Early autism research focused on behavior and cognition. In recent decades, the pace of research has accelerated, and advances in imaging and genetics have allowed the accumulation of biological data. Nevertheless, a coherent picture of the syndrome at either phenotypic or biological level has not emerged. We see two fundamental obstacles to progress in basic understanding of autism. First, the two defining features (impairment in social interactions and communication, and restricted, repetitive behaviors and interests) are historically seen as integrally related. Others hold that these two major traits are fractionable and must be studied independently, casting doubt on autism as a coherent syndrome. Second, despite much recent research on brain structure and function, environmental factors, and genetics/genomics, findings on the biological level have not generally aligned well with those on the phenotypic level. In the first two sections, we explore these challenges, and in the third section, we review approaches that may facilitate progress, such as (1) including in studies all individuals defined by social impairment without regard to repetitive behaviors, (2) forming narrowly defined subtypes by thorough characterization on specific features, both diagnostic and non-diagnostic, (3) focusing on characteristics that may be relatively robust to environmental influence, (4) studying children as early as possible, minimizing environmental influence, and including longitudinal course as an important part of the phenotype, (5) subtyping by environmental risk factors, (6) distinguishing between what participants can do and what they typically do, and (7) aggregating large data sets across sites. (JINS, 2017, 23, 903–915)

In addition to having difficulties with social communications, individuals with an autism spectrum disorder (ASD) often also experience impairment in higher-order, executive skills. The present study examined the effects of pharmacological modulation of the norepinephrine system on the severity of such impairments. A sample of 14 high-functioning adults with ASD and a demographically-matched comparison group of 13 typically developing individuals participated. An AX continuous performance test (AX-CPT) was used to evaluate working memory and inhibitory control. AX-CPT performance was assessed following administration of a single dose of propranolol (a beta adrenergic antagonist) and following placebo (sugar pill) administration. Individuals with ASD performed more poorly than non-ASD individuals in the working memory condition (BX trials). Importantly, administration of propranolol attenuated this impairment, with the ASD group performing significantly better in the propranolol condition than the placebo condition. Working memory performance of the non-ASD group was unaffected by propranolol/placebo administration. No group or medication effects were observed for the inhibition condition (AY trials). The present findings suggest that norepinephrine may play a role in some, but not necessarily all, cognitive impairments associated with ASD. Additional research is needed to fully understand whether this role is primarily causal or compensatory in nature. (JINS, 2012, 18, 556–564)

Prior studies suggest that autism spectrum disorders (ASD) are associated with a domain-specific memory impairment for faces. The underlying cause of this problem and its relation to impaired visual scanning of faces—particularly of the eyes—remains to be determined. We recorded eye movements while 22 high-functioning ASD and 21 typically developing (TD) adolescents encoded and later recognized faces and objects from a single, nonsocial object category (electric fans). Relative to TD subjects, ASD individuals had poorer memory for faces, but not fans. Correlational analyses showed significant relationships between recognition memory and fixations. Eye tracking during encoding revealed that TD subjects made more fixations to faces than fans, whereas ASD individuals did not differ in number of fixations made to each stimulus type. Moreover, although both the TD and ASD groups showed a strong preference for fixating the eyes more than the mouth, the ASD subjects were less likely than TD subjects to scan regions of the face outside of the primary facial features (i.e., eyes, nose, and mouth). We concluded that ASD individuals have a domain-specific memory impairment for faces relative to mechanical objects and that this impairment may be related to abnormal scanning during encoding. (JINS, 2011, 17, 1021–1029)

Currently, the heterogeneity in the developmental trajectories of autism spectrum disorders (ASD) is poorly understood. Preschool children with ASD participating in a longitudinal study received a battery of neurocognitive tasks that measured the learning of reward associations (Lrn-Rew), spatial working memory (SpatWM), and imitation from memory and novelty preference (Mem/Nov), as well as a measure of nonverbal problem-solving ability (NVDQ). Growth curve analyses via HLM were used to predict the variability in growth rates between age 4 to age 6.5 in Vineland Socialization and Communication scores. Individual differences in both Lrn-Rew and Mem/Nov were significantly related to Socialization and Communication growth rates above and beyond NVDQ, whereas SpatWM was not. Thus, specific aspects of neurocognitive functioning appear to be important predictors of developmental variability during the preschool years in children with ASD. We speculate that these findings support the combined role of ventromedial prefrontal and medial temporal lobe systems in the early pathogenesis of ASD and may be useful in predicting developmental trajectory. The benefits and challenges of assessing specific neurocognitive functions in children with autism is discussed with regard to general cognitive/developmental ability and the behavioral requirements of most assessment settings. (JINS, 2008, 14, 956–966.)

This study tested the hypothesis that affective arousal in response to eye contact is negatively associated with face identification skills in children with autism spectrum disorder (ASD). Participants were 20 children and adolescents with ASD and 20 age- and IQ-matched typically developing (TD) children. Skin conductance response (SCR), a psychophysiological measure of autonomic arousal, was collected while participants viewed faces with gaze directed toward them and faces with gaze averted away from them. Participants also completed an independent match-to-sample face recognition test. Children with ASD exhibited significantly larger SCRs than TD children to faces with direct and averted gaze. There were no differences between SCRs to direct gaze and averted gaze in either group. Children with ASD exhibited a marginally significant decrease in face recognition accuracy relative to TD children, particularly when face recognition depended on the eye region of the face. Face recognition accuracy among children with ASD was negatively correlated with the amplitude of SCRs to direct gaze but not to averted gaze. There was no association between face recognition accuracy and SCRs to gaze in the TD group. These findings suggest that autonomic reactivity to eye contact may interfere with face identity processing in some children with ASD. (JINS, 2008, 14, 947–955.)

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by language and communication impairments, social impairments, and repetitive behaviors or restricted interests. Previous studies of semantic functions have found differences in semantic processing and differences in the activation of the language network in adults with ASD compared to controls. The goal of this study is to examine semantic functions in adolescents with ASD compared to typically developing adolescents. We utilized fMRI with a reading version of a response-naming task to investigate activation in 12 right-handed adolescent boys with ASD and 12 typically developing boys. Both groups performed the task at ceiling levels. Boys with ASD had significantly stronger activation than controls in Broca's area, which was less left lateralized in ASD individuals. Controls had a significant correlation between frontal and temporal language area activation in the left hemisphere, whereas ASD adolescents did not. Direct group comparisons revealed additional regions activated in the ASD group relative to the control group. These results suggest differences in semantic organization, approaches to the semantic task, or efficiency in semantic processing in ASD adolescents relative to typically developing adolescents. (JINS, 2008, 14, 967–979.)

Autism is a severe neurodevelopmental disorder of early childhood. Genetic factors play an important role in the aetiology of the disorder. In this study, we considered the NRCAM gene as a candidate gene of autism. This gene is expressed in the central nervous system and located in the 7q region, a susceptibility locus of autism. We conducted a case-control study of 18 single nucleotide polymorphisms (SNPs) within the NRCAM gene for possible association with autism in 170 autistic patients and 214 normal controls in a Japanese population. Seven SNPs in the NRCAM gene were significantly associated with autism, among which rs2300045 indicated the most prominent result (p=0.0009 uncorrected, p=0.017 corrected). In haplotype analyses, several individual haplotypes, including a common NRCAM haplotype C-T-T-C-T-T-G-C for rs3763463, rs1859767, rs1034825, rs2300045, rs2300043, rs2300039, rs722519, and rs2216259, showed a significant association after Bonferroni correction (p=0.0035 uncorrected, p=0.028 corrected). These haplotypes were located in the 5′ intron-2 region of the gene. In addition, we also assessed the above mentioned SNPs and haplotypes using the transmission disequilibrium test with 148 trios of autistic families. Haplotype G-T-T-T-T-C-G-C in the same eight SNPs was also associated with autism. In summary, our findings provide evidence for a significant association of NRCAM with autism. Considering the important role of the NRCAM gene in brain development, our results therefore indicated that the NRCAM gene is one of the strong candidate genes for autism.

Atypical amygdala development may play a key role in the emergence of social disability and other symptoms of autism (Baron-Cohen et al., 2000; Schultz, 2005). The mechanisms by which this may occur have received little attention, however, and most support from behavioral and imaging studies has been concerned with socially relevant stimuli such as faces. Given the complexity of amygdala function and its known role in many other emotional tasks, we examined whether individuals with autism would demonstrate impaired performance on several tasks that have been shown to require activation of the amygdala but that do not have any explicit social meaning. Relative to a typical comparison group matched for age and IQ, our sample of 37 adolescents and adults with autism (mean age = 19.7 years) demonstrated equivalent facilitation for perception and learning of emotionally relevant stimuli. On each of four tasks, there were significant main effects of emotion condition on performance for both groups. Future research regarding atypical amygdala function and emotion processing in autism should consider whether the response to nonsocial emotion factors (including negative valence or high arousal) may be intact, despite difficulties in responding to socially relevant stimuli. (JINS, 2008, 14, 42–54.)

A battery of tests of auditory and visual memory was used to investigate memory function in 52 high-functioning adolescents and young adults with autism and 40 group-matched normal controls. It was hypothesized that memory dysfunction is present in autism but is not modality specific and is produced by poor utilization of organizing strategies. It was therefore hypothesized that memory impairment in autism would become more prominent as task complexity was increased. The participants with autism performed as well as controls on short-term memory and paired-associate learning tasks, but performed significantly less well than controls on a list learning task. They also performed significantly more poorly on immediate and delayed recall of a story and of a complex geometric figure. On a maze learning task, their performance became progressively worse relative to controls as the complexity of the maze increased. On a series of span tasks, they did not differ from controls on letter span, but did significantly worse on word span and sentences of increasing complexity. These findings indicate a lack of modality specificity and a failure to initiate organizing strategies as evidenced by inefficiency in new learning, poor utilization of contextual cues in story and complex pattern recall, and greater impairment with increasing complexity of the material.

Twenty-eight children with autism and 33 MLD children were given two tasks tapping social understanding and a control task tapping probability understanding. For each task there was a measure of eye gaze (where children looked when anticipating the return of a story character or an object) and a verbal measure (a direct question). We found that eye gaze was better than verbal performance at differentiating children with autism from children with MLD. Children with autism did not look to the correct location in anticipation of the story character's return in the social tasks, but they did look to the correct location in the nonsocial probability task. We also found that within the autistic group, children who looked least to the correct location were rated as having the most severe autistic characteristics. Further, we found that whereas verbal performance correlated with general language ability in the autistic group, eye gaze did not. We argue that: (a) eye gaze probably taps unconscious but core insights into social behavior and as such is better than verbal measures at differentiating children with autism from mentally handicapped controls, (b) eye gaze taps either spontaneous processes of simulation or rudimentary pattern recognition, both of which are less based in language, and (c) the social understanding of children with autism is probably based mostly on verbally mediated theories whereas control children also possess more spontaneous insights indexed by eye gaze.

Face recognition is often considered to be a modular (encapsulated) function. This annotation supports the proposal that faces are special, but suggests that their identification makes use of general-purpose cortical systems that are implicated in high-level vision and also in memory and learning more generally. These systems can be considered to function within two distinct cortical streams: a medial stream (for learning and salience of faces encountered) and a lateral stream (for distributed representations of visual properties and identities of faces). Function in the lateral stream, especially, may be critically dependent on the normal development of magnocellular vision. The relevance of face recognition anomalies in three developmental syndromes (Autism, Williams syndrome, and Turner syndrome) and the two-route model sketched above is considered.

Information on everyday life activities and preferences in both social and nonsocial domains was obtained from parents and children who had taken part in an experimental study of central coherence. Comparisons were made between parents who had a son with autism, parents with a dyslexic son, and families without a history of developmental disorder, as well as the male siblings in these families. Data on everyday preferences and abilities were elicited by means of an experimental questionnaire. Significant group differences in social and nonsocial preferences were found, suggesting that some parents showed similarities with their son with autism, in preference for nonsocial activities and ability in detail-focused processing. A similar experimental questionnaire, completed by parents on behalf of their sons, discriminated between autism group probands and controls, but did not differentiate sibling groups. The relevance of the nonsocial items to central coherence is discussed in the light of the findings in Part I: autism parents who reported more autism-related nonsocial (but not social) preferences, tended to show a piecemeal processing style on the experimental tasks.

Previous twin and family studies have indicated that there are strong genetic influences in the etiology of autism, and provide support for the notion of a broader phenotype in first-degree relatives. The present study explored this phenotype in terms of one current cognitive theory of autism. Parents and brothers of boys with autism, boys with dyslexia, and normal boys were given tests of “central coherence”, on which children with autism perform unusually well due to an information-processing bias favouring part/detail processing over processing of wholes/meaning. Results indicated that fathers of boys with autism, as a group, showed piecemeal processing across four tests of central coherence. This was not true for any other group. These findings raise the possibility that the broader autism phenotype may include a “cognitive style” (weak central coherence) that can confer information-processing advantages.

Executive functioning was investigated in 34 children (24 boys and 10 girls) with developmental language disorder (DLD) and 21 children (18 boys and 3 girls) with high-functioning autistic disorder (HAD) matched on Full Scale IQ, Nonverbal IQ, age (mean age 9 year, 1 month), and SES. The DLD group had a Verbal IQ that was 10 points higher than the HAD group. These children were given the Wisconsin Card Sorting Test (WCST), the Mazes subtest from the WISC-R, the Underlining test, and the Rapid Automatized Naming test. In addition, these children were given the Vineland Scales of Adaptive Functioning and the Wing Diagnostic Symptom Checklist in order to assess severity of autistic symptomatology. Results indicated that the only significant difference between the two groups on the cognitive tasks was perseverative errors on the WCST; there was no significant difference on total number of categories achieved or total number of errors on the WCST or on the other executive function measures. There was also significant overlap in the scores between the two groups and the difference in perseverative errors was no longer significant when Verbal IQ was partialled out. Executive functioning was strongly related to all IQ variables in the DLD group and particularly related to Verbal IQ in the HAD group. Although there was a relationship in the HAD group between executive functioning and adaptive functioning, as well as between executive functioning and autistic symptomatology, these relationships were generally no longer significant in the HAD group after the variance due to Verbal IQ was accounted for. The results are interpreted to indicate that although impaired executive functioning is a commonly associated feature of autism, it is not universal in autism and is unlikely to cause autistic behaviors or deficits in adaptive function.

In 1997 in this Journal we published the “Reading the Mind in the Eyes” Test, as a measure of adult “mentalising”. Whilst that test succeeded in discriminating a group of adults with Asperger syndrome (AS) or high-functioning autism (HFA) from controls, it suffered from several psychometric problems. In this paper these limitations are rectified by revising the test. The Revised Eyes Test was administered to a group of adults with AS or HFA (N = 15) and again discriminated these from a large number of normal controls (N = 239) drawn from different samples. In both the clinical and control groups the Eyes Test was inversely correlated with the Autism Spectrum Quotient (the AQ), a measure of autistic traits in adults of normal intelligence. The Revised Eyes Test has improved power to detect subtle individual differences in social sensitivity.