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M.D., Ph.D.,
M.D., Ph.D.,
Objective: The amygdala and hippocampus are key components of the neural system
mediating emotion perception and regulation and are thought to be involved in the
pathophysiology of autism. Although some studies in children with autism suggest that there
is an enlargement of amygdala and hippocampal volume, findings in adolescence are
sparse. Method: We measured amygdala and hippocampus volume in a homogeneous
group of adolescents with autism (12 through18 years; n 23) and compared them with an
age-, sex-, and IQ-matched control group (n 29) using a validated automated segmentation
procedure in 1.5-T magnetic resonance images. All analyses were adjusted for total brain
volume. Results: Repeated-measures analysis revealed a significant group hemisphere
brain structure interaction (p .038), even when corrected for total brain volume. Post-hoc
analysis showed that the right amygdala and left hippocampus were significantly enlarged (p
.010; p .015) in the autism compared with the control group. There were no significant
correlations between age and amygdala or hippocampus volume. Conclusions: The abnormal enlargement of the amygdala and hippocampus in adolescents with autism adds to
previous findings of enlargement of these structures in children with autism. This may reflect
increased activity of these structures and thereby altered emotion perception and regulation.
Our results could therefore be interpreted in light of developmental adaptation of the autistic
brain to a continuous overflow of emotional learning experiences. J. Am. Acad. Child Adolesc.
Psychiatry, 2010;49(6):552560. Key Words: autism, emotion, amygdala, hippocampus
Autism is a neurodevelopmental disorder characterized by impaired social interaction, language and communication
deficits, and stereotyped repetitive behavior. Despite the great variation in clinical presentation, a
central feature of autism is the impairment in
social and emotional behavior. Persons with autism typically do not exhibit adequate socioemotional reciprocity, have difficulty understanding social-emotional cues, and often display
blunted affect.1 Development of adequate socioemotional behavior depends on the structural
and functional integrity of brain regions mediating emotion perception and regulation.2 Volumetric investigation of these brain regions may
provide important clues that can help to eluci-
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TABLE 1
Group
PD
Dager 20075
Nicolson 20066
Rojas 20067
Nacewicz 20068
Palmen 20069a
Rojas 200410
Schumann 200411
Schumann 200411
Herbert 200312
Bigler 200313
Sparks 200214
Pierce 200115
Saitoh 200116
Haznedar 200017
Howard 200018a
Abell 199919
Aylward 199920
Piven 199821
Saitoh 199522
29
21
24
23
42
15
19
19
17
38
29
7
59
10
10
15
14
35
33
16
AS
11
11
16
Sex
HP
Age
IQ
13
24
23
26
42
17
11
11
15
27
26
8
51
17
10
15
14
36
32
3-4
6-16
7-44
8-25
7-25
19-47
7-12
12-18
7-11
7-31
3-4
20-42
2-49
27b
16-40
28,8b
20,5b
12-29
13,8b
45
45
47
54
81
11
41
41
22
65
56
15
92
30
20
24
28
71
58
13
0
0
0
3
11
0
0
0
0
15
0
18
4
0
6
0
25
7
NR
70
60-133
97c
80
62-140
/70
/70
80
62
NR
73-102
41-135
55-125
NR
NR
106c
52-136
NR
MF
Sex
Age,
Age,
Age,
Age,
Age,
Age
Age
Sex
Age,
Age
Age,
NR
NR
Age,
Age,
Age,
NR
Age
TBVa
HC, VIQ
IQ, educ
sex
sex, IQ
sex
sex
sex
VIQ, sex
sex, IQ
sex, IQ
AM
L1
L2 L1
1
1
1
2d 2d
1e 1
2
2f
L1
2
2
Note: A autistic disorder; AM amygdala volume; AS Aspergers disorder; C controls; educ education; F female; HC head circumference;
HP hippocampus; IQ intelligence quotient; M male; MF matching factors; NR not reported; PD pervasive developmental disorder not
otherwise specified; s shape; TBVa total brain volume adjusted; v volume; VIQ verbal IQ.
a
Autism sample includes people with Aspergers disorder.
b
Mean age.
c
Mean IQ.
d
Combined measurement of the amygdala and hippocampus.
e
Disproportional enlargement of the amygdala in the autistic disorder subgroup.
f
Decreased area dentata (part of the hippocampus).
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TABLE 2
Age (years)
Sex (m/f)
Full scale IQ
Performance IQ
Verbal IQ
ADI: social deficits
ADI: communication deficits
ADI: repetitive behavior
Controls (n29)
p-value
Statistic (t or 2)
15.15 1.86
20/3
99.52 20.12
99.39 16.64
99.52 21.68
16.30 5.89
20.00 8.09
12.52 4.93
15.65 1.66
23/5
104.93 8.68
105.24 11.56
104.90 9.62
NA
NA
NA
0.31
0.68
0.23
0.14
0.28
1.03
0.17
1.20
1.49
1.11
METHOD
Participants
Two groups participated in the study: 29 typically
developing (TD) adolescents (five girls and 24 boys)
and 23 adolescents with autism (three girls and
20 boys). All participants were between 12 and 18
years of age, right-handed, and Caucasian. Written
informed consent was obtained from all participants
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TABLE 3
Effect
Group
Brain structure
Hemisphere
Group brain structure
Group hemisphere
Brain structure hemisphere
Brain structure hemisphere group
df
F ratio
1.49
1.49
1.49
1.49
1.49
1.49
1.49
5.53
32.57
0.28
1.28
1.07
0.13
4.55
.023
.001
.598
.264
.307
.722
.038
Data Analysis
Statistical analysis was performed with Statistical Program for the Social Sciences (SPSS) Edition 15.0 (SPSS
Inc., Chicago, IL). To investigate the presence of volume
differences between the groups, we performed a group
(autism versus controls) hemisphere (right versus left)
brain structure (amygdala and hippocampus) repeated-measures analysis of covariance, with group as a
between-subjects variable and hemisphere and brain
structure as within-subject variables. In these and subsequent analyses, total brain volume was used as a covariate to control for possible differences in brain volume
between the autism and control group. Post-hoc analyses
of covariance (ANCOVAs) with total brain volume as
covariate were performed to investigate significant effects. To investigate whether the developmental time
course showed a deviant pattern in the autism group, we
calculated Pearsons correlations between age, amygdala,
and hippocampus volume in both participant groups. To
explore whether the brain volumes were associated with
social impairment in autism, we calculated Pearsons
correlations between the social impairment score on the
ADI-R and volumes of the amygdala and hippocampus.
RESULTS
All volumes were distributed normally. Table 3
shows a summary of the results. As expected, the
repeated-measures ANCOVA with TBV as a covariate revealed a significant main effect for brain
structure (F(1,49) 32.57, p .001), reflecting the
larger size of hippocampus when compared with
the amygdala. We also found a significant main
effect of group (autism versus controls; F(1,49)
5.53, p .023) and a significant main effect of
brain structure (amygdala and hippocampus;
F(1,49) 32.57, p .001). Importantly, we found
a significant group hemisphere brain structure interaction (F(1,49) 4.55, p .038), indicating that the group differences of the amygdala
volume and hippocampus volume differed per
hemisphere. Post-hoc ANCOVAs for each hemi-
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GROEN et al.
DISCUSSION
In the current study, we used an automated
segmentation procedure to investigate amygdala
and hippocampus volumes in a well-defined
sample of high-functioning adolescents with autism (12 through 18 years) and a carefully
matched control group. Although there were no
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Volumes of right and left amygdala and hippocampus. Note: ASD subjects with autism spectrum
disorder; TD typically developing participants. *Significantly different from controls at p .05.
FIGURE 1
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GROEN et al.
TABLE 4
1683259 210873.4
1756.22 199.78*
1685.35 202.49
4724.91 408.00
4875.26 448.16*
Controls (n 29)
1637902 185139.9
1629.10 143.86
1593.45 157.63
4553.31 406.63
4588.38 366.58
emotional learning experiences. Note that a parallel enlargement of both hippocampus and
amygdala throughout childhood and adolescence in autism is more long lasting than, for
example, the state-related volumetric abnormalities during a first depressive episode, in which
only amygdala enlargement has been found.26
Our findings in individuals with autism, combined with previous work, suggest that there is a
volume increase of the amygdala and hippocampus in childhood that persists into adolescence. Yet,
as individuals with autism pass from adolescence
into adulthood, their amygdala and hippocampus
volumes seem to normalize, suggesting that there is
a relative loss of volume. We hypothesize that a
process of chronic stress in autism, possibly caused
by a hyperexcitory amygdala, may lead to initial
hypertrophy of the amygdala and hippocampus
and to damaging effects in later life. Daily life, with
its social demands and constantly changing situations, causes severe stress in children with autism.
A number of studies reported significant correlations between enlarged amygdala volumes and
increased anxiety in autism.36,39 Animal models
have demonstrated that stress initially evokes hypertrophy of the amygdala neuron.34 Yet, chronic
dysregulation of the stress response (also referred
to as allostatic overload) may lead to amygdala and
hippocampal volume decreases in later life. This
has been supported by studies on recurrent major
depression, a disorder that is associated with
chronic stress, in which volume decreases of the
amygdala and hippocampus have been shown late
in the disease process.40,41 Animal studies have
demonstrated that chronic repeated stress evokes
excitotoxic changes in the hippocampus, resulting
in degeneration.42 To conclude, a model of hyperactivity-induced structural changes is compatible
with the majority of previous findings on amygdala
and hippocampus volume in autism, as initial
enlargement in childhood and subsequent decline
of amygdala and hippocampal volume may result
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