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Mosconi2009 A Mas Grande en Bbs
Mosconi2009 A Mas Grande en Bbs
Context: Cerebral cortical volume enlargement has been lation to joint attention ability measured with a new ob-
reported in 2- to 4-year-olds with autism. Little is known servational coding system, the Social Orienting Con-
about the volume of subregions during this period of de- tinuum and Response Scale; group comparisons including
velopment. The amygdala is hypothesized to be abnormal total tissue volume, sex, IQ, and age as covariates.
in volume and related to core clinical features in autism.
Results: Amygdala enlargement was observed in sub-
Objectives: To examine amygdala volume at 2 years with jects with autism at both 2 and 4 years of age. Signifi-
follow-up at 4 years of age in children with autism and cant change over time in volume was observed, al-
to explore the relationship between amygdala volume and though the rate of change did not differ between groups.
selected behavioral features of autism. Amygdala volume was associated with joint attention abil-
ity at age 4 years in subjects with autism.
Design: Longitudinal magnetic resonance imaging study.
Conclusions: The amygdala is enlarged in autism rela-
Setting: University medical setting.
tive to controls by age 2 years but shows no relative in-
crease in magnitude between 2 and 4 years of age. A sig-
Participants: Fifty autistic and 33 control (11 devel-
opmentally delayed, 22 typically developing) children be- nificant association between amygdala volume and joint
tween 18 and 35 months (2 years) of age followed up at attention suggests that alterations to this structure may
42 to 59 months (4 years) of age. be linked to a core deficit of autism.
Main Outcome Measures: Amygdala volumes in re- Arch Gen Psychiatry. 2009;66(5):509-516
A
UTISM IS A COMPLEX NEU- amygdala volumes have been observed
rodevelopmental dis- across multiple structural MR imaging
order likely involving studies of adolescents and adults with au-
multiple brain systems. tism.8-13 Altered amygdala activation in re-
Converging evidence from sponse to facial and emotion processing
magnetic resonance (MR) imaging, head tasks also has been reported in func-
circumference, and postmortem studies tional MR imaging studies of individuals
suggests that brain volume enlargement is with autism.14-16 Abnormal activation pat-
a characteristic feature of autism,1 with its terns were not evident in functional neu-
onset most likely occurring in the latter roimaging studies of individuals with au-
part of the first year of life.2 On the basis tism presented with nonfacial social
of functional MR imaging data identify- processing paradigms. 17-20 Taken to-
ing decreased amygdala activity during gether, studies of the amygdala in autism
gaze processing,3 Baron-Cohen et al4 first suggest that both the morphologic char-
proposed that amygdala dysfunction may acteristics and function of this structure
account for core social characteristics of are abnormal and that amygdala dysfunc-
autism. Neuropathological and struc- tion may be associated with social defi-
tural MR imaging studies have also high- cits involving facial processing.
Author Affiliations: UNC lighted alterations within the amygdala. Adolphs et al21 observed deficits in rec-
Neurodevelopmental Disorders Postmortem studies of individuals with au- ognition of negative facial emotions among
Research Center, The University tism have noted immature-appearing and patients with bilateral focal lesions of the
of North Carolina densely packed cells5,6 and fewer neu- amygdala. The authors reported that these
at Chapel Hill. rons within the amygdala.7 Abnormal deficits were the consequence of a failure
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Control
Abbreviations: AE, age equivalent; DD, developmentally delayed; TYP, typically developing.
a Mullen Scales of Early Learning composite IQ standard score.
to orient to the eye region when viewing faces. Sasson et sample from the Sparks et al13 study, Munson et al33 re-
al22 recently reported that, on an emotion recognition task ported that right amygdala enlargement at age 3 to 4 years
sensitive to deficits related to amygdala damage,23 indi- is associated with worse concomitant social functioning
viduals with autism show decreased attention to face re- and is predictive of worse social functioning at age 6 years.
gions relative to age- and IQ-matched healthy control sub- However, that study did not specify the aspects of social
jects and age-matched individuals with schizophrenia. impairment in autism associated with amygdala vol-
Individuals with autism in this study, in contrast to healthy ume. Nacewicz et al9 reported that amygdala volumes were
controls and individuals with schizophrenia, did not reduced in a small group of adolescents with autism
modulate their attention to social scenes according to (N=21) and that decreased amygdala volume was sig-
whether faces were present or absent. Failure to orient nificantly associated with decreased amount of time spent
to faces and, more specifically, the eye region of the face fixating on the eye region of faces.9
is inherent in multiple aspects of social impairment unique We examined amygdala volumes and growth in chil-
to autism (eg, joint attention [JA], facial emotion pro- dren with autism at 2 years of age (the earliest age of gen-
cessing) and may be linked to amygdala abnormalities. erally accepted diagnosis) with follow-up at 4 years of
Multiple studies have identified JA deficits as the most age. We developed an observational coding system to ex-
reliable marker of autism in the first 2 years of life24-31 amine JA and its relationship to amygdala volume. Joint
and thus suggest that the amygdala plays a key role in attention was targeted because (1) it consistently has been
neurodevelopmental alterations unique to autism. shown to be impaired in young children with autism24-31
Both increased12,13 and decreased8-11 amygdala vol- and (2) as measured herein, it requires attention to the
umes have been noted in structural MR imaging studies eye region of the face. Amygdala volumes were hypoth-
of individuals with autism. Schumann et al12 first sug- esized to be enlarged in autism and significantly associ-
gested that inconsistencies across studies are the result ated with JA deficits that involve orienting to the eye re-
of age-dependent effects. Observing amygdala enlarge- gion but would not be associated with other social
ment in school-aged (71⁄2-121⁄2 years) but not adoles- behaviors not involving orienting to the eye region (eg,
cent (123⁄4-181⁄2 years) autistic children, the authors hy- nonverbal gesture). Amygdala volumes were also exam-
pothesized that enlargement of the amygdala in autism ined in relation to nonsocial characteristic features of
is an early-occurring phenomenon. Consistent with this children with autism, specifically restricted and repeti-
report, Sparks et al13 reported amygdala enlargement in tive behaviors.
3- to 4-year-olds with autism, whereas studies of ado-
lescents and adults with autism have highlighted re- METHODS
duced amygdala volumes compared with typically de-
veloping individuals.8,10 None of these studies has observed
individuals over time. Giedd et al32 previously showed SAMPLE
that longitudinal studies are necessary for characteriz-
ing neuroanatomical development within the context of Fifty children with autism entered this MR imaging study at 2
interindividual variability and nonlinear growth. Stud- 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).
ies of amygdala growth in young children with autism
Thirty-three control subjects (22 typically developing [TYP]
observed over time are needed to map developmental pat- children and 11 nonautistic, developmentally delayed [DD] chil-
terns and brain-behavior relationships unique to this dis- dren) entered the study at 2 years of age. The sample of con-
order. trol children was enriched with DD children to more closely
Two recent studies reported that amygdala volume is match the autism study group in terms of IQ. The TYP and DD
associated with social deficits in autism. Examining the children were not analyzed separately because of the small
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STATISTICAL ANALYSES
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Response to JA JA
JA initiation total
2.7
Table 2. Group Means and Differences in Amygdala Volume
Adjusted for Age, Sex, and IQ
2.6
Autism vs Controls
2.5
Time 1
2.3
Total 0.324 (0.085) .03 20
Right 0.368 (0.086) ⬍.001 23
2.2
Left 0.279 (0.088) ⬍.001 18
Time 2
Total 0.249 (0.102) .02 13 2.1
Right 0.293 (0.105) .006 15
Left 0.204 (0.104) .05 11 2.0
ers ders ator
s
ator
s t JA h JA
Main effect ond pon initi Initi hou Wit
r esp Res Non Wit dren
Total 0.295 (0.085) ⬍.001 17 Non d ren Chil
Chil
Right 0.339 (0.087) ⬍.002 19
Left 0.250 (0.087) .005 15
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.
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 8 of 39 children with autism (21%) initiated and/or re-
not significant before or after controlling for TTV. sponded to JA (ie, a JAT score of 1); 9 of 23 children (39%)
Because no group differences were observed in rate initiated and/or responded to JA at time 2. At time 1,
of amygdala volume change over time, amygdala vol- 7 of the 39 autistic children (18%) initiated JA; 9 of 23
umes at times 1 and 2 were averaged (Table 2 and children (39%) initiated JA at time 2. At time 1, 7 of 39
Table 3). When average amygdala volumes were com- children with autism (18%) responded to JA (ie, shifts
pared, individuals with autism had significantly larger in eye gaze) bids from the examiner; at time 2, 4 of 21
right and left amygdala volumes than controls. After con- children (19%) responded to JA initiated by the exam-
trolling for TTV, only the right amygdala remained en- iner. At time 1, 19 of 39 children (49%) made at least 1
larged in the autism group relative to the control group. nonverbal communicative gesture; 16 of 24 (67%) ges-
Results did not change when the 2 high-functioning chil- tured at time 2.
dren with autism were excluded from analyses, nor did The relationship between amygdala volume and JA
they change when females were excluded. indexes did not differ when right and left amygdala vol-
ume were analyzed separately; therefore, right and left
AMYGDALA AND JA volumes were averaged and combined for analysis. A sig-
nificant positive association was observed at age 4 years
Clinical correlates of amygdala volume were examined between amygdala volume and JAT (Figure 3; =0.25,
for the autism group only; ADOS (and, consequently, SE = 0.07, P ⬍ .001). This relationship was also signifi-
SOC-RS) data were not available for controls. At time 1, cant for amygdala volume and IJA ( = 6.04, SE = 2.04,
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