Copyright © 2012 S. Karger AG, Basel
Autism spectrum conditions (ASC) (referred to as pervasive developmental disorders by the Diagnostic and Statistical Manual of Mental Disorders [1]) constitute a diverse group of neurodevelopmental conditions including classic autism, Asperger syndrome (AS), and childhood disintegrative disorder. While individual children with ASC may differ markedly in phenotype, the conditions share three major domains of features: (1) qualitative impairments in social interaction, (2) qualitative impairments in communication, and (3) restricted, repetitive, and stereotyped patterns of behavior, interests, and activities. Impairments in social interaction may include difficulties in the use of nonverbal social behavior, such as eye contact and gestures, failure to develop peer relationships appropriate for the developmental level, and a lack of social or emotional reciprocity. Communication impairments may include delay in the development of spoken language or difficulties in initiating or sustaining a conversation. Restricted behaviors and interests may manifest as an encompassing preoccupation with a particular topic, inflexible adherence to specific routines or rituals, stereotyped and repetitive motor mannerisms (e.g. hand or finger flapping or twisting or complex whole-body movements), unusual sensory behaviors, and/or persistent preoccupation with parts of objects. In all cases, ‘symptom’ onset is in early childhood [1].
Epidemiology
As a group, ASC is one of the most common neurodevelopmental conditions, with a prevalence as high as 1% [2]. The condition is highly heritable [3] and appears to represent an etiologically heterogeneous set of conditions in which multiple genetic and environmental risk factors produce convergent behavioral features. While numerous hypotheses have been put forward regarding the primary nature of these conditions at the molecular, anatomical, and functional levels, there is no consensus on the underlying causes and no known cure. Note that for, ‘high-functioning’ individuals, even the concept of a cure is debated since one view of high functioning autism and/or AS is that it involves both a ‘difference’ and a disability. Best practices for early detection and intervention are constantly evolving.
Prevalence
ASC is diagnosed significantly more often in males than in females. The majority of studies report a male:female ratio of 4:1, but ratios in cognitively high-functioning individuals with ASC are even higher, on the order of 10:1. ASC is not unique among neurodevelopmental conditions in being more common among males; a similar pattern is seen in attention deficit hyperactivity disorder (ADHD), dyslexia, conduct disorder, specific language impairment, Tourette syndrome, and learning difficulties. However, the biased ratio in ASC is particularly strong and consistent. In addition, ASC is distinctive in that the condition has been conceptualized by some researchers as an ‘extreme male brain’ [4].
Pathogenesis
The Extreme Male Brain Theory of Autism Spectrum Conditions
The term ‘extreme male brain’ was first applied to autism anecdotally by Hans Asperger in 1944; he wrote that ‘the autistic personality is an extreme variant of the male intelligence’ [translation from p. 84 in 5]. Recently, this theory has been systematically reexamined as an explanation of cognition and neuroanatomy in individuals with ASC. In order to understand ASC as an extreme male brain, it is necessary to understand ASC as an extreme of typical development in general. Most people have approached ASC research with a medical model that assumes a categorical distinction between ASC and ‘normality’. Such a model implies a bimodal distribution and focuses research on finding one or more mutations that produce the ‘disorder’.
It is increasingly suggested that ASC is a spectrum of conditions that blends into the whole of the population. In other words, ASC occurs in the tails of a normal distribution. This model is multifactorial and will include polygenic effects and environmental influences, one of which may be testosterone (for reasons to be discussed). It is also important to understand that, in terms of cognition and brain structure, ‘male’ and ‘female’ are not distinct categories; they too are dimensional. Within each sex, there is individual variability, and there is a substantial overlap between male and female distributions.
Regarding cognition, individuals with ASC tend to display an exaggerated male profile. For example, on the Embedded Figures Test (EFT) and on tests of intuitive physics, both males and females with ASC perform better than typical males, who perform better than typical females [6– 8]. On tests involving complex language and ‘intuitive psychology’, they perform worse than typical males, who perform worse than typical females. A similar pattern is seen on questionnaires designed to assess the extent to which an individual shows autistic traits, including the Autism Spectrum Quotient (AQ; adult, adolescent, and child versions), the Childhood Autism Screening Test (CAST), the Quantitative Checklist for Autism in Toddlers (Q-CHAT), and the Social Responsivity Questionnaire (SRS) [see 4 for review].
Analogies can also be drawn between sex differences in brain development and neuroanatomical characteristics found in ASC. Although there is a great deal of individual variation in human brain morphometry, the cerebrum as a whole is about 9% larger in men and in boys. One of the most consistent anatomical findings in children with ASC is that young children with autism tend to have larger-than-average heads. Magnetic resonance imaging confirms that these large heads contain abnormally large brains. Reports of regional differences in sexual dimorphism are more controversial, but correcting for the overall larger size of male brains, the amygdala is disproportionately large in boys while the hippocampus and caudate are disproportionately large in girls. Like an exaggeration of typical boys, children with ASC show greater growth of the amygdala [see 4 for review].
Finally, studies of brain function also reveal similarities between typical sex differences and differences between those with ASC and neurotypicals. The ‘default mode network’ (DMN) is decreased in functional connectivity in males relative to females during resting conditions. In ASC, connectivity within the DMN is even more decreased during rest. Using task-related functional MRI, typical males show decreased activity in the posterior parietal cortex (BA 7) during the EFT and people with ASC show even less activity in BA 7 during this task. Finally, typical males show decreased activity bilaterally in the inferior frontal gyrus (BA 44/45) during the ‘Reading the Mind in the Eyes’ Test relative to typical females, and people with ASC show even less activity in this region during this task [see 4 for review].
So, which biological mechanisms shape the sex differences described above and is there evidence that these mechanisms are disrupted in individuals