Neurobiological correlates of autism: a review of recent research.

This review paper integrates recent structural and functional imaging, postmortem, animal lesion, and neurochemical research about the pathophysiology of autism. An understanding of the neurobiological correlates of autism is becoming increasingly important as more children are diagnosed with the condition and funding for well-targeted interventions increases. Converging evidence suggests that autism involves abnormalities in brain volume, neurotransmitter systems, and neuronal growth. In addition, evidence firmly links autism with abnormalities in the cerebellum, the medial temporal lobe, and the frontal lobe. Potential implications of these findings and suggestions for future research are reviewed.     

Autism and the experience of a perceptual object

Sewards and Sewards (2002) argue that while computations necessary for object recognition occur throughout the ventral visual stream, object recognition awareness involves the anterior temporal lobe and the medial orbital prefrontal cortex. The present paper suggests, however, that the medial orbital prefrontal cortex has a unique contribution, namely that of producing a basic experience of a perceptual object. It is further argued that the mechanisms that produce this experience also result in making the object more important than its subparts and features. Finally, it is argued that a reduction in this importance may account for some perceptual difficulties in high-functioning autism. This view is consistent with evidence for early selective abnormalities in other systems involving the medial prefrontal cortex in autism.     

自闭症儿童的心理理论与中心信息整合的关系探讨

自闭症儿童的心理理论一直是儿童心理理论研究的重要领域,自闭症儿童身上心理理论缺失这一领域特殊性的加工缺损与弱的中心信息整合这一领域一般性的加工异常之问的关系研究逐渐受到了广泛关注。在阐述自闭症领域的心理理论研究,并介绍弱的中心信息整合理论的基本观点和实验证据之后,在此探讨了两者之间的关系,包括两者相互独立的观点、相互关联的观点以及其他的不同观点,并对今后的研究方向做出了展望。     

Epileptic encephalopathies and their relationship to developmental disorders: do spikes cause autism?

Epileptic encephalopathies are progressive clinical and electroencephalographic syndromes where deterioration is thought to be caused by frequent seizures and abundant EEG epileptiform activity. Seizures occur in approximately 10-15% of children with pervasive developmental disorders (PDD) and 8-10% have epileptiform EEG abnormalities without seizures. Thirty percent of children with PDD have regression of social behavior and language at 2-3 years of age. Some authors speculate that the regression is caused by epileptiform activity even in the absence of overt clinical seizures ("autism with epileptic regression") and suggest that elimination of the epileptiform activity, either medically or surgically, should lead to improvement in behavior. This review examines the data showing that interictal epileptiform discharges are associated with transient clinical dysfunction and discusses the implications of these observations for autistic behavioral abnormalities. The results of resective surgery, vagal nerve stimulation, and multiple subpial transaction on children with autism and epileptiform EEG abnormalities are also discussed. I conclude that there is no evidence that interictal discharges per se cause (or contribute to) the complex behavioral phenotype of autism. There is no justification to support the use of anticonvulsant medication or surgery in children with PDD without seizures; that is, there is no evidence that treatment to eliminate EEG spikes will have a therapeutic effect on the behavioral abnormalities of PDD and autism.     

Altered face scanning and impaired recognition of biological motion in a 15-month-old infant with autism

Mounting clinical evidence suggests that abnormalities of social engagement in children with autism are present even during infancy. However, direct experimental documentation of these abnormalities is still limited. In this case report of a 15-month-old infant with autism, we measured visual fixation patterns to both naturalistic and ambiguous social stimuli: video scenes of a caregiver and point-light animations of human action. Results suggested that viewing patterns of the child with autism were driven by the physical contingencies of the stimuli rather than by their social context. If corroborated in larger studies, this observation would advance the hypothesis that mechanisms of social development which rely on preferential engagement with socially contingent conspecifics - and which emerge in the very first weeks of life in typical infants - are developmentally derailed in children with autism.     

Serotonin in autism and pediatric epilepsies

Serotonergic abnormalities have been reported in both autism and epilepsy. This association may provide insights into underlying mechanisms of these disorders because serotonin plays an important neurotrophic role during brain development--and there is evidence for abnormal cortical development in both autism and some forms of epilepsy. This review explores the hypothesis that an early disturbance in the serotonin system affects cortical development and the development of thalamocortical innervation, and is a potential mechanism, common to autism and pediatric epilepsies associated with cortical dysplasia. An argument is made that cortical malformation leads to abnormalities of thalamocortical connectivity, and that serotonin plays a critical role in this process. Finally, a role for altered metabolism of the serotonin precursur, tryptophan, in both epilepsy and autism is discussed.     

Executive dysfunction in autism

"Executive function" is an umbrella term for functions such as planning, working memory, impulse control, inhibition and mental flexibility, as well as for the initiation and monitoring of action. The primacy of executive dysfunction in autism is a topic of much debate, as are recent attempts to examine subtypes of executive function within autism and other neurodevelopmental disorders that are considered to implicate frontal lobe function. This article will review cognitive behavioural studies of planning, mental flexibility and inhibition in autism. It is concluded that more detailed research is needed to fractionate the executive system in autism by assessing a wide range of executive functions as well as their neuroanatomical correlates in the same individuals across the lifespan.     

自闭症谱系障碍的生物基础

自闭症谱系障碍是一组发病于生命早期, 由一系列生理、心理因素引起的神经发育障碍。遗传、脑神经结构、营养素等是自闭症谱系障碍的生物基础的重要来源。个体在孕育早期形成的大脑和机体异常可能是导致自闭症谱系障碍的关键。这种异常在出生后的发育中具体作用于神经活动、脑发育、免疫系统等生理途径。研究者们今后可以尝试横跨不同自闭症谱系障碍亚型、年龄和发育阶段, 开展横向与纵向相结合的大范围研究, 以进一步明确自闭症谱系障碍的生物基础。     

Genetics of autism spectrum disorders

Characterized by a combination of abnormalities in language, social cognition and mental flexibility, autism is not a single disorder but a neurodevelopmental syndrome commonly referred to as autism spectrum disorder (ASD). Several dozen ASD susceptibility genes have been identified in the past decade, collectively accounting for 10-20% of ASD cases. These findings, although demonstrating that ASD is etiologically heterogeneous, provide important clues about its pathophysiology. Diverse genetic and genomic approaches provide evidence converging on disruption of key biological pathways, many of which are also implicated in other allied neurodevelopmental disorders. Knowing the genes involved in ASD provides us with a crucial tool to probe both the specificity of ASD and the shared neurobiological and cognitive features across what are considered clinically distinct disorders, with the goal of linking gene to brain circuits to cognitive function.     

Memory in autistic spectrum disorder

Behavioral evidence concerning memory in forms of high-functioning autism (HFA) and in moderately low-functioning autism (M-LFA) is reviewed and compared. Findings on M-LFA are sparse. However, it is provisionally concluded that memory profiles in HFA and M-LFA (relative to ability-matched controls) are similar but that declarative memory impairments are more extensive in M-LFA than in HFA. Specifically, both groups have diminished memory for emotion- or person-related stimuli. Regarding memory for nonsocial stimuli, both groups probably have mental-age-appropriate nondeclarative memory, and within declarative memory, both groups have mental-age-appropriate immediate free recall of within-span or supraspan lists of unrelated items, as well as cued recall and paired associate learning. By contrast, recognition is largely unimpaired in HFA but moderately impaired in M-LFA, and free recall of meaningful or structured stimuli is moderately impaired in HFA but more severely impaired in M-LFA. Theoretical explanations of data on declarative memory in HFA identify problems in the integrative processing, or the consolidation and storage, of complex stimuli or a specific problem of recollection. Proposed neural substrates include the following: disconnectivity of primary sensory and association areas; dysfunctions of medial prefrontal cortex, hippocampus, or posterior parietal lobe; or combinations of these associated with neural disconnectivity. Hypothetically, perirhinal dysfunction might explain the more extensive declarative memory impairments in M-LFA. Foreseeable consequences of uneven memory abilities in HFA and M-LFA are outlined, including possible effects on language and learning in M-LFA. Finally, priorities for future research are identified, highlighting the urgent need for research on memory in lower functioning individuals.     

A qualitative examination of the work–family interface: Parents of children with autism spectrum disorder

Within the work–family literature little is known about the work–family challenges and opportunities faced by families that have one or more children with autism spectrum disorder. However, it has been consistently demonstrated that parents of children with autism spectrum disorder are at a higher risk of experiencing a host of negative outcomes. Using a qualitative design, within grounded theory, the present study sheds light on the needs, experiences, and challenges that parents of children with autism spectrum disorder face and also offers insight into ways to expand the scope of work–family research in this area. The present research provides evidence of how the family domain can greatly impact experiences and decisions made in the work domain for families with special needs. The present research adds to the small but growing literature examining the interplay between home and work life for families with special needs and demonstrates that this is an important research domain in need of additional conceptual and empirical consideration.     

The neurocognitive basis of autism

The cognitive study of the underlying mental abnormalities in autism has advanced rapidly, while the biological study of the underlying brain abnormalities and of putative genetic mechanisms is lagging somewhat behind. However, the linking of cognitive and biological studies has become a real possibility. Developmental cognitive neuroscience has transformed our understanding of this enigmatic disorder, which was once misguidedly thought to be caused by maternal rejection. The hypothesis of a specific theory of mind deficit was a crucial step in this process. It explains the puzzle of the characteristic social and communication impairments of autism and allows for the fact that they can coexist with good general abilities. This hypothesis has been widely accepted and a start has been made at pinpointing the brain basis of theory of mind. The non-social impairments of autism have now become a major focus for cognitive research. One theory proposes dysfunction in executive processes, in an attempt to explain repetitive behaviour and inflexibility. Another theory proposes weak information integration, in an attempt to explain narrow interests and special talents. Autism research has thus stimulated ideas on important mind-brain systems that may be dedicated to the development of social awareness, executive functions and integrative processing.     

A qualitative examination of the work–family interface: Parents of children with autism spectrum disorder

Within the work–family literature little is known about the work–family challenges and opportunities faced by families that have one or more children with autism spectrum disorder. However, it has been consistently demonstrated that parents of children with autism spectrum disorder are at a higher risk of experiencing a host of negative outcomes. Using a qualitative design, within grounded theory, the present study sheds light on the needs, experiences, and challenges that parents of children with autism spectrum disorder face and also offers insight into ways to expand the scope of work–family research in this area. The present research provides evidence of how the family domain can greatly impact experiences and decisions made in the work domain for families with special needs. The present research adds to the small but growing literature examining the interplay between home and work life for families with special needs and demonstrates that this is an important research domain in need of additional conceptual and empirical consideration.     

Brain development in autism: early overgrowth followed by premature arrest of growth

Due to the relatively late age of clinical diagnosis of autism, the early brain pathology of children with autism has remained largely unstudied. The increased use of retrospective measures such as head circumference, along with a surge of MRI studies of toddlers with autism, have opened a whole new area of research and discovery. Recent studies have now shown that abnormal brain overgrowth occurs during the first 2 years of life in children with autism. By 2-4 years of age, the most deviant overgrowth is in cerebral, cerebellar, and limbic structures that underlie higher-order cognitive, social, emotional, and language functions. Excessive growth is followed by abnormally slow or arrested growth. Deviant brain growth in autism occurs at the very time when the formation of cerebral circuitry is at its most exuberant and vulnerable stage, and it may signal disruption of this process of circuit formation. The resulting aberrant connectivity and dysfunction may lead to the development of autistic behaviors. To discover the causes, neural substrates, early-warning signs and effective treatments of autism, future research should focus on elucidating the neurobiological defects that underlie brain growth abnormalities in autism that appear during these critical first years of life.     

Functional neuroimaging of autistic disorders

Functional neuroimaging methods hold promise for elucidating the neurobiology of autistic disorders, yet they present difficult practical and scientific challenges when applied to these complex and heterogeneous syndromes. Single-state studies of brain metabolism and blood flow thus far have failed to yield consistent findings, but suggest considerable variability in regional patterns of cerebral synaptic activity. Patients with idiopathic autism are less likely to show abnormalities than are patients with comorbid illness or epilepsy. Activation studies have begun to suggest alterations in brain organization for language and cognition. Neurotransmitter studies using positron emission tomography (PET) suggest abnormalities of serotonergic and dopaminergic function. Studies using magnetic resonance spectroscopy (MRS) have begun to document metabolic deficits in the frontal cortex and cerebellum. A single study using magnetoencephalography suggests a high incidence of epileptiform activity in children with autistic regression. Research needs include well-controlled developmental studies, particularly of young subjects and relatively homogeneous subgroups, which balance scientific rigor with ethical constraints. Investigations of the serotonergic and dopaminergic systems, limbic-based memory and emotional systems, and the role of epileptiform activity in autism represent priorities for future research.     

Genetic Studies of Autism: From the 1970s into the Millennium

Reviewers in the 1960s and early 1970s were skeptical about any substantial role for genetic factors in the etiology of autism. A realization that the 2% rate of autism in siblings (as estimated at that time) was far above the general population base rate, and that this suggested a possible high genetic liability, led to the first small-scale twin study of autism. The replicated evidence from both twin and family studies undertaken in the 1970s and 1980s indicated both strong genetic influences and the likelihood that they applied to a phenotype that was much broader than the traditional diagnostic category of autism. Medical and chromosomal findings also indicated genetic heterogeneity. Advances in molecular genetics led to genome-wide scans of affected relative pair samples with a positive log of the odds to base 10 score for a location on chromosome 7. The major remaining research challenges and the likely clinical benefits that should derive from genetic research are considered in relation to both current knowledge and that anticipated to emerge from research over the next decade.     

Auditory abnormalities in autism: toward functional distinctions among findings

Recently, findings on a wide range of auditory abnormalities among individuals with autism have been reported. To date, functional distinctions among these varied findings are poorly established. Such distinctions should be of interest to clinicians and researchers alike given their potential therapeutic and experimental applications. This review suggests three general trends among these findings as a starting point for future analyses. First, studies of auditory perception of linguistic and social auditory stimuli among individuals with autism generally have found impaired perception versus normal controls. Such findings may correlate with impaired language and communication skills and social isolation observed among individuals with autism. Second, studies of auditory perception of pitch and music among individuals with autism generally have found enhanced perception versus normal controls. These findings may correlate with the restrictive and highly focused behaviors observed among individuals with autism. Third, findings on the auditory perception of non-linguistic, non-musical stimuli among autism patients resist any generalized conclusions. Ultimately, as some researchers have already suggested, the distinction between impaired global processing and enhanced local processing may prove useful in making sense of apparently discordant findings on auditory abnormalities among individuals with autism.     

Neuroepileptic correlates of autistic symptomatology in tuberous sclerosis

Tuberous sclerosis is a genetic condition that is strongly associated with the development of an autism spectrum disorder. However, there is marked variability in expression, and only a subset of children with tuberous sclerosis develop autism spectrum disorder. Clarification of the mechanisms that underlie the association and variability in expression will potentially throw light on the biological processes involved in the etiology of idiopathic forms of autism spectrum disorder. Current evidence indicates that the likelihood of a child with tuberous sclerosis developing an autism spectrum disorder is greater if the child has a mutation in the TSC2 gene, although autism can and does develop in children with TSC1 mutations. The likelihood is also greater if the child has early-onset infantile spasms that are difficult to control, especially if there is an epileptiform focus in the temporal lobes. The emerging evidence is consistent with the notion that early onset electrophysiological disturbances within the temporal lobes (and perhaps other locations) has a deleterious effect on the development and establishment of key social cognitive representations concerned with processing social information, perhaps especially from faces. However, alternative mechanisms to account for the findings cannot yet be ruled out. Future research will have to employ prospective longitudinal designs and treatment trials to clarify the processes involved.     

A systems neuroscience approach to autism: biological,cognitive, and clinical perspectives

Autism is a behaviorally defined disorder characterized by a broad constellation of symptoms. Numerous studies directed to the biological substrate demonstrate clear effects of neurodevelopmental differences that will likely point to the etiology, course, and long-term outcomes of the disorder. Consistently replicated research on the neural underpinnings of autism is reviewed. In general, results suggest several main conclusions: First, autism is a heterogeneous disorder and is likely to have multiple possible etiologies; second, structural brain studies have indicated a variety of diffuse anatomical differences, reflective of an early developmental change in the growth or pruning of neural tissue, rather than localized lesions; similarly, neurochemical studies suggest early, neuromodulatory discrepancies rather than gross or localized abnormalities; and finally, there are a number of limitations on studies of brain activity that to date preclude definitive answers to questions of how the brain functions differently in autism. The large number of active research programs investigating the cognitive neuroscience of autism spectrum disorders, in combination with the exciting development of new methodologies and tools in this area, indicates the drama and excitement of work in this area.