The study of autism as a distributed disorder

Past autism research has often been dedicated to tracing the causes of the disorder to a localized neurological abnormality, a single functional network, or a single cognitive-behavioral domain. In this review, I argue that autism is a "distributed disorder" on various levels of study (genetic, neuroanatomical, neurofunctional, behavioral). "Localizing" models are therefore not promising. The large array of potential genetic risk factors suggests that multiple (or all) emerging functional brain networks are affected during early development. This is supported by widespread growth abnormalities throughout the brain. Interactions during development between affected functional networks and atypical experiential effects (associated with atypical behavior) in children with autism further complicate the neurological bases of the disorder, resulting in an "exponentially distributed" profile. Promising approaches to a better characterization of neural endophenotypes in autism are provided by techniques investigating white matter and connectivity, such as MR spectroscopy, diffusion-tensor imaging (DTI), and functional connectivity MRI. According to a recent hypothesis, the autistic brain is generally characterized by "underconnectivity." However, not all findings are consistent with this view. The concepts and methodology of functional connectivity need to be refined and results need to be corroborated by anatomical studies (such as DTI tractography) before definitive conclusions can be drawn.     

The Implications of Brain Connectivity in the Neuropsychology of Autism

Autism is a neurodevelopmental disorder that has been associated with atypical brain functioning. Functional connectivity MRI (fcMRI) studies examining neural networks in autism have seen an exponential rise over the last decade. Such investigations have led to the characterization of autism as a distributed neural systems disorder. Studies have found widespread cortical underconnectivity, local overconnectivity, and mixed results suggesting disrupted brain connectivity as a potential neural signature of autism. In this review, we summarize the findings of previous fcMRI studies in autism with a detailed examination of their methodology, in order to better understand its potential and to delineate the pitfalls. We also address how a multimodal neuroimaging approach (incorporating different measures of brain connectivity) may help characterize the complex neurobiology of autism at a global level. Finally, we also address the potential of neuroimaging-based markers in assisting neuropsychological assessment of autism. The quest for a neural marker for autism is still ongoing, yet new findings suggest that aberrant brain connectivity may be a promising candidate.     

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.     

孤独症生命早期脑过度生长现象及启示

孤独症神经结构研究中近来一个重要的发现是,孤独症生命早期存在脑过度生长的现象。进一步的探查表明,孤独症个体脑的过度生长主要由脑白质的过度生长造成,并且脑的过度生长又主要体现于那些较晚成熟的高级脑区。这一研究成果有助于孤独症儿童的早期发现和诊断,也提示孤独症并不是由单一的局部神经缺陷造成,其存在着广泛分布式的神经发展障碍     

Neural processing of intentional biological motion in unaffected siblings of children with autism spectrum disorder: An fMRI study

Despite often showing behaviorally typical levels of social cognitive ability, unaffected siblings of children with autism spectrum disorder have been found to show similar functional and morphological deficits within brain regions associated with social processing. They have also been reported to show increased activation to biological motion in these same regions, such as the posterior superior temporal sulcus (pSTS), relative to both children with autism and control children. It has been suggested that this increased activation may represent a compensatory reorganization of these regions as a result of the highly heritable genetic influence of autism. However, the response patterns of unaffected siblings in the domain of action perception are unstudied, and the phenomenon of compensatory activation has not yet been replicated. The present study used functional magnetic resonance imaging to determine the neural responses to intentional biological actions in 22 siblings of children with autism and 22 matched controls. The presented actions were either congruent or incongruent with the actor’s emotional cue. Prior studies reported that typically developing children and adults, but not children with autism, show increased activation to incongruent actions (relative to congruent), within the pSTS and dorsolateral prefrontal cortex. We report that unaffected siblings did not show a compensatory response, or a preference for incongruent over congruent trials, in any brain region. Moreover, interaction analyses revealed a sub-region of the pSTS in which control children showed an incongruency preference to a significantly greater degree than siblings, which suggests a localized deficit in siblings. A sample of children with autism also did not show differential activation in the pSTS, providing further evidence that it is an area of selective disruption in children with autism and siblings. While reduced activation to both conditions was unique to the autism sample, lack of differentiation to incongruent and congruent intentional actions was common to both children with ASD and unaffected siblings.     

Young children with autism show atypical brain responses to fearful versus neutral facial expressions of emotion

Evidence suggests that autism is associated with impaired emotion perception, but it is unknown how early such impairments are evident. Furthermore, most studies that have assessed emotion perception in children with autism have required verbal responses, making results difficult to interpret. This study utilized high-density event-related potentials (ERPs) to investigate whether 3-4-year-old children with autism spectrum disorder (ASD) show differential brain activity to fear versus neutral facial expressions. It has been shown that normal infants as young as 7 months of age show differential brain responses to faces expressing different emotions. ERPs were recorded while children passively viewed photos of an unfamiliar woman posing a neutral and a prototypic fear expression. The sample consisted of 29 3-4-year-old children with ASD and 22 chronological age-matched children with typical development. Typically developing children exhibited a larger early negative component (N300) to the fear than to the neutral face. In contrast, children with ASD did not show the difference in amplitude of this early ERP component to the fear versus neutral face. For a later component, typically developing children exhibited a larger negative slow wave (NSW) to the fear than to the neutral face, whereas children with autism did not show a differential NSW to the two stimuli. In children with ASD, faster speed of early processing (i. e. N300 latency) of the fear face was associated with better performance on tasks assessing social attention (social orienting, joint attention and attention to distress). These data suggest that children with ASD, as young as 3 years of age, show a disordered pattern of neural responses to emotional stimuli.     

Neural processing of intentional biological motion in unaffected siblings of children with autism spectrum disorder: An fMRI study

Despite often showing behaviorally typical levels of social cognitive ability, unaffected siblings of children with autism spectrum disorder have been found to show similar functional and morphological deficits within brain regions associated with social processing. They have also been reported to show increased activation to biological motion in these same regions, such as the posterior superior temporal sulcus (pSTS), relative to both children with autism and control children. It has been suggested that this increased activation may represent a compensatory reorganization of these regions as a result of the highly heritable genetic influence of autism. However, the response patterns of unaffected siblings in the domain of action perception are unstudied, and the phenomenon of compensatory activation has not yet been replicated. The present study used functional magnetic resonance imaging to determine the neural responses to intentional biological actions in 22 siblings of children with autism and 22 matched controls. The presented actions were either congruent or incongruent with the actor’s emotional cue. Prior studies reported that typically developing children and adults, but not children with autism, show increased activation to incongruent actions (relative to congruent), within the pSTS and dorsolateral prefrontal cortex. We report that unaffected siblings did not show a compensatory response, or a preference for incongruent over congruent trials, in any brain region. Moreover, interaction analyses revealed a sub-region of the pSTS in which control children showed an incongruency preference to a significantly greater degree than siblings, which suggests a localized deficit in siblings. A sample of children with autism also did not show differential activation in the pSTS, providing further evidence that it is an area of selective disruption in children with autism and siblings. While reduced activation to both conditions was unique to the autism sample, lack of differentiation to incongruent and congruent intentional actions was common to both children with ASD and unaffected siblings.     

Early detection of core deficits in autism

The goal of this review of the research literature is to discuss approaches to the early detection of autism in infancy. Early detection would enable diagnoses to be made before 18 months of age rather than at 24-30 months, the age where diagnoses start to be made now. After summarizing the criteria for a deficit to be considered "core" to the disorder, the literature on research strategies used in early detection is examined. In order to guide the design of future studies, the review then turns to an overview of what is known about the processes of early social development in typically developing children that underlie the domains in which core deficits are manifested in young children with autism. The social domains covered in the review are those that show development in typically developing infants below 18 months of age: dyadic interaction and imitation; emotion discrimination; and attachment. The review concludes that all of these areas are worthy of investigation in young children, particularly those at higher risk of showing some of the core deficits of autism such as the infant siblings of children with autism.     

Stuttering: a dynamic motor control disorder

The purpose of this review is to determine what neural mechanisms may be dysfunctional in stuttering. Three sources of evidence are reviewed. First, studies of dynamic inter-relationships among brain regions during normal speech and in persons who stutter (PWS) suggest that the timing of neural activity in different regions may be abnormal in PWS. Second, the brain lesions associated with acquired stuttering are reviewed. These indicate that in a high percentage of cases, the primary speech and language regions are not affected but lesions involve other structures, such as the basal ganglia, which may modulate the primary speech and language regions. Third, to characterize the motor control disorder in stuttering, similarities and differences from focal dystonias such as spasmodic dysphonia (SD) and Tourette’s syndrome (TS) are reviewed. This review indicates that the central control abnormalities in stuttering are not due to disturbance in one particular brain region but rather a system dysfunction that interferes with rapid and dynamic speech processing for production.

Educational objectives: The reader will be able to describe: (1) the similarities and differences between stuttering and other speech motor control disorders, (2) which brain lesions are most likely to produce acquired stuttering in adults, and (3) what type of brain abnormality most likely underlies stuttering.     

Autism: cognitive deficit or cognitive style?

Autism is a developmental disorder characterized by impaired social and communicative development, and restricted interests and activities. This article will argue that we can discover more about developmental disorders such as autism through demonstrations of task success than through examples of task failure. Even in exploring and explaining what people with autism find difficult, such as social interaction, demonstration of competence on contrasting tasks has been crucial to defining the nature of the specific deficit. Deficit accounts of autism cannot explain, however, the assets seen in this disorder; for example, savant skills in maths, music and drawing, and islets of ability in visuospatial tests and rote memory. An alternative account, reviewed here, suggests that autism is characterized by a cognitive style biased towards local rather than global information processing – termed ‘weak central coherence’. Evidence that weak coherence might also characterize the relatives of people with autism, and form part of the extended phenotype of this largely genetic disorder, is discussed. This review concludes by considering some outstanding questions concerning the specific cognitive mechanism for coherence and the neural basis of individual differences in this aspect of information processing.     

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。     

视听跨通道信息的整合与冲突控制

多通道信息交互是指来自某个感觉通道的信息与另一感觉通道的信息相互作用、相互影响的一系列加工过程。主要包括两个方面：一是不同感觉通道的输入如何整合；二是跨通道信息的冲突控制。本文综述了视听跨通道信息整合与冲突控制的行为心理机制和神经机制，探讨了注意对视听信息整合与冲突控制的影响。未来需探究视听跨通道信息加工的脑网络机制，考察特殊群体的跨通道整合和冲突控制以帮助揭示其认知和社会功能障碍的机制。     

自闭症谱系障碍个体的注意解离

注意解离是注意定向网络的重要组成部分, 指在注意转移过程中对原来刺激进行注意分离的过程。自闭症个体注意解离的早期受损会直接影响其它重要功能的发展, 尤其是唤醒调节和共同注意发展。采用间隙重叠范式的研究发现, 自闭症个体注意解离能力是否异常还存在争议, 被试年龄及取样、测量指标和刺激特征可能是影响的因素; 其神经机制可能涉及额叶、顶叶、小脑和胼胝体等脑区。未来应从脑机制研究入手, 综合考虑被试特征、研究方法和刺激特征对注意解离结果的影响, 明确其在自闭症早期预测和识别中的作用。     

Developmental regression in autism spectrum disorders

The occurrence of developmental regression in autism is one of the more puzzling features of this disorder. Although several studies have documented the validity of parental reports of regression using home videos, accumulating data suggest that most children who demonstrate regression also demonstrated previous, subtle, developmental differences. Counter to clinical intuition, the earlier development of social, language, and attachment behaviors followed by regression does not seem to support later recovery of skills or better developmental outcomes compared to children who never had speech or typical social responsivity. In fact, this regressive group may have somewhat greater developmental impairment than the nonregressive group, though the two groups do not appear to present different behavioral phenotypes. Although autism is not the only condition in which regression occurs, it appears to be the most frequent condition. Other disorders that demonstrate an early regression with no known etiology include total blindness from birth and childhood disintegrative disorder, both of which demonstrate behavioral relations to autism. In addition, two biological conditions with known etiologies also involve regression with some behaviors resembling autism behavioral phenotype: Rett syndrome (a genetic disorder; see Glaze, this issue) and Landau-Kleffner syndrome (see McVicar and Shinnar, this issue), which involves a seizure disorder.     

From early markers to neuro-developmental mechanisms of autism

A fast growing field, the study of infants at risk because of having an older sibling with autism (i.e. infant sibs) aims to identify the earliest signs of this disorder, which would allow for earlier diagnosis and intervention. More importantly, we argue, these studies offer the opportunity to validate existing neuro-developmental models of autism against experimental evidence. Although autism is mainly seen as a disorder of social interaction and communication, emerging early markers do not exclusively reflect impairments of the “social brain”. Evidence for atypical development of sensory and attentional systems highlight the need to move away from localized deficits to models suggesting brain-wide involvement in autism pathology. We discuss the implications infant sibs findings have for future work into the biology of autism and the development of interventions.     

Neurobiological models of attention-deficit/hyperactivity disorder: a brief review of the empirical evidence

Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric disorder characterized by inattention, impulsivity, and overactivity that begins in childhood. While considerable research has focused on the neurobiological substrates of this disorder, the specific nature of the brain dysfunction in ADHD has remained elusive. However, early data from pharmacological treatment studies, as well as from basic research in animals and humans, initially led several investigators to develop neurobiological models of ADHD. These models of ADHD and more recent evidence from neuropsychological, neuroimaging, neurochemical, and genetic research are briefly reviewed. While not completely consistent, the empirical data suggest that dysfunction in prefrontal-striatal neural circuits, as well as in brain stem catecholamine systems that innervate these circuits, may underlie the executive function deficits in ADHD.     

Neural correlates underlying true and false associative memories

Despite the fact that associative memory studies produce a large number of false memories, neuroimaging analyses utilizing this paradigm typically focus only on neural activity mediating successful retrieval. The current study sought to expand on this prior research by examining the neural basis of both true and false associative memories. Though associative false memories are substantially different than those found in semantic or perceptual false memory paradigms, results suggest that associative false memories are mediated by similar neural mechanisms. Specifically, we found increased frontal activity that likely represents enhanced monitoring and evaluation compared to that needed for true memories and correct rejections. Results also indicated that true, and not false associative memories, are mediated by neural activity in the MTL, specifically the hippocampus. Finally, while activity in early visual cortex distinguished true from false memories, a lack of neural differences between hits and correct rejections failed to support previous findings suggesting that activity in early visual cortex represents sensory reactivation of encoding-related processing.     

fNIRS在自闭症脑功能研究中的应用与展望

社会交往能力是人类生存的基本技能。社交能力的缺失会导致严重的行为障碍和精神疾病,如自闭症。由于自闭症儿童的特殊性,绝大多数的自闭症脑成像研究多集中在年龄较大的高功能自闭症儿童在静息态或简单的任务态下的脑激活模式或功能连接状态。自闭症的核心症状—社会交往障碍和语言交流障碍却较少有研究触及。近年来,近红外光学脑功能成像技术的发展为我们在真实的交流和互动中研究自闭症儿童的神经病理机制提供了新的工具和机遇。     

Toward a developmental neurobiology of autism

Autism is a complex, behaviorally defined, developmental brain disorder with an estimated prevalence of 1 in 1,000. It is now clear that autism is not a disease, but a syndrome with a strong genetic component. The etiology of autism is poorly defined both at the cellular and the molecular levels. Based on the fact that seizure activity is frequently associated with autism and that abnormal evoked potentials have been observed in autistic individuals in response to tasks that require attention, several investigators have recently proposed that autism might be caused by an imbalance between excitation and inhibition in key neural systems including the cortex. Despite considerable ongoing effort toward the identification of chromosome regions affected in autism and the characterization of many potential gene candidates, only a few genes have been reproducibly shown to display specific mutations that segregate with autism, likely because of the complex polygenic nature of this syndrome. Among those, several candidate genes have been shown to control the early patterning and/or the late synaptic maturation of specific neuronal subpopulations controlling the balance between excitation and inhibition in the developing cortex and cerebellum. In the present article, we review our current understanding of the developmental mechanisms patterning the balance between excitation and inhibition in the context of the neurobiology of autism.     

Parent Prediction of Autism Spectrum Disorder in Infants at Risk: A Follow-up Study

Later-born siblings of children with autism spectrum disorder are considered at biological risk for autism spectrum disorder and the broader phenotype. Early screening may detect first signs of autism spectrum disorder and expedite diagnosis and early intervention. In this follow-up study, we re-examine a validated second-degree autism spectrum disorder screener for children at biological risk of autism spectrum disorder, the parent observation of early markers scale. Using available follow-up information up to age 13 years, 110 children (the original 108 infants plus 2 infants recruited after the completion of the original study) were divided into three groups: diagnosed group (n?=?13), lost diagnosis group (n?=?5), and undiagnosed group (n?=?92). The parent observation of early markers scale continued to show acceptable predictive validity. The parent observation of early markers scale total scores and mean number of elevated items were significantly higher in the diagnosed group than the undiagnosed group. The lost-diagnosis group did not differ from the undiagnosed group on parent observation of early markers scale total scores and elevated items at any age, but the lost-diagnosis group had significantly lower total scores, and number of elevated items than the diagnosed group starting at 18 months. Both autism spectrum disorder core and subsidiary behaviors differentiated the diagnosed and undiagnosed groups from 9 to 36 months of age. We hereby provide further evidence that the parent observation of early markers scale may serve as a low-cost early screener for autism spectrum disorder in at-risk children and pinpoint specific developmental ,and behavioral problems that may be amenable to very early intervention.