenotype of ASD (e.g., 'early brain overgrowth hypothesis', 'amygdala theory', 'disconnectivity hypothesis'), none of these frameworks has been without controversy. Methodological sources of inconsistent results may include differences in subject inclusion criteria, variability in image processing, and analysis methodology. However, inconsistencies may also relate to high heterogeneity across the autism spectrum itself. It, therefore, remains to be investigated whether a consistent imaging phenotype that adequately describes the entire autism spectrum can, in fact, be established. On the other hand, as previous findings clearly emphasize the value of neuroimaging in identifying atypical brain morphology, function, and connectivity, they ultimately support its high potential to identify biologically and clinically relevant endophenotypes.
    Article · Mar 2016
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