Comparison of amygdala volume showed bilateral enlargement in children with autism. Right amygdala volume was enlarged disproportionate to TTV increases and left amygdala was enlarged proportionately to TTV increases. Consistent with previous research7,33
right 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 years34
while observed amygdala volumes were 16% larger than the group of 2 to 4 year-old controls. Amygdala enlargement was present 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 autism34
and studies of amygdala volume in childhood,12, 13, 33
amygdala growth trajectories are accelerated before age 2 years in autism and remain enlarged during early childhood. Moreover, amygdala enlargement in 2-year-old children with autism is disproportionate to overall brain enlargement and remains disproportionate 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 enlargement, the strength of the relationship between JA and amygdala volumes did not differ by hemisphere. It is important to note that the left amygdala is enlarged but this enlargement is not disproportionate to TTV. These results are consistent with both prior studies establishing a significant association between amygdala volume and social functioning in autism.9,33
Amygdala enlargement was associated with JA ability at age 4 years but not with communicative gestures. Analysis of the relationship between caudate nuclei volumes and JA in this sample was not significant at either 2 or 4 years of age (unpublished data) suggesting that the relationship between amygdala volume and JA is specific. JA is distinct from other social behaviors measured in the present study because it involves social orienting and eye contact with others. Adolphs21
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 suggests that amygdala alterations in autism reflect diminished social orienting behavior and, more specifically, reduced tendency to coordinate eye contact. Reduced JA engagement in autism precludes shared social experiences and thus can have a cascade of developmental effects, including disrupted cognitive, communication, and social cognitive growth.26
The association between amygdala volume abnormalities and attention to eyes has now been established in two independent studies (the present study and that of Nacewicz et al9
), suggesting that that this association is evident from early childhood through adulthood.
Nacewicz et al.9
amygdala volumes associated with reduced
eye contact in adolescents and adults with autism. The association between amygdala enlargement
JA ability in autism observed herein is consistent with these findings but also suggests non-linear growth patterns in autism.45
Both Schumann and Amaral7
and Nacewicz et al.9
hypothesize an ‘allostatic overload’ model to explain non-linear 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 involves excess production of corticotropins and glucocorticoids that, upon surpassing a threshold concentration (allostatic overload), result in cell death within the amygdala. Initial amygdala hypertrophy in autism is thus followed by reduced amygdala volume later in development. 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 enlargement and JA ability are not known, the present results are consistent with the hypothesis that an allostatic 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 processing of facial expression19, 46–48
and in alerting cortical areas to the emotional significance of an event.49
The amygdala, via afferent connections projecting from the superior colliculus and pulvinar nucleus of the thalamus,50
alerts upstream cortical regions, including the fusiform face area of the fusiform gyrus, orbitofrontal cortex, 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 development, leads to increased social fear within novel environments51, 52
. Amygdala disturbances early in development, therefore, disrupt the appropriate assignment of emotional significance to faces and social interaction.
previously suggested that early amygdala alterations in autism during social processing contribute to later deficits in face processing and higher order social 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. Dawson et al.26
hypothesized that early social deprivation in autism resulting from a lack of social attention (and concomitant failure to promote interaction through JA) disrupts normative trajectories of neural and behavioral development. The association between amygdala enlargement and JA ability observed herein thus suggests that amygdala overgrowth in autism may contribute to subsequent cortical face processing system disturbances54
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 present 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 increase power to identify children with autism who engage 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 non-autistic children will be important for understanding brain-behavior associations unique to autism. Last, the small number of females with autism included 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. Continued 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 non-autistic individuals, or whether a second period of accelerated growth or period of volumetric atrophy occurs in autism after age 4 years. Similarly, longitudinal MR imaging studies of high risk neonates will provide insights into the onset of amygdala overgrowth in autism.