Portal de Periódicos da CAPES

Autism spectrum disorder

2005; Elsevier BV; Volume: 15; Issue: 19 Linguagem: Inglês

10.1016/j.cub.2005.09.033

1879-0445

Uta Frith, Francesca Happé,

Family and Disability Support Research

Autism is a developmental disorder diagnosed on the basis of early-emerging social and communication impairments and rigid and repetitive patterns of behaviour and interests. The manifestation of these varies greatly with age and ability, and the notion of an autism spectrum has been introduced to recognise this diversity. We begin our discussion of research on the nature and causes of autism spectrum disorders (ASDs) with a single case history that illustrates the range of symptoms seen in this disorder. When Paul was two he spent hours lining up toy cars and gazing at them from different angles. He did not turn when his name was called, or take any notice of others. He remained oblivious when his mother hurt herself and cried out in pain. He did not speak to communicate, but he could echo back phrases from the television news, and arranged plastic letters to form words from TV credits. He would often have tantrums for no reason his parents could discern, but was noticeably calmed by music, especially Bach Goldberg Variations. He did not look at others’ faces or point out things of interest — he would take an adult’s hand and move it towards an object he wanted, as if the hand were a tool. By five years, Paul was notably unaware of other children, apparently uninterested in making friends. He did not play make-believe games and was confused when another child poured him a cup of pretend tea. However, he liked to have the attention of adults and spoke in a formally correct, rather stilted manner. A strong obsession with locks, and protest at any change of routine in the daily events made his family’s life difficult. At school he screamed when required to finish a task and change activity, while at other times he seemed hyperactive and unfocused. He would not sit and listen to a story with other children, but would wander off to play with the computer. In the playground he was easily teased, and had no idea when children were joking or being sarcastic. As an adult, Paul is now isolated and friendless, but successful in his career as a computer software specialist. He irritates customers with his monologues on technicalities, and is depressed by his lack of promotion and inability to find a girlfriend. His interest in locks has developed into a vast collection of locks. He eats the same food for lunch every day, and was very upset when his usual type of sandwich was discontinued. When very distressed he will rock, and must be reminded not to do so in public. He still lives with his parents as he seems very helpless in dealing with the mundane demands of life. In his spare time he plays the piano and catalogues his lock collection. Although Paul’s presentation has changed with age, at each age he has met the diagnostic criteria of qualitative impairments in social interaction and communication, with restricted and repetitive interests and activities. At three he was diagnosed as having autism, although his presentation as an adult would resemble the more recent diagnostic subtype of Asperger Syndrome. This term is used for individuals with autistic characteristics but not the accompanying delay in language and intellectual development. Speculation proliferates that famous people from the past, such as the philosopher Wittgenstein and the physicist Cavendish, may have had Asperger Syndrome. Hans Asperger himself believed that a little bit of autism was necessary to be an original thinker. He also said that autism might be considered an exaggerated form of male intelligence: up to ten times as many boys as girls have an ASD. Does this change in the diagnostic concept from narrow autism to the wider autism spectrum and Asperger syndrome explain the apparent explosion in the number of cases? Prevalence estimates for autism in the 1960s, when the first systematic studies were carried out, were around 4 per 10,000, while current estimates for the whole autism spectrum are around 60 per 10,000. This 15-fold increase has lead to fears of an epidemic. However, diagnostic criteria have changed dramatically over this period, and only a small proportion of the current spectrum would have met 60s criteria. Widened diagnostic criteria and increased awareness, diagnostic facilities and specialist provision may all account for the much higher prevalence of identified cases. Where were these cases in previous decades? Some were in mental hospitals, others were eccentrics, who were often bullied and sometimes respected, but who did not come to clinical attention. It remains unclear whether the real incidence of ASD has increased. If it has, this would have major implications for understanding the causes of autism. Autism is among the most heritable of developmental disorders: siblings of those with autism have a fifty times higher risk of ASD than the general population, and identical twins show a 60–90% concordance, compared to 0–5% in fraternal twins. If incidence has risen in recent years this might well point to environmental triggers for some susceptible cases. Parents are understandably anxious about such putative risk factors, which have included vaccines, mercury, viruses, allergens and gastric inflammation. Concern with dietary factors has led to widespread experimentation with different regimes with as yet unsubstantiated benefits. To date there is no good evidence for any environmental pathogen. It is likely that any environmental factors act by interacting with genetic vulnerabilities. An appropriate example may be phenylketonuria, in which a normal phenylalanine-rich diet poisons the developing brain when a specific genetic defect disturbs enzyme functions. Thus, genetically sensitive designs may be needed to isolate possible environmental triggers to ASD. An enormous research effort, in multicentre studies and international consortia, is being made to identify the genes that predispose individuals to ASD, with limited success to date. The most consistently replicated genetic linkage findings have implicated sites on chromosome 2q, 7q and 15q. Current opinion is that several genes, maybe ten or more, can predispose to ASD. This, as well as the likely heterogeneity within the autism spectrum, may explain why identifying genes for ASD has so far proved very difficult. The search for the brain basis of ASD has also been far from straightforward. Early expectations that the dramatic behavioural deficits of autism would be reflected in equally dramatic brain lesions were quickly disappointed. Instead, it has proved very difficult to identify anatomical abnormalities that are specific or universal to autism. Just as in the search for genes, extensive efforts have been made to find the basis of autism in terms of abnormal brain structure and histopathology. However, no coherent story has emerged. Under- or over-connectivity within the brain, rather than localized lesions, is now the most commonly assumed brain abnormality. This is a change from previous attempts which focussed on particular brain areas thought to be associated with social and with attentional deficits, for instance the amygdala or the cerebellum. The challenge that has not yet been met is to explain how developmental processes in the brain affect the development of cognitive abilities. One of the most exciting findings in recent years has been that increased brain size, both volume and weight, are strongly associated with ASD. In contrast, in other disorders with severe developmental delays decreased brain size is more common. Importantly, the brain increase is not present at birth, but arises during early childhood. The consensus is that the increase likely reflects a failure of the pruning that takes place in the normal reorganisation of brain connections during childhood. One hypothesis is that this failure largely concerns lateral and feedback connections rather than feedforward connections. This kind of failure might begin to explain the deficits in the initiation and control of novel behaviour, and in particular flexible social behaviour, in contrast to the integrity of well practiced routine behaviour and interactions with objects. Hampering both genetic and brain research into the causes of ASD is the heterogeneity amongst those currently diagnosed with this disorder. As yet it is entirely unclear what subgroups exist at the genetic, neurological or behavioural levels. How etiological subgroups map onto symptom presentations is completely unknown. Bridging biology and behaviour, theories at the cognitive level may be vital in making sense of heterogeneity in ASD. A recently emerging consensus is that no one cognitive deficit will explain all the key symptoms of autism. Instead, distinct accounts have emerged for the social and non-social features of ASD. Social accounts must explain a large variety of impairments in social communication. Some of the most puzzling of these impairments, seen in even intelligent people with ASD, include being locked into an egocentric stance, being unable to make friends, tending to interpret utterances literally and failing to notice when others are mocking them or taking advantage of them. An influential social theory, which is able to explain all of these features, places at the heart of autism an inability to think about thoughts, referred to as ‘theory of mind’. People with autism appear to be ‘mindblind’, while the rest of us effortlessly ‘read minds’ in the sense of recognising what others know, want and feel. Mindreading enables even young children to understand nonliteral language (“give me a hand”), to join others in pretend games, to affect other minds through lying or persuasion and communication generally. People with autism struggle with all of these, and fail simple tests where it is necessary to put one’s self in another’s shoes. In addition to the problems with understanding other people’s behaviour in terms of their mental states (mindblindness), people with ASD have difficulty reading emotions from the face and voice, and have problems recognising and remembering faces. One hypothesis to explain these problems is that they are the result of a chronic lack of preferential attention to social stimuli such as faces. However, the reason for this lack of social orientation remains unclear. While typically-developing neonates orient preferentially to faces, and children quickly become face experts, individuals with autism tend to look at other parts of the environment, or at irrelevant parts of the face. Beyond the social-communication impairments, the diagnosis of autism requires that there is striking rigidity, adherence to routine and rituals, narrow special interests or repetitive motor mannerisms. These features have been explained as resulting from a deficit in executive functions, which concern the high-level planning and organisation of non-routine behaviour. Problems in planning ahead and in flexible behaviour in novel situations have evoked parallels with symptoms of frontal lobe damage and frontal dementia. People with ASD do poorly on tests of executive function, although they may not differ from other developmentally delayed groups in this respect, especially early in childhood. However, it is undeniably true that persisting problems in organising their lives limit the adaptation and independence of even the most highly intelligent individuals on the autism spectrum. Alongside these social and non-social deficits, autism is notable for so-called ‘islets of ability’. Almost every individual with ASD is surprisingly good at something given their general level of ability: jigsaw-type tasks, rote memory for facts, or spotting small changes. At the extreme these isolated skills become ‘savant’ abilities in music, calculation or art (Figure 1). Such skills are at least ten times more common in ASD than in other groups with developmental delays, and the explanation of these assets presents a serious challenge to psychological theory. One current attempt to understand these skills is the ‘weak coherence’ account, which postulates a detail-focused cognitive style underlying ASD. While we typically recall the gist of something and forget details, people with ASD seem to attend to features rather than wholes. As a result, people with ASD can be remarkably good at spotting a detail in a picture, for example. A detail-focused processing style is generally agreed to be typical of at least a proportion of the ASD population. There are currently different interpretations of the causes of this information processing style: in some accounts this is attributed to a superior ability to process low level perceptual features; in others it is attributed to an inferior ability to integrate pieces of information in to a coherent whole. Both types of account agree that the balance between bottom-up and top-down processing streams appears to be anomalous in ASD, resulting in a strikingly uneven profile of abilities and difficulties. These cognitive accounts give a new tool to explore the brain basis of ASD, through functional imaging techniques. It is possible to identify which brain regions and pathways are active when ordinary people solve the sorts of tasks that are problematic for individuals with ASD. For example, functional imaging (fMRI) studies have identified components of a network subserving theory of mind, which include medial prefrontal cortex, temporal poles, and superior temporal sulcus (STS). The components of the ‘theory of mind’ network are more weakly activated and show reduced connectivity in fMRI studies of volunteers with ASD. Reduced connectivity has also been shown between language areas of the left hemisphere, and between areas involved in face processing in ASD. These findings fit with the structural imaging evidence of larger but anomalously connected brains. Abnormal functional connectivity might explain the co-occurrence of cognitive strengths and weaknesses in ASD. If mis-connection, rather than specific regional abnormality, is the main feature of the ASD brain, then perhaps the heterogeneity of symptoms is less surprising. Studies of eye gaze patterns have shown that people with ASD tend to look preferentially at the mouth area of the face rather than the eyes (Figure 2). While hypo-activation in the fusiform face area (FFA) has been observed when individuals with ASD are presented with pictures of faces, it has recently been noted that, when they are made to look at the eyes, activation in amygdala and FFA increased. Eye gaze is an important source in reading a person’s desires and intentions. Normally the posterior part of the right superior temporal sulcus (STS) shows heightened activation when we see another person gazing into an unexpected direction. This activation is reduced in ASD and suggests a disconnection between the perceptual processing of gaze and the social interpretation of its meaning. The STS region, which is implicated in the perception of biological motion and the attribution of mental states, has been found to be hypo-functional during resting state in children with ASD and also shows anatomical differences (Figure 3). This region is also involved in the processing of eye gaze.Figure 3Decreases in grey matter concentration in the superior temporal sulcus in children with ASD.Show full captionPlots show relative normalized grey matter concentration for each of the autistic and normally developing children. From Boddaert et al. (2004). Reprinted with kind permission from the authors.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Plots show relative normalized grey matter concentration for each of the autistic and normally developing children. From Boddaert et al. (2004). Reprinted with kind permission from the authors. A new target of theories trying to explain social deficits in autism is the ‘mirror neuron system’. This system contains neurons that fire equally when a specific goal-directed action is either performed by the self or observed to be performed by another. Mirror-neurons have been hypothesized to be implicated in the development of imitation, in emotional contagion, in the development of empathic responsiveness and theory of mind. The progress that is now possible by combining cognitive theories, functional and structural brain imaging in genetically sensitive designs, should yield some long awaited answers. In particular, it should become clear which features of autism have separate and independent causes, and which arise from one and the same origin in the brain. When the genes for susceptibility to ASD are identified, the diagnosis may be revolutionized. Then cases that are now considered to fall on the same spectrum may be revealed to belong to completely different etiological subgroups, while previously unidentified cases may be identified within genetic pedigrees. Once genes are isolated, then animal models will become truly useful for identifying the neurophysiological mechanisms and devising means of repairing and preventing neurological abnormalities. All of this progress, however, requires a real understanding of how autism unfolds through development, which are core elements and which merely secondary and avoidable knock-on effects. This long-term aim can only be achieved by integrating bottom-up approaches, such as genome-wide screening, and top-down research such as establishing the neural basis of hypothesised cognitive assets and deficits.