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There now exist multiple reports of a constellation of language, personality, and social-behavioral features present among relatives that mirror the symptom domains of autism, but much milder in expression. Studies of this ‘broad autism phenotype’ (BAP) may provide a potentially important, complementary approach for detecting the genes causing autism and defining associated neural circuitry, by identifying more refined phenotypes which can be measured quantitatively in both affected and unaffected individuals, and which are tied to functioning in particular regions of the brain.
To gain insights into neuropsychological features that index genetic liability to autism.
Thirty-eight high-functioning individuals with autism and parents of autistic individuals, both with and without the BAP (N=83), as well as control groups.
A comprehensive battery of neuropsychological tasks tapping social cognition, executive function, and global/local processing strategies (central coherence).
Both individuals with autism and parents with the BAP differed from controls on measures of social cognition, with performance in the other two domains more similar to controls.
Data suggest that the social cognitive domain may be an important target for linking phenotype to cognitive process to brain structure in autism, and may ultimately provide insights into genes involved in autism.
Autism is a severe, life-long developmental disorder that compromises functioning across multiple domains, including social behavior, language, sensory function, and ritualistic/repetitive behaviors and interests. While the etiology of autism is complex and not fully understood, strong evidence from twin and family studies points toward a large genetic contribution, with heritability estimates as high as 90% (1, 2). Twin and family studies have also shown that genetic liability appears to be expressed among unaffected relatives of people with autism through features that are milder, but qualitatively similar, to the defining characteristics of autism.
The first observation of such subclinical traits can be credited to child psychiatrist Leo Kanner, whose original narrative descriptions of autism also noted among relatives a strong preoccupation with “abstractions of a scientific, literary, or artistic nature, and limited in genuine interest in people.” (1943, p. 250). A decade later, Leon Eisenberg further described relatives, and fathers in particular, as “perfectionistic to an extreme … pre-occupied with detailed minutiae to the exclusion of concern for over-all meanings” (1957, p. 721). These early observations were unfortunately misinterpreted as evidence faulting parents’ behaviors in the etiology of autism, and it would be another 20 years before this myth would be dispelled by the landmark twin study of Folstein and Rutter (3).
This study not only detected markedly higher concordance rates of autism among monozygotic twins than dizygotic, but also found even higher MZ concordance for a more broadly defined phenotype including subclinical language and cognitive features. Family studies following up on these striking findings have repeatedly confirmed the presence of such subclinical phenotypes among relatives, now referred to as constituting a ‘broad autism phenotype’ or ‘BAP’. The features of the BAP closely parallel the core symptom domains in autism (i.e., impaired social functioning, language and communication deficits, and restricted/repetitive interests, respectively), yet are subtle in expression and not usually associated with any functional impairment (4). Importantly, whereas by definition autism involves impairment across all three symptom domains, evidence suggests that these features may decouple and segregate independently in unaffected (with autism) relatives (5–7), consistent with the observation that they appear to be uncorrelated in neurotypical populations (8). Studies of relatives may therefore help to disentangle the complex autistic phenotype to identify component traits more amenable to neurocognitive and genetic dissection than the full clinical syndrome.
The present study is an attempt to inform the neuropsychological basis of autism and the BAP via detailed neuropsychological assessment of high-functioning individuals with autism and parents of autistic individuals (both with and without the BAP). We investigate performance within the three principal neuropsychological domains that have each been proposed as key cognitive abilities in which impairments may explain the autistic phenotype -- social cognition, central coherence and executive function. Autistic individuals’ impairments in each of these domains have been reported [for reviews see (8, 9)], and an emerging literature has begun to document parallel performance patterns among unaffected relatives (10–14).
We assessed performance using a battery of tasks selected to assess processing comprehensively within a given domain, and chose our battery with an eye towards links to studies of subjects with circumscribed neurological lesions that could shed light on specific neural structures that are involved in autism, and potentially the BAP. For instance, several of our social cognition tasks had been shown to tap amygdala function, a structure that has also been hypothesized to play a role in autism (15–17). We focused on high-functioning adults with autism such that an identical battery of tasks might be administered to both the parent and autistic groups, thus affording direct comparisons relative to respective control groups.
To summarize, the goals of this study were 1) to provide an in-depth characterization of the neuropsychological profile of autism and the BAP; 2) to identify patterns of performance within and across neuropsychological domains which were common to both autistic individuals and parents; and 3) to identify cosegregation between clinical phenotype and neuropsychological functioning that might serve to carve out specific phenotypic subtypes and that could form the basis for stronger genotype-phenotype associations.
Participants included 36 high-functioning individuals with autism, 41 autism controls (neurotypical individuals with no family history of autism), 83 autism parents, and 32 parent controls (i.e., neurotypical parents with no family history of autism or developmental delays). Intact nuclear families were targeted to afford analysis of parent-child correlations. Twenty-two intact families were successfully recruited (i.e., 44 parents and their high-functioning autistic child). The remaining families included either a single parent and their autistic child (n=15), or only parents (n=24) who participated without their child. Control groups (both parent and autism controls) were recruited through local advertisement, and were screened to be similar in demographic characteristics to the autism and autism-parent groups (see Table 1).
To ensure that all participants were capable of completing the same battery of tasks, only autistic individuals >16 years of age, with performance IQ ≥ 80 on the Wechsler Abbreviated Scale of Intelligence (18) were included. The Autism Diagnostic Interview, Revised (19) and the Autism Diagnostic Observational Schedule, Revised (20), were administered to all participants. Clinical diagnoses were assigned according to current DSM-IV criteria (21). All participants gave informed consent to participate in accordance with a protocol approved by the Institutional Review Board of the University of North Carolina.
Characteristics of the BAP were assessed through clinically based interviews using the Modified Personality Assessment Schedule-Revised, or MPAS-R. This instrument has been used in a number of studies to define key features of the BAP (5, 6, 22). Interviewers guide participants through a number of questions to probe personality characteristics and dispositions relevant to autism and the BAP, namely, rigid or perfectionistic personality, and socially aloof or untactful personality. These traits are thought to parallel the ritualistic/repetitive and social symptom domains of autism, respectively. Such features have been shown to reliably distinguish autism relatives from controls (5).
Ratings were assigned by two independent raters, by combining information from the subject and informant (typically a spouse) interviews according to specified rules. Ratings are based on behavioral examples given by the subject and/or informants in response to a number of probes. Characteristics are rated either as present (2), absent (0) or unknown (1). BAP (+) status was assigned for ratings of ‘present’ (2), and BAP (−) status assigned for scores of 0 or 1 (absent, unknown). Readers are referred elsewhere (5, 6) for additional details on rating procedures. Inter-rater agreement exceeded 85% for all BAP personality traits. Disagreements were resolved by a third independent rater. Control parents were included as a population control for contrasts with parents of autistic individuals and were not administered the MPAS.
Measures of social cognition, executive function, and central coherence were selected based on 1) their theoretical and empirical ties to the neuropsychological domains of interest; 2) psychometric properties, including reliability and indication that each was suitable for individuals with autism, parents, and controls without danger of floor or ceiling effects; and 3) evidence from fMRI and/or lesion studies suggesting associations with particular structures or regions of the brain thought to be important for the three domains and putatively implicated also in autism (23, 24). Tasks are described below.
These tasks have been described in detail elsewhere (citations provided below) and so are reviewed briefly below.
We assessed the executive skills of planning, set shifting and cognitive control through two well established tasks: the Tower of Hanoi and the Trailmaking Task. These tasks are believed to tap prefrontal cortical regions (40, 41).
Weak Central Coherence, is a theory concerning the detail-focused cognitive style prevalent among individuals with autism, assessed through tasks which index the salience of parts over wholes, and relative insignificance of overall gestalt. Global, integrative processing skills are predominantly mediated by the right hemispheric areas (44–46), whereas local featural processing is associated with left hemisphere functioning (46).
For each domain we examined differences between individuals with autism vs. autism controls, and differences between autism parents and parent controls. Within the autism parent group, specific comparisons were conducted to investigate differences between individuals with the BAP and those without. We hypothesized that specific BAP traits would co-segregate with performance in conceptually similar neuropsychological domains (e.g., parents displaying social BAP features would demonstrate differences on social cognitive tasks, whereas those who exhibited the rigid/perfectionistic personality traits were hypothesized to show differences on tasks of executive skills, which involve cognitive flexibility). Within the autistic group, where both rigid/ritualistic behavior and social impairment are defining features, we expected that performance would be impaired across all domains: social cognition, executive function, and central coherence.
Analyses were performed using SAS 9.1. Descriptive statistics were performed to assess raw data distributions for normality. General linear models were used to examine group differences for each outcome2. All possible interactions between groups and the within subject variables were included in the models, as were interactions with age, sex, and IQ. To help control type I error rates, interactions were not interpreted unless significant at p <.05. Where interactions were not significant, only main effects are reported. In cases where interactions with sex were detected, separate estimates and tests of group differences for males and females were calculated using post-estimation procedures. To ensure specificity of findings related to BAP status, all BAP features (social and rigid/perfectionistic) were included in the models.
Twenty-two autism parents were identified as positive for social BAP features,34 rated positive for the rigid/pefectionistic BAP traits, and 40 showed neither characteristic, and are referred to as BAP (−). There were 5 mothers and 8 fathers who displayed both rigid and social BAP traits. Whereas fathers more often showed features of the social BAP (41% of Fathers vs. only 16% of Mothers; χ2 = 6.75, p = .009), rigid/perfectionistic BAP traits were observed in roughly equal numbers of fathers and mothers(43% of fathers vs. 41% of mothers; χ2 = .14, p = .70). As noted in Analyses, above, findings related to BAP status reported below control for the co-occurrence of the BAP features.
Table 2 summarizes findings across domains and specific patterns are described below by domain. For each task, results are first presented for autism vs. control comparisons, followed by parent group comparisons (social or rigid/perfectionistic BAP (+) vs. BAP (−) vs. controls) . As noted previously, parent comparisons examined the specific hypothesis that performance would vary by BAP status. Thus, findings are reported for BAP (+) vs. BAP (−) vs. controls. Adjusted mean differences, standard errors, and p values are presented in Tables 3 (social cognition) and 4 (executive functioning and central coherence). For measures of social cognition, all tasks except the Eyes Test were analyzed as z-scored differences from norms, resulting in mean differences in standard deviations (i.e., a mean difference of ‘1.0’ reflects a full standard deviation difference between groups).
Though not described below in the interest of space, we note here that parent-child correlations were examined but did not reveal significant associations across domains or specific tasks.
The autistic group performed significantly less accurately than controls (see Table 3).
Significant differences were also detected among parents, but these differences were only present among those parents with the social BAP (hereafter referred to as BAP (+)). The BAP (+) group was less accurate than controls and BAP (−) parents. There were no significant differences between controls and BAP (−) parents or parents showing the rigid feature of the BAP. A significant effect of sex was detected among parents, revealing that differences were more profound among BAP (+) mothers than fathers.
The autistic group was less accurate at identifying fearful expressions across all variations of expression intensity, both high and low morphedness (i.e., faces closer to prototypical facial expression and therefore presumably easier to decipher, as well as those closest to neutral/faintly expressed). No differences were observed for happy or sad faces.
Analysis revealed significantly lower accuracy identifying fearful faces among the social BAP (+) group, but only when expressions were most faintly expressed. That is, at low levels of morphedness parents in the social BAP (+) group were significantly less accurate in identifying fearful expressions than the other parent groups (controls, BAP (−), rigid BAP). As observed in the autistic group, no significant differences were observed for happy or sad stimuli.
The autistic group differed from controls in judging the trustworthiness of faces. Individuals with autism differed from norms significantly more than controls only on the negatively valenced slides (i.e., on ‘unfriendly’ stimuli). Relative to controls, individuals with autism significantly over-rated the trustworthiness of negatively valenced faces (i.e., they rated ‘unfriendly’ faces as overly friendly).
The social BAP (+) group differed from norms significantly more than controls and BAP (−) parents on the positively valenced stimuli, where they rated ‘friendly’ faces as significantly less trustworthy than the other parent groups. In other words, relative to the other groups’ ratings, they rated these faces as somewhat threatening. No significant differences were detected between the other parent groups.
The autistic group differed significantly from controls across all emotions, though patterns differed for each condition, faces omitted vs. faces present. When stimuli were shown without faces, the autistic group differed from controls on all emotions – they were less accurate identifying sadness and anger, and better than controls at identifying fearful scenes. When faces were present, individuals with autism were less accurate identifying anger, and no longer showed any advantage identifying fear, suggesting they benefited less from viewing facial information than did controls.
Findings among parents were consistent with this pattern – across all emotions, BAP (+) parents were significantly less accurate than controls and BAP (−) groups only when faces were present. Thus, whereas controls and parents without the social BAP became more accurate in judging emotions when facial expressions were revealed, parents with the social BAP did not show this increase in accuracy, suggesting they were less apt to take advantage of facial information when judging the emotional content of complex scenes. BAP (−) and control groups performed similarly to each other.
In the basic emotion condition, individuals with autism were significantly less accurate at identifying positive emotions from point light displays. Differences were also observed in the more complex emotion condition involving judgments of trustworthiness. The autistic group showed less sensitivity to positively valenced stimuli, failing to modulate their ratings as stimuli became increasingly positive.
Parent groups showed no differences in their ratings of the basic emotions, but the social BAP (+) group exhibited differences in judgments of trustworthiness for both positively and negatively valenced slides. Whereas controls and parents without the social BAP judged positively valenced slides as trustworthyand negative displays less so, the social BAP (+) group appeared relatively insensitive to variations in positive and negative valence, rating these stimuli as ‘neutral’.
There were no significant differences in time or number of moves required to complete the correct tower configuration.
No significant differences were observed among parent groups. Parents with the rigid/perfectionistic traits of the BAP parents performed similarly to BAP (−) and control parents. Parents who displayed the social BAP also performed comparably to BAP (−) and control groups.
There was no significant difference between the autistic and control groups in time to complete the trailmaking task.
Parents of autistic individuals performed comparably to controls, and there were no significant differences associated with BAP status (rigid/perfectionistic or social BAP).
There were no significant differences between autistic and control groups on either the mean time to completion or the likelihood of arriving at a correct answer.
The autism parent group performed comparably to controls on time and accuracy, and there were no associations with any BAP features.
Significant differences were detected in the frequency of errors and time to completion – the autistic group produced more non-global responses (i.e., local and other non-global completions) and took longer to respond than controls.
Parent group comparisons revealed no differences in response type, but autism parents (both rigid/perfectionistic BAP (+) and BAP (−)) responded significantly faster than controls.
The autistic group took significantly longer than controls to complete designs when blocks were segmented. No significant difference was observed when blocks were presented as a whole.
There were no significant differences between parent groups, and no associations with any BAP features.
Results suggest that measures of social cognition most robustly differentiate performance of individuals with autism and parents with the social BAP from controls and BAP (−) parents. As illustrated in Table 2, on five of the six social cognitive measures differences were observed in both individuals with autism and parents with the social BAP, and the autistic group demonstrated differences from controls on all six tasks. By contrast, measures of executive function and central coherence did not differentiate groups as clearly. These findings both validate the concept of the social BAP and highlight the potential utility of neuropsychological measures of social cognition in studies of the brain and gene basis of autism. Importantly, parents with the social BAP are not impaired clinically, yet show neurocognitive patterns similar to those observed in autism.
Our data suggest that specific social cognitive profiles shared by individuals with autism and a subgroup of parents (i.e., those with the social BAP) may be wide ranging, involving a number of different social cognitive skills -- making complex social judgments of trustworthiness from facial information (trustworthiness of faces), interpreting the emotional content of complex scenes with and without affective facial information (movie stills), inferring emotions from very subtle variations in facial expression (morphed faces), and interpreting complex emotional content from biological motion (point light).
Importantly, patterns of performance were in some instances qualitatively different in the autistic and parent groups. In the trustworthiness of faces task, for instance, individuals with autism judged negative faces as significantly ‘more positive’ than controls, whereas BAP (+) parents judged positively valenced faces as ‘more negative’ than controls and BAP (−) parents. Such a divergence in performance demonstrates how neurocognitive characteristics may manifest variably in autism and the BAP. Below we discuss further the implications of these findings for studies of the brain and gene basis of autism, and conclude with limitations and questions for future studies.
As with other studies of the BAP, these results may help to narrow the empirical target from an otherwise highly complex and heterogeneous phenotype (i.e., a diagnosis of autism), to more specific component features that are likely to be more amenable to genetic and neurobiological investigation. And, because our measures constitute quantitative indices of neuropsychological functioning in both affected and unaffected individuals, studies implementing these measures may profit from larger sample sizes and resulting increases in power.
As these tasks derived from lesion and fMRI studies, and have therefore been linked with specific brain regions, we may also speculate on the neuroanatomical structures that could underlie observed patterns of performance, and which may be mediated by autism susceptibility genes. Lesion and imaging studies strongly implicate amygdala function in performance on each of the social cognitive tasks with which autistic individuals and parents with the BAP demonstrated differences (27, 28, 32, 34, 36). And, while a number of neural mechanisms have been implicated in the pathophysiology of autism (for review, see (50)) the amygdala has figured prominently in hypotheses concerning the basis of the social impairments of the disorder (e.g, (15, 17). Our findings support this link, and further suggest that the amygdala may play a role in the subtle social-behavioral manifestation of genetic liability to autism, among unaffected relatives. Results also support involvement of the medial prefrontal cortex, (linked to performance on the ‘eyes’ and ‘pointlight’ tasks (37, 39)) and the superior temporal gyrus, which has also been linked to performance on the eyes test (27–30).
It will be important for future work to replicate these findings with larger samples. Indeed, the possibility of false positives cannot be ruled out; however, we note that all differences on social cognitive measures were consistent with hypotheses. Nonetheless, studies with larger samples will be important for clarifying some intriguing and unexpected results, such as the stronger differences detected among BAP (+) mothers vs. controls than fathers on the Eyes Test. It will also be important to investigate the specificity of findings to autism, as there is suggestion of phenotypic overlap between autism and other neurogenetic disorders (e.g., schizophrenia)(51). Such work should inform both genetic and neurobiological studies of these disorders.
The lack of group differences within the domains of executive function and central coherence remains puzzling, particularly given the large body of research demonstrating executive control deficits and a local processing bias/limited drive for central coherence associated with autism (for reviews see (52, 53). However, some other studies have also failed to detect differences in thesedomains (54, 55), raising the possibility that effects within these domains are more subtle and/or heterogeneous. Also, the net cast by our task battery was not as broad as some other studies’ and this may have hindered our ability to capture group differences.
A related issue concerns the neurocognitive correlates of the rigid/perfectionistic features of the BAP. It is possible that this feature may not constitute as valid a construct as the social BAP, or alternatively, may relate to additional cognitive mechanisms not considered here (e.g., sensorimotor processing, which has been associated with repetitive behaviors in autism (56)).
A final question is why we did not detect parent-child associations in social cognition or the other domains. This could be due to insufficient variation within the autistic group, where most individuals were unequivocally impaired on social cognition measures. And while we targeted intact families, we were only able to recruit 22 such families, raising the possibility that we lacked power to detect such associations. Future studies may therefore benefit by including more heterogeneous autistic groups, and larger samples of intact families.
In sum, our findings raise some important questions for future studies, and at the same time add to current understanding of the neuropsychological basis of autism and the BAP. Results support further study of the component features of the BAP and the neuropsychological characteristics that underlie the components of this construct, which may add important new information about the psychological, neural, and genetic mechanisms underlying autism. From this study, social cognition has emerged as a promising candidate for future studies incorporating the BAP approach and more direct measures of neurocognitive functions, such as structural and functional imaging.
This project was funded by STAART Center Grant #1 U54 MH66418 to JP. ML acknowledges support from Autism Speaks and KL2RR025746 from the National Center for Research Resources.
We gratefully acknowledge the contributions of the families and individuals who participated in this research. We are also grateful to Dr. Francesca Happé for her guidance in use of measures of central coherence, and to Morgan Parlier, M.S.W., for her considerable efforts overseeing and participating in data collection and coding for this project, as well as the members of the UNC Clinical Core for their work assisting in recruitment and testing. This project was funded by STAART Center Grant #1 U54 MH66418 to JP. ML acknowledges support from Autism Speaks and KL2RR025746 from the National Center for Research Resources. ML had full access to all of the data in this study and takes responsibility for its integrity and the accuracy of the data analysis.
1These stimuli were kindly provided by Dr. A. Heberlein, Harvard University
2Most of the tasks are complexly designed with repeated within-subject measures that are defined by the emotion (happy, sad, angry, scared), intensity of emotion (neutral – extreme), and/or degree of difficulty (as in the morphed faces, high vs. low morphedness). To account for such complexities, a repeated measures mixed model was fit for each outcome. Three alternative within-person covariance structures were considered in guiding model selection: unstructured, compound symmetric heterogeneous, and compound. Bayesian information criterion (BIC) scores were used to evaluate these alternative covariance structures and guided selection of the most appropriate model