Autism is characterized by disruption in multiple dimensions of perception, emotion, language and cognition. Many hypotheses for the underlying neurophysiological basis have been proposed. Among these is the excitation/inhibition (E/I) imbalance hypothesis, which states that levels of cortical excitation and inhibition are disrupted in autism. We tested this theory in the visual system, because vision is one of the better understood systems in neuroscience, and because the E/I imbalance theory has been proposed to explain hypersensitivity to sensory stimuli in autism. We conducted two experiments on binocular rivalry, a well-studied psychophysical phenomenon that depends critically on excitation and inhibition levels in cortex. Using a computational model, we made specific predictions about how imbalances in excitation and inhibition levels would affect perception of two aspects of binocular rivalry: mixed perception (Experiment 1) and traveling waves (Experiment 2). We found no significant differences in either of these phenomena between high-functioning adults with autism and controls, and no evidence for a relationship between these measurements and the severity of autism. These results do not conclusively rule out an excitation/inhibition imbalance in visual system of those with autism, but they suggest that such an imbalance, if it exists, is likely to be small in magnitude.
binocular rivalry; psychophysics; computational model; autism
Deficits or atypicalities in attention have been reported in individuals with autism spectrum disorder (ASD), yet no consensus on the nature of these deficits has emerged. We conducted three experiments that paired a peripheral precue with a covert discrimination task, using protocols for which the effects of covert exogenous spatial attention on early vision have been well established in typically developing populations. Experiment 1 assessed changes in contrast sensitivity, using orientation discrimination of a contrast-defined grating; Experiment 2 evaluated the reduction of crowding in the visual periphery, using discrimination of a letter-like figure with flanking stimuli at variable distances; and Experiment 3 assessed improvements in visual search, using discrimination of the same letter-like figure with a variable number of distractor elements. In all three experiments, we found that exogenous attention modulated visual discriminability in a group of high-functioning adults with ASD and that it did so in the same way and to the same extent as in a matched control group. We found no evidence to support the hypothesis that deficits in exogenous spatial attention underlie the emergence of core ASD symptomatology.
covert attention; exogenous attention; crowding; visual search; contrast sensitivity; adults; autism; ASD
Current theories concerning the cause of autism spectrum disorders (ASDs) have converged on the concept of abnormal development of brain connectivity. This concept is supported by accumulating evidence from functional imaging, diffusion tensor imaging, and high definition fiber tracking studies which suggest altered microstructure in the axonal tracts connecting cortical areas may underly many of the cognitive manifestations of ASD. Additionally, large-scale genomic studies implicate numerous gene candidates known or suspected to mediate neuritic outgrowth and axonal guidance in fetal and perinatal life. Neuropathological observations in postmortem ASD brain samples further support this model and include subtle disturbances of cortical lamination and subcortical axonal morphology. Of note is the relatively common finding of poor differentiation of the gray–white junction associated with an excess superficial white matter or “interstitial” neurons (INs). INs are thought to be remnants of the fetal subplate, a transient structure which plays a key role in the guidance and morphogenesis of thalamocortical and cortico-cortical connections and the organization of cortical columnar architecture. While not discounting the importance of synaptic dysfunction in the etiology of ASD, this paper will briefly review the cortical abnormalities and genetic evidence supporting a model of dysregulated axonal growth and guidance as key developmental processes underlying the clinical manifestations of ASD.
autism spectrum disorders; connectivity; neuritic outgrowth; axonal guidance; subplate
Autism has been described as a disorder of general neural processing, but the particular processing characteristics that might be abnormal in autism have mostly remained obscure. Here, we present evidence of one such characteristic: poor evoked response reliability. We compared cortical response amplitude and reliability (consistency across trials) in visual, auditory, and somatosensory cortices of high-functioning individuals with autism and controls. Mean response amplitudes were statistically indistinguishable across groups, yet trial-by-trial response reliability was significantly weaker in autism, yielding smaller signal-to-noise ratios in all sensory systems. Response reliability differences were evident only in evoked cortical responses and not in ongoing resting-state activity. These findings reveal that abnormally unreliable cortical responses, even to elementary non-social sensory stimuli, may represent a fundamental physiological alteration of neural processing in autism. The results motivate a critical expansion of autism research to determine whether (and how) basic neural processing properties such as reliability, plasticity, and adaptation/habituation are altered in autism.
Autism; Autism spectrum disorders; fMRI; response variability; response reliability; sensory systems; visual; auditory; somatosensory; noise; neural reliability; neural noise
Autism spectrum disorders are defined behaviorally by the Diagnostic and Statistical Manual (DSM) IV-TR based on abnormal development in social interaction and communication and restricted, repetitive, and stereotyped patterns of behaviors and interests that are evident before the age of 3. After decades of debate, research has demonstrated that the distinctions among autism, Asperger disorder, and pervasive developmental disorder not otherwise specified are neither clinically reliable nor based on valid neurobiological or genetic differences. The fifth edition of the DSM therefore proposes to collapse all of the clinical syndromes under the single diagnosis of autism spectrum disorder (ASD).
There is a growing amount of evidence suggesting that individuals with autism have difficulty with categorization. One basic cognitive ability that may underlie this difficulty is the ability to abstract a prototype. The current study examined prototype and category formation with dot patterns in high-functioning adults with autism and matched controls. Individuals with autism were found to have difficulty forming prototypes and categories of dot patterns. The eye-tracking data did not reveal any between group differences in attention to the dot patterns. However, relationships between performance and intelligence in the autism group suggest possible processing differences between the groups. Results are consistent with previous studies that have found deficits in prototype formation and extend these deficits to dot patterns.
categorization; prototype; autism; cognition; eye-tracking; implicit
It has been established that typically developing individuals have a bias to attend to facial information in the left visual field (LVF) more than in the right visual field (RVF). This bias is thought to arise from the right hemisphere’s advantage for processing facial information, with evidence suggesting it to be driven by the configural demands of face processing. Considering research showing that individuals with autism have impaired face processing abilities, with marked deficits in configural processing, it was hypothesized that they would not demonstrate a LVF bias for faces. Eye-tracking technology was used to show that, individuals with autism were not spontaneously biased to facial information in the LVF, in contrast to a control group, while discriminating facial gender.
Autism; face processing; left visual field (LVF) bias
Varied presentations of emotion dysregulation in autism complicate diagnostic decision making and may lead to inaccurate psychiatric diagnoses or delayed autism diagnosis for high-functioning children. This pilot study aimed to determine the concordance between prior psychiatric diagnoses and the results of an autism-specific psychiatric interview in adolescents with high-functioning autism.
Participants included 35, predominantly Caucasian and male, verbal 10 – 17 year olds with a confirmed autism spectrum disorder and without intellectual disability. The average age of autism spectrum diagnosis was 11-years-old. Lifetime psychiatric diagnoses were established via the Autism Comorbidity Interview, developed to identify co-morbid conditions within the context of autism. Autism Comorbidity Interview results were compared to parent report of prior community psychiatric diagnoses.
Approximately 60% of prior psychiatric diagnoses were not supported on the Autism Comorbidity Interview; the lowest diagnostic concordance was for prior bipolar disorder and obsessive-compulsive disorder diagnoses. While 51% of children met Autism Comorbidity Interview criteria for at least one psychiatric disorder, rates of prior diagnoses were much higher, with 77% having at least one prior psychiatric diagnosis and 60% having two or more.
Although many participants met criteria for comorbid psychiatric disorders, the majority of previous psychiatric diagnoses were not supported when autism-related manifestations were systematically taken into account. These findings require replication and may not generalize to lower-functioning and earlier diagnosed children with ASD. Results emphasize the importance of increasing awareness of the manifestations of high-functioning autism in order to improve accuracy of diagnosis and appropriateness of interventions.
Autism; Asperger’s Disorder; Psychiatric Comorbidity; Diagnosis
Despite extensive reports of sensory symptoms in autism, there is little empirical support for their neurological basis. Sixty individuals with high-functioning autism and 61 matched typical comparison participants were administered a sensory questionnaire and standardized neuropsychological tests of elementary and higher cortical sensory perception. Thirty-two per cent of participants with autism endorsed more sensory sensitivity items than any of the participants in the comparison group. On the sensory perceptual exam, both groups made few errors on elementary sensory perception items. Controls made few errors on higher cortical sensory perception items, but 30% of the participants with autism made high numbers of errors, though there was no evidence of the neglect syndrome. There was little correlation between the sensory sensitivities and the sensory perceptual deficits, likely due to the low correspondence between the measures. These results support the common occurrence of disturbances in sensory experiences in high functioning individuals with autism based on first person report, and the presence of neurological abnormalities in higher cortical sensory perception.
autism; sensory sensitivities; sensory perception; sensory neglect
This functional magnetic resonance imaging study compared the neural activation patterns of 18 high-functioning individuals with autism and 18 IQ-matched neurotypical control participants as they learned to perform a social judgment task. Participants learned to identify liars among pairs of computer-animated avatars uttering the same sentence but with different facial and vocal expressions, namely those that have previously been associated with lying versus truth-telling. Despite showing a behavioral learning effect similar to the control group, the autism group did not show the same pattern of decreased activation in cortical association areas as they learned the task. Furthermore, the autism group showed a significantly smaller increase in interregion synchronization of activation (functional connectivity) with learning than did the control group. Finally, the autism group had decreased structural connectivity as measured by corpus callosum size, and this measure was reliably related to functional connectivity measures. The findings suggest that cortical underconnectivity in autism may constrain the ability of the brain to rapidly adapt during learning.
autism; functional connectivity; functional magnetic resonance imaging; learning; social cognition
To investigate the functional integrity of cerebellar and frontal system in autism using oculomotor paradigms.
Cerebellar and neocortical systems models of autism have been proposed. Courchesne and colleagues have argued that cognitive deficits such as shifting attention disturbances result from dysfunction of vermal lobules VI and VII. Such a vermal deficit should be associated with dysmetric saccadic eye movements because of the major role these areas play in guiding the motor precision of saccades. In contrast, neocortical models of autism predict intact saccade metrics, but impairments on tasks requiring the higher cognitive control of saccades.
A total of 26 rigorously diagnosed nonmentally retarded autistic subjects and 26 matched healthy control subjects were assessed with a visually guided saccade task and two volitional saccade tasks, the oculomotor delayed-response task and the antisaccade task.
Metrics and dynamic of the visually guided saccades were normal in autistic subjects, documenting the absence of disturbances in cerebellar vermal lobules VI and VII and in automatic shifts of visual attention. Deficits were demonstrated on both volitional saccade tasks, indicating dysfunction in the circuitry of prefrontal cortex and its connections with the parietal cortex, and associated cognitive impairments in spatial working memory and in the ability to voluntarily suppress context-inappropriate responses.
These findings demonstrate intrinsic neocortical, not cerebellar, dysfunction in autism, and parallel deficits in higher order cognitive mechanisms and not in elementary attentional and sensorimotor systems in autism.
Prior studies have indicated brain abnormalities underlying social processing in autism, but no fMRI study has specifically addressed the differential processing of direct and averted gaze, a critical social cue. Fifteen adolescents and adults with autism and 14 typically developing comparison participants viewed dynamic virtual-reality videos depicting a simple but realistic social scenario, in which an approaching male figure maintained either direct or averted gaze. Significant group by condition interactions reflecting differential responses to direct versus averted gaze in people with autism relative to typically developing individuals were identified in the right temporoparietal junction, right anterior insula, left lateral occipital cortex, and left dorsolateral prefrontal cortex. Our results provide initial evidence regarding brain mechanisms underlying the processing of gaze direction during simple social encounters, providing new insight into the social deficits in individuals with autism.
Autism; direct gaze; averted gaze; gaze processing; functional magnetic resonance imaging
There is a growing amount of evidence suggesting that individuals with autism have difficulty with face processing. One basic cognitive ability that may underlie face processing difficulties is the ability to abstract a prototype. The current study examined prototype formation with natural faces using eye-tracking in high-functioning adults with autism and matched controls. Individuals with autism were found to have significant difficulty forming prototypes of natural faces. The eye-tracking data did not reveal any between group differences in the general pattern of attention to the faces, indicating that these difficulties were not due to attentional factors. Results are consistent with previous studies that have found a deficit in prototype formation and extend these deficits to natural faces.
prototype; autism; face perception; cognition
This review covers a fraction of the new research developments in autism but establishes the basic elements of the new neurobiologic understanding of autism. Autism is a polygenetic developmental neurobiologic disorder with multiorgan system involvement, though it predominantly involves central nervous system dysfunction. The evidence supports autism as a disorder of the association cortex, both its neurons and their projections. In particular, it is a disorder of connectivity, which appears, from current evidence, to primarily involve intrahemispheric connectivity. The focus of connectivity studies thus far has been on white matter, but alterations in functional magnetic resonance imaging activation suggest that intracortical connectivity is also likely to be disturbed. Furthermore, the disorder has a broad impact on cognitive and neurologic functioning. Deficits in high-functioning individuals occur in processing that places high demands on integration of information and coordination of multiple neural systems. Intact or enhanced abilities share a dependence on low information-processing demands and local neural connections. This multidomain model with shared characteristics predicts an underlying pathophysiologic mechanism that impacts the brain broadly, according to a common neurobiologic principle. The multiorgan system involvement and diversity of central nervous system findings suggest an epigenetic mechanism.
Autism spectrum disorders (ASD) are neurodevelopmental disorders with a prevalence of nearly 1:100. Structural imaging studies point to disruptions in multiple brain areas, yet the precise neuroanatomical nature of these disruptions remains unclear. Characterization of brain structural differences in children with ASD is critical for development of biomarkers that may eventually be used to improve diagnosis and monitor response to treatment.
We use voxel-based morphometry (VBM) along with a novel multivariate pattern analysis (MPA) approach and searchlight algorithm to classify structural magnetic resonance imaging data acquired from 24 children and adolescents with autism and 24 age-, gender-, and IQ-matched neurotypical participants.
Despite modest VBM differences, MPA revealed that the groups could be distinguished with accuracies of around 90% based on gray matter in the posterior cingulate cortex (PCC), medial prefrontal cortex, and bilateral medial temporal lobes, all regions within the default mode network (DMN). Abnormalities in the PCC were associated with impaired ADI-R communication scores. Gray matter in additional prefrontal, lateral temporal, and subcortical structures also discriminated between the two groups with accuracies between 81-90%. White matter in the inferior fronto-occipital and superior longitudinal fasciculi, and the genu and splenium of the corpus callosum, achieved up to 85% classification accuracy.
Multiple brain regions, including those belonging to the DMN, exhibit aberrant structural organization in children with autism. Brain-based biomarkers derived from structural MRI data may eventually contribute to identification of the neuroanatomical basis of symptom heterogeneity and to the development of more targeted early intervention.
voxel-based morphometry; autism spectrum disorders; default mode network; multivariate pattern analysis; support vector machine; biomarker
Individuals with autism often violate social rules and have lower accuracy in identifying and explaining inappropriate social behavior. Twelve children with autism (AD) and thirteen children with typical development (TD) participated in this fMRI study of the neurofunctional basis of social judgment. Participants indicated in which of two pictures a boy was being bad (Social condition) or which of two pictures was outdoors (Physical condition). In the within-group Social–Physical comparison, TD children used components of mentalizing and language networks [bilateral inferior frontal gyrus (IFG), bilateral medial prefrontal cortex (mPFC), and bilateral posterior superior temporal sulcus (pSTS)], whereas AD children used a network that was primarily right IFG and bilateral pSTS, suggesting reduced use of social and language networks during this social judgment task. A direct group comparison on the Social–Physical contrast showed that the TD group had greater mPFC, bilateral IFG, and left superior temporal pole activity than the AD group. No regions were more active in the AD group than in the group with TD in this comparison. Both groups successfully performed the task, which required minimal language. The groups also performed similarly on eyetracking measures, indicating that the activation results probably reflect the use of a more basic strategy by the autism group rather than performance disparities. Even though language was unnecessary, the children with TD recruited language areas during the social task, suggesting automatic encoding of their knowledge into language; however, this was not the case for the children with autism. These findings support behavioral research indicating that, whereas children with autism may recognize socially inappropriate behavior, they have difficulty using spoken language to explain why it is inappropriate. The fMRI results indicate that AD children may not automatically use language to encode their social understanding, making expression and generalization of this knowledge more difficult.
A clinical memory test was administered to 38 high-functioning children with autism and 38 individually matched normal controls, 8–16 years of age. The resulting profile of memory abilities in the children with autism was characterized by relatively poor memory for complex visual and verbal information and spatial working memory with relatively intact associative learning ability, verbal working memory, and recognition memory. A stepwise discriminant function analysis of the subtests found that the Finger Windows subtest, a measure of spatial working memory, discriminated most accurately between the autism and normal control groups. A principal components analysis indicated that the factor structure of the subtests differed substantially between the children with autism and controls, suggesting differing organizations of memory ability.
autism; memory assessment; discriminant analysis; principal components analysis
A wide range of abilities was assessed in 56 high-functioning children with autism and 56 age- and IQ-matched controls. Stepwise discriminant analyses produced good group discrimination for sensory-perceptual, motor, complex language, and complex memory domains but lower agreement for the reasoning domain than previously obtained for adults. Group discrimination did not occur for attention, simple language, simple memory, and visuospatial domains. Findings provide additional support for a complex information-processing model for autism, previously based on adult data, demonstrating a pattern across domains of selective impairments on measures with high demands for integration of information and sparing when demands were low. Children as compared to adults with autism exhibited more prominent sensory-perceptual symptoms and less pronounced reasoning deficits reflecting brain maturation.
This study examined the relationships between volumetric measurements of frontal lobe structures and performance on executive function tasks in individuals with autism. MRI scans were obtained from 38 individuals with autism and 40 matched controls between the ages of 8 and 45 years. Executive function was assessed using neuropsychological measures including the Wisconsin Card Sorting Test and Tower of Hanoi. Differences in performance on the neuropsychological tests were found between the two groups. However, no differences in dorsolateral prefrontal cortex volumes were observed between groups. No correlations between volumetric measurements and performance on the neuropsychological tests were found. Findings from this study suggest that executive function deficits observed in autism are related to functional but not anatomical abnormalities of the frontal lobe. The absence of correlations suggests that executive dysfunction is not the result of focal brain alterations but, rather, is the result of a distributed neural network dysfunction.
autism; frontal lobe; dorsolateral prefrontal cortex; magnetic resonance imaging; executive function
Personal pronouns, such as ‘I’ and ‘you’, require a speaker/listener to continuously re-map their reciprocal relation to their referent, depending on who is saying the pronoun. This process, called ‘deictic shifting’, may underlie the incorrect production of these pronouns, or ‘pronoun reversals’, such as referring to oneself with the pronoun ‘you’, which has been reported in children with autism. The underlying neural basis of deictic shifting, however, is not understood, nor has the processing of pronouns been studied in adults with autism. The present study compared the brain activation pattern and functional connectivity (synchronization of activation across brain areas) of adults with high-functioning autism and control participants using functional magnetic resonance imaging in a linguistic perspective-taking task that required deictic shifting. The results revealed significantly diminished frontal (right anterior insula) to posterior (precuneus) functional connectivity during deictic shifting in the autism group, as well as reliably slower and less accurate behavioural responses. A comparison of two types of deictic shifting revealed that the functional connectivity between the right anterior insula and precuneus was lower in autism while answering a question that contained the pronoun ‘you’, querying something about the participant’s view, but not when answering a query about someone else’s view. In addition to the functional connectivity between the right anterior insula and precuneus being lower in autism, activation in each region was atypical, suggesting over reliance on individual regions as a potential compensation for the lower level of collaborative interregional processing. These findings indicate that deictic shifting constitutes a challenge for adults with high-functioning autism, particularly when reference to one’s self is involved, and that the functional collaboration of two critical nodes, right anterior insula and precuneus, may play a critical role for deictic shifting by supporting an attention shift between oneself and others.
autism; functional connectivity; pronoun reversal; precuneus; insula
Multiple studies suggest that the corpus callosum in patients with autism is reduced in size. This study attempts to elucidate the nature of this morphometric abnormality by analyzing the shape of this structure in 17 high-functioning patients with autism and an equal number of comparison participants matched for age, sex, IQ, and handedness. The corpus callosum was segmented from T1 weighted images acquired with a Siemens 1.5 T scanner. Transformed coordinates of the curvilinear axis were aggregated into a parametric map and compared across series to derive regions of statistical significance. Our results indicate that in subjects with autism reduction in size of the corpus callosum occurs over all of its subdivisions (genu, body, splenium) with a small area of overgrowth at its caudal pole. Since the commisural fibers that traverse the different anatomical compartments of the corpus callosum originate in disparate brain regions our results suggest the presence of widely distributed cortical abnormalities in people with autism.
Autistic Disorder; Cerebral Cortex/growth & development; Corpus Callosum; Magnetic Resonance Imaging
MRI diffusion-tensor tracking (DTT) was performed in 17 high-functioning adolescents/adults with autism and 17 pairwise-matched controls. White matter pathways involved in face processing were examined due to the relevance of face perception to the social symptoms of autism, and due to known behavioral and functional imaging findings in autism. The hippocampo-fusiform (HF) and amygdalo-fusiform (AF) pathways had normal size and shape but abnormal microstructure in the autism group. The right HF had reduced across-fiber diffusivity (D-min) compared with controls, opposite to the whole-brain effect of increased D-min. In contrast, left HF, right AF, and left AF had increased D-min and increased along-fiber diffusivity (D-max), more consistent with the whole-brain effect. There was a general loss of lateralization compared with controls. The right HF D-min was markedly low in the autism subgroup with lower Benton face recognition scores, compared with the lower-Benton control subgroup, and compared with the higher-Benton autism subgroup. Similar behavioral relationships were found for performance IQ. Such results suggest an early functionally-significant pathological process in right HF consistent with small-diameter axons (with correspondingly slower neural transmission) and/or higher packing density. In left AF and HF, changes were interpreted as secondary, possibly reflecting axonal loss and/or decreased myelination.
Autism; Diffusion tensor MRI; White matter fiber tracking; Fusiform face area; Amygdala; Hippocampus; Face recognition; DTT; White matter pathways
Previous research suggests hypoactivity in response to the visual perception of faces in the fusiform gyri and amygdalae of individuals with autism. However, critical questions remain regarding the mechanisms underlying these findings. In particular, to what degree is the hypoactivation accounted for by known differences in the visual scanpaths exhibited by individuals with and without autism in response to faces? Here, using functional magnetic resonance imaging (fMRI), we report “normalization” of activity in the right fusiform gyrus, but not the amygdalae, when individuals with autism were compelled to perform visual scanpaths that involved fixating upon the eyes of a fearful face. These findings hold important implications for our understanding of social brain dysfunction in autism, theories of the role of the fusiform gyri in face processing, and the design of more effective interventions for autism.
Autism; Face Perception; Functional Magnetic Resonance Imaging; Fusiform Gyrus; Amygdala
Cortical and central white matter (WM) volumes were measured to assess short- and long-range connectivity in autism, respectively. Subjects included 23 boys with autism and 23 matched controls, all without intellectual disability. Magnetic resonance imaging data obtained at 1.5-T were analyzed using BRAINS2 software. Central WM volume was quantified by subtracting cortical from supratentorial WM volumes. Reduced central WM volume was observed in the autism group. IQ was higher in controls with no observed correlations between WM volumes and IQ. This preliminary evidence of reduced central WM volume in autism suggests abnormal long-range connectivity.
autism; brain; child and adolescent psychiatry; magnetic resonance imaging
Performance IQ (PIQ) greater than verbal IQ (VIQ) is often observed in studies of the cognitive abilities of autistic individuals. This characteristic is correlated with social and communication impairments, key parts of the autism diagnosis. We present the first genetic analyses of IQ discrepancy (PIQ–VIQ) as an autism-related phenotype. We performed genome-wide joint linkage and segregation analyses on 287 multiplex families, using a Markov chain Monte Carlo approach. Genetic data included a genome-scan of 387 micro-satellite markers in 210 families augmented with additional markers added in a subset of families. Empirical P values were calculated for five interesting regions. Linkage analysis identified five chromosomal regions with substantial regional evidence of linkage; 10p12 [P = 0.001; genome-wide (gw) P = 0.05], 16q23 (P = 0.015; gw P = 0.53), 2p21 (P = 0.03, gw P = 0.78), 6q25 (P = 0.047, gw P = 0.91) and 15q23–25 (P = 0.053, gw P = 0.93). The location of the chromosome 10 linkage signal coincides with a region noted in a much earlier genome-scan for autism, and the chromosome 16 signal coincides exactly with a linkage signal for non-word repetition in specific language impairment. This study provides strong evidence for a QTL influencing IQ discrepancy in families with autistic individuals on chromosome 10, and suggestive evidence for a QTL on chromosome 16. The location of the chromosome 16 signal suggests a candidate gene, CDH13, a T-cadherin expressed in the brain, which has been implicated in previous SNP studies of autism and ADHD.