Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin
Department of Psychological Medicine, Institute of Psychiatry, London, UK
Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
Correspondence: Fiona Toal, Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland. E-mail: ftoal{at}rcsi.ie
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ABSTRACT |
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INTRODUCTION |
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Individuals with autism (Wing, 1997; Gillberg, 1998) also have delayed language development, and many have learning disability. However, around 20% are classified as high-functioning, because they have normal or superior general intellectual skills, despite having a history of early language delay. Individuals with Asperger syndrome have no history of language delay and have normal or superior intellectual abilities, but also show the characteristic impairments of reciprocal social interaction. Although by definition (ICD10; World Health Organization, 1992) there is always a disparity between social understanding and cognitive skills in autism, this disparity is particularly marked in high-functioning individuals with autism/Asperger syndrome. However, the biological associates of abnormal social behaviour in autism are poorly understood.
Prevalence rates of up to 60 per 10 000 for autistic-spectrum disorder are reported (Chakrabarti & Fombonne, 2001; Charman, 2002) for the broader phenotype making it approximately half as common as schizophrenia. Controversially, some mental health services do not provide services for adults with autistic-spectrum disorder arguing that it is not a psychiatric disorder. This logic is at best flawed. Just like attention-deficit hyperactivity disorder and psychosis, autistic-spectrum disorder is a highly genetic neurodevelopmental disorder and is defined as a psychiatric disorder in both ICD10 and DSMIV (American Psychiatric Association, 1994); it is associated with significant comorbid mental health symptoms both in patients and in their families; and it responds to appropriate pharmacological, psychological and social interventions. There are currently few services for adults with autistic-spectrum disorder, and most child and adolescent services do not offer long-term follow-up when their young patients become adults.
The cause of autistic-spectrum disorder is unknown, but is most likely to be a complex interaction between genetic and environmental factors. It was still believed in the 1960s that cold, refrigerator-type parenting was responsible for the behavioural characteristics associated with this syndrome. One of the earliest indicators that it was in fact a neurobiological disorder was the high rate of epilepsy, which was found to affect approximately a third of autistic children. Twin studies have since shown autism to be among the most heritable of neuropsychiatric disorders (Bailey et al, 1995). Particularly poor science led to reports that autistic-spectrum disorder was caused by the measles, mumps and rubella vaccine, and this caused much alarm and a reduction in immunisation. This is ironic, given that this vaccine protects against one of the established causes of autism intrauterine exposure to rubella. The challenge therefore exists to define the biological determinants of autistic-spectrum disorder.
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CONTRIBUTION OF NEUROIMAGING |
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Anatomical imaging
The most consistent finding to date is the replication of Kanners
original observation of increased brain volume (megalen-cephaly) in autism,
and there is some evidence that this may be age-dependent (Courchesne,
2002,
2004). It has been proposed
that people with autistic-spectrum disorder have an early period of
accelerated brain growth followed by a period of decelerated development. It
is also clear that in adulthood brain ageing is significantly different in
people with autistic-spectrum disorder compared with controls
(McAlonan et al,
2002). Thus, the biology of the disorder should not be seen as an
initial hit followed by a static disorder. Rather, the initial
early biological differences most probably modify brain maturation across the
lifespan.
In addition to differences in volume of whole brain, however, some specific brain regions are particularly implicated, including the frontal, limbic, basal ganglia and cerebellar regions (for a review, see Sokol & Edwards-Brown, 2004). For example, it was reported that people with Asperger syndrome had significantly less grey matter in frontostriatal and cerebellar regions than controls, and widespread differences in white matter (McAlonan et al, 2002). Furthermore, people with Asperger syndrome had significant differences in ageing of the cerebral hemispheres and caudate nuclei. These findings were also replicated in a study of a Chinese population of children with high-functioning autism (McAlonan et al, 2005), which found that they had significant differences in the volume and connectivity of frontostriatal networks. In another study (McAlonan et al, 2005) these authors found that children with autistic-spectrum disorder had a significant difference in the grey matter volumes of the ventral and superior temporal lobes, and the white matter volumes of the cerebellum, internal capsule and fornices (McAlonan et al, 2005). In summary, taken together these data suggest that people with autistic-spectrum disorder have abnormalities in the anatomy and connectivity of limbicstriatal brain systems and that this is true in samples from different countries, cultures and age groups.
Therefore, there is growing evidence that people with autistic-spectrum disorder have specific abnormalities in brain development and anatomy. However, it is unclear how variation in genetic systems which are important for brain growth and development relates to neurobiological differences.
Functional imaging
Functional magnetic resonance imaging (MRI) has allowed the investigation
of the neural networks underlying cognitive impairments in autism, including
face and emotion processing, which has been one of the most extensively
explored areas. Hypo-activation of the so-called face area in
the right fusiform gyrus has repeatedly been reported in adults with
autistic-spectrum disorder while looking at faces
(Critchley et al,
2000). However, more recently it has been identified that this
response can be modulated, depending on the familiarity and personal emotional
content of the faces presented (Hadjikhani
et al, 2004; Pierce
et al, 2004).
The ability to attribute mental states to others (theory of mind) underpins many aspects of normal social interaction and is impaired in people with autism. Decreased activation of medial prefrontal cortex and amygdala during mentalising tasks has been reported in people with autistic-spectrum disorder, and suggests that these areas form a crucial component of the brain system that underlies the normal understanding of other minds (Happe et al, 1996; Castelli et al, 2002). Thus, people with autism also have functional differences in brain regions which are reported as anatomically abnormal and which are essential to normal social function.
Proton magnetic resonance spectroscopy
Proton magnetic resonance spectroscopy can be used to measure
concentrations and ratios of N-acetylaspartate, creatine and
phosphocreatine, and choline, which act as indicators of neuronal density and
mitochondrial metabolism, phosphate metabolism and membrane turnover,
respectively. This imaging technique has shown that people with
autistic-spectrum disorder have significant abnormalities in prefrontal lobe
neuronal integrity, and this is related to severity of clinical symptoms
(Murphy et al, 2002). These results suggest that regional differences in neurodevelopment
(programmed cell death) may underpin a proportion of the symptoms typical of
the disorder.
Other neuroimaging techniques
Studies using positron emission tomography (PET) reported differences in
the connectivity of cortico-cortical and corticalbasal ganglia circuits
(Horwitz et al,
1988), and these findings are supported by the MRI studies noted
above. Also, some studies reported significant differences in serotonin
(5-hydroxytryptamine; 5-HT) synthesis
(Chugani, 2004). The potential
role of 5-HT in autistic-spectrum disorder is of importance, because 5-HT acts
as a trophic or differentiation factor during brain development, and helps
modulate social and repetitive behaviours. There is also growing evidence that
some symptoms in people with autistic-spectrum disorder may benefit from
medications that affect the 5-HT system (e.g. selective serotonin reuptake
inhibitors and atypical antipsychotics).
In a recent edition of the Journal we were presented with a PET study of individuals with autism and savant abilities (Boddaert et al, 2005). On the basis of their findings, the investigators postulate that savant capacities may be sustained by a memory-processing network involving the temporo-frontal regions (including the hippocampus). Structures in the medial temporal lobe are critical to normal memory functions, including acquisition of new information. Early abnormal development of this system is thought to result in abnormalities of long-term memory and lead to reliance on more habit-type memory processing. The preservation of the habit memory system also accounts for many characteristics typical of children with autism. It is consistent with Kanners observations of an anxiously obsessive desire for the preservation of sameness, excellent rote memory and limitation in the variety of spontaneous activity in autism (Kanner, 1943). Boddaert et als study is of particular interest, as it has been suggested that as babies, all humans possess savant abilities, as can be seen in the rapid language acquisition at that age as well as the fact that absolute pitch and eidetic memory are much more commonly present in children and may reflect the reliance on habit memory processing in all humans at this stage.
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FUTURE RESEARCH |
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REFERENCES |
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Received for publication March 7, 2005. Accepted for publication March 21, 2005.
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