Journal of Autism and Developmental Disorders, Vol. 33, No.

5, October 2003 ( 2003)

Abnormal Brain Lateralization in High-Functioning Autism

Paul R. Escalante-Mead,1 Nancy J. Minshew,2 and John A. Sweeney1,3

Disturbances in lateral preference in autism are of interest because of their potential to shed light on brain maturational processes in this disorder. Forty-seven autistic individuals with a history of disordered early language development and 22 autistic individuals with normal early language acquisition were matched with 112 healthy individuals and compared on a standardized measure of lateral preference, the Edinburgh Handedness Inventory. Autistic individuals with a history of early language disturbance showed more atypical cerebral dominance than both healthy participants and autistic individuals with normal early language skills. The data indicated maturational disturbances in establishing lateral preference rather than increased rates of left handedness. Atypical establishment of cerebral dominance may be one cause of disordered language development in autism.
KEY WORDS: Autism; Aspergers disorder; pervasive developmental disorders; brain lateralization; handedness; neuropsychology.

Disturbance in the development of brain lateralization in autism is important for its potential to illuminate the timing and nature of developmental disturbances in cerebral organization. Both genetic and environmental factors initiate lateralization in the fetal brain as early as 12 weeks into gestation (McCartney & Hopper, 1999). Normal lateralization typically involves a relative left-hemisphere dominance for language and motor skills and relative right-hemisphere dominance for spatial processing (Annett, 1999). Some investigations using standardized lateralization instruments have reported increased rates of left handedness in autism; however, more studies have reported increased rates of inconsistent lateral preference in comparison with other developmentally handicapped populations (Bryson, 1990; Cornish & McManus, 1996; Fein, Humes, Kaplan, Lucci, & Waterhouse, 1984; Soper et al., 1986).
1 2

University of Illinois at Chicago, Chicago, IL. University of Pittsburgh, Pittsburgh, PA. 3 Correspondence should be addressed to John A. Sweeney, Center for Cognitive Medicine, University of Illinois at Chicago, Chicago, IL 60612; e-mail: jsweeney@psych.uic.edu.

On dichotic listening tasks, disturbances in hemispheric specialization in autism are exemplified by a reduced right-ear advantage for speech processing (Prior & Bradshaw, 1979). Autistic children show leftear preference for both musical and verbal stimuli, whereas healthy children typically prefer to use their left ear for music and their right ear for verbal stimuli (Blackstock, 1978). Brain imaging studies of autism have demonstrated reversed cortical asymmetries in anatomy and reversed patterns of regional cerebral blood flow that are consistent with a generalized disturbance in the establishment of a normal pattern of cerebral dominance (Hier, LeMay, & Rosenberger, 1979; Hashimoto et al., 2000; McAlonan et al., 2002). Twin and family studies provide evidence that autism is strongly genetically influenced (Folstein & Santangelo, 1999). Recent evidence attests that linkage signals obtained on chromosome 7q and at least one signal on 13q can be attributed to the subgroup of families in which both autistic probands and their parents had language delay (Bradford et al., 2001). This finding raises the question of whether early developmental language disturbances may be related to more general problems in brain organization in 539
0162-3257/03/1000-0539/0 2003 Plenum Publishing Corporation

540 autistic individuals with and without disordered language development. The evaluation of hand preference during performance of various daily activities is a standard clinical approach for assessing cerebral dominance (Bryson, 1990; Fein et al., 1984). In this study, we used the Edinburgh Handedness Inventory, which has not been commonly used in previous studies of autism but is a widely accepted clinical instrument for the measurement of lateral preference (Raczkowski & Kalat, 1974). We contrasted lateral preference in autistic individuals with a history of early language disturbance with preference in those whose early language abilities were not significantly impaired. Prior studies of lateralization in autism have not considered these subgroups separately, and they typically used smaller samples and lower-functioning patients than were employed in this study (Bryson, 1990; Fein et al., 1984; McManus, Murray, Doyle, & BaronCohen, 1992). Our prediction was that those with early language impairment would show greater evidence of disruption in hemispheric specialization that would be reflected in reduced right-hand dominance.

Escalante-Mead, Minshew, and Sweeney Wechsler IQ scales (WISC-III or WAIS-R) to assess Full Scale, Verbal, and Performance IQ. Groups were matched on age, race, gender, and Full, and Verbal IQ (see Table I). All individuals were high functioning, with Full Scale and Verbal IQ scores of at least 75. All autistic participants, regardless of their history of language development, met diagnostic criteria for autistic disorder on both the Autism Diagnostic InterviewRevised (Lord, Rutter, & Couteur, 1994) and the Autism Diagnostic Observation Schedule or Autism Diagnostic Observation Schedule-G (Lord et al., 2000). The diagnosis of autism on these instruments was confirmed by expert clinical opinion. All participants met criteria for autism, but only a subset had a history on the Autism Diagnostic Interview-Revised of delayed or disordered early language development. Despite this difference in developmental history, at the time of assessment, subjects in both groups presented with the impairment in language comprehension typically associated with autism, but this was not severe enough to interfere with subjects ability to comprehend the simple phrases on our handedness inventory. No subject had a history of a medical disorder known to cause autistic features such as tuberous sclerosis or fragile-X syndrome. Healthy individuals had no current or past history of a psychiatric or neurological disorder. All participants provided informed consent before participating in the study. Laterality Assessment Lateral dominance was ascertained using a modified version of the Edinburgh Handedness

METHOD Participants Participants included 47 autistic individuals with disordered early language development, 22 autistic individuals with a history of normal early language acquisition, and 112 healthy subjects. Participants were administered the age-appropriate version of the

Table I. Intelligence, Age, and Handedness Data from Healthy Individuals and Autistic Individuals with and without Early Language Delay (Standard Deviations in Parentheses) Autism without disordered early language development (n = 22) 18.42 (13.83) 113.20 (15.16) 108.10 (15.98) 111.85 (12.27) 13.31 (12.80) (median: 19.00) Autism with disordered early language development (n = 47) 16.85 (9.83) 106.70 (17.71) 101.64 (16.05) 104.77 (17.15) 10.45 (11.45) (median: 15.00)

Healthy individuals (n = 112) Age Verbal IQ Performance IQ Full Scale IQ Edinburgh Handedness Inventory 18.82 (10.17) 108.16 (12.37) 106.20 (12.32) 107.79 (12.94) 17.29 (8.02) (median: 19.00)

Statistics F<1 F(2,165) = 1.45 n.s. F(2,165) = 2.02 n.s. F(2,164) = 1.63 n.s. 2 (2) = 28.08 p < .01

Abnormal Brain Lateralization in High-Functioning Autism Inventory (Raczkowski & Kalat, 1974). The Edinburgh Handedness Inventory is a self-report measure asking participants to state which hand or foot (right, left, or both) would be used to perform a series of 23 tasks under normal everyday conditions.

541

RESULTS The assessment of lateral preference has both quantitative (degree of lateral preference) and qualitative (left or right handed) dimensions. Therefore, we analyzed data from this study in two ways. First, we contrasted the three subject groups with raw scores from the Edinburgh Handedness Inventory to assess degree of lateralization, using a nonparametric test because the distributions were non-normal. Second, we contrasted the groups in rates of right-hand dominance and rates at which subjects established dominance of either hand based on scores from the Edinburgh scale. A significant overall group difference on the raw scores of the Edinburgh Handedness Inventory were ascertained using the Kruskal Wallis test [2 (2) = 27.81, p < .01]. Follow-up tests with the Mann-Whitney procedure revealed a less robust establishment of right-hand preference in autistic participants with disordered language development as compared with both healthy participants ( z = 5.27, p < .01) and autistic individuals with normal early language acquisition ( z = 2.63, p < .01) . There was no significant difference between autistic individuals with normal early language acquisition and healthy participants. To compare the prevalence of established handedness across groups, we applied a criterion of 17 of the 23 items from the Edinburgh scale scored with the same lateral preference to identify those with reasonably well established lateral dominance. An overall group comparison using a 2 analysis revealed a significant group difference in rates of established right lateral dominance [2 (2) = 28.5, p < .01]. Autistic individuals with a history of disordered language development had lower rates of right handedness than healthy individuals [2 (2) = 25.21, p < .01], as did autistic individuals with normal early language acquisition [2 (2) = 11.04, p < .01]. The two autism groups did not significantly differ in this regard. A subsequent assessment of the presence or absence of established lateral preference for either hand revealed a significant overall group difference for rates of failed establishment of lateral preference

Fig. 1. Percentages of left, right, and mixed lateral dominance in healthy individuals and autistic individuals with and without early language delay, based on the Edinburgh Handedness Inventory scores. L = left handed, R = right handed, M = mixed dominance.

[2 (2) = 24.34, p < .01] (see Figure 1). The autistic individuals with early language impairment had lower rates of established lateral preference than the healthy group [2 (1) = 27.40, p < .01], as did autistic individuals with normal early language acquisition [2 (1) = 6.01, p < .05]. Autistic individuals with disordered language development were not significantly different from autistic individuals with normal early language acquisition. There were no group differences in rates of left handedness [2 (2) = 1.10, ns].

DISCUSSION High-functioning autistic individuals with disordered early language development had significantly reduced rates of established left or right lateral hand preference. Autistic individuals with normal early language acquisition had less pronounced but still significantly reduced rates of established lateral preference, intermediate between the autistic individuals with disordered language development and healthy individuals. This sample of high-functioning autistic individuals did not demonstrate a pattern of increased rates of left handedness as observed in some prior studies (Cornish et al., 1996; Soper et al., 1986).

542 The results of this study confirm previous reports documenting inconsistent cerebral dominance in autism (Bryson, 1990; Hauck & Dewey, 2001). Previous studies have not compared lateral dominance of subgroups within the autism spectrum as defined by their early language abilities, nor have they typically focused on a high-functioning population as in this study. Our demonstration of an association between lateralization deficits in the motor domain and disturbances in early language acquisition represents a new observation, and a logical one given the wellestablished left-hemispheric specialization for language abilities. Our observation of reduced cerebral dominance is consistent with other findings indicating atypical regional specialization of brain function in autism. Studies of face recognition have suggested maturational disturbances in the specialization of localized circuitry for face recognition (Carver & Dawson, 2002). Other studies have provided evidence of maturational disturbances of the interregional (Boddaert & Zilbovicius, 2002) and interhemispheric circuitry (Egaas, Courchesne, & Saitoh, 1995; Hardan, Minshew, & Keshavan, 2000; Keshavan et al., 2002) that underlie specialization and integration of regional brain function. The association of dysmaturation in hemispheric specialization with deficits in the early development of language skills indicates that language disturbances in autism may be related to an atypical development of left-hemispheric specialization for language skills. Because language delay has been related to specific genetic disturbances in autism (Bradford et al., 2001), it is possible that this linkage may result from a more generalized genetically mediated disturbance in the cerebral organizational events that give rise to specialization in hemispheric function. In this context, the degree of establishment of differentiated cerebral lateralization may complement linguistic endophenotypic markers to enhance identification of neurobiologically and genetically distinct subgroups of individuals with autism (Rinehart, Bradshaw, Brereton, & Tonge, 2002).

Escalante-Mead, Minshew, and Sweeney REFERENCES

Annett, M. (1999). The theory of agnostic right shift gene in schizophrenia and autism. Schizophrenia Research, 39, 177182. Blackstock, E. G. (1978). Cerebral asymmetry and the development of early infantile autism. Journal of Autism and Childhood Schizophrenia, 8, 339353. Boddaert, N., & Zilbovicius, M. (2002). Functional neuroimaging and childhood autism. Pediatric Radiology, 32, 17. Bradford, Y., Haines, J., Hutcheson, H., Gardiner, M., Braun, T., Sheffield, V., Cassavant, T., Huang, W., Wang, K., Vieland, V., Folstein, S., Santangelo, S., & Piven, J. (2001). Incorporating language phenotypes strengthens evidence of linkage to autism. American Journal of Medical Genetics (Neuropsychiatric Genetics), 105, 539547. Bryson, S. E. (1990). Autism and Anomalous Handedness. In S. Coren (Ed.), Left handedness (pp. 441456). Amsterdam: Elsevier. Carver, L. J., & Dawson, G. (2002). Development and neural bases of face recognition in autism. Molecular Psychiatry, 7 Suppl 2, S18S20. Cornish, K. M., & McManus, I. C. (1996). Hand preference and hand skill in children with autism. Journal of Autism and Developmental Disorders, 26, 597609. Egaas, B., Courchesne, E., & Saitoh, O. (1995). Reduced size of corpus callosum in autism. Archives of Neurology, 52, 794801. Fein, D., Humes, M., Kaplan, E., Lucci, D., & Waterhouse, L. (1984). The question of left hemisphere dysfunction in infantile autism. Psychological Bulletin, 95, 258281. Folstein, S. E., & Santangelo, S. L. (1999). Autism: A genetic perspective. In Tager-Flusberg (Ed.), Neurodevelopmental disorders (pp. 431451). Cambridge, MA: MIT Press. Hardan, A. Y., Minshew, N. J., & Keshavan, M. S. (2000). Corpus callosum size in autism. Neurology, 55, 10331036. Hashimoto, T., Sasaki, M., Fukumizu, M., Hanaoka, S., Sugai, K., & Matsuda, H. (2000). Single-photon emission computed tomography of the brain in autism: Effect of the developmental level. Pediatric Neurology, 23, 416420. Hauck, J. A., & Dewey, D. (2001). Hand preference and motor functioning in children with autism. Journal of Autism and Developmental Disorders, 31, 265277. Hier, D. B., LeMay, M., & Rosenberger, P. B. (1979). Autism and unfavorable left-right asymmetries of the brain. Journal of Autism and Developmental Disorders, 9, 153159. Keshavan, M. S., Diwadkar, V. A., DeBellis, M., Dick, E., Kotwal, R., Rosenberg, D. R., Sweeney, J. A., Minshew, N., & Pettegrew, J. W. (2002). Development of the corpus callosum in childhood, adolescence and early adulthood. Life Sciences, 70, 19091922. Lord, C., Risi, S., Lambrecht, L., Cook, E. H., Jr., Leventhal, B. L., DiLavore, P. C., Pickles, A., & Rutter, M. (2000). The autism diagnostic observation schedule-generic: A standard measure of social and communication deficits associated with the spectrum of autism. Journal of Autism and Developmental Disorders, 30, 205223. Lord, C., Rutter, M., & Couteur, A. L. (1994). Autism diagnostic interview-revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Journal of Autism and Developmental Disorders, 24, 659685. McAlonan, G. M., Daly, E., Kumari, V., Critchley, H. D., Amelsvoort, T. T., Suckling, J., Simmons, A., Sigmundsson, T., Greenwood, K., Russell, A., Schmitz, N., Happe, F., Howlin, P., & Murphy, D. G. (2002). Brain anatomy and sensorimotor gating in Aspergers syndrome. Brain, 125, 15941606. McCartney, G., & Hopper, P. (1999). Development of lateralized behaviour in the human fetus from 12 to 27 weeks gestation. Developmental Medicine and Child Neurology, 41, 8386.

ACKNOWLEDGMENTS Funded by grants MH01433 and NS33355 from the National Institute of Health and by an NICHD Collaborative Program of Excellence in Autism (HD35469).

Abnormal Brain Lateralization in High-Functioning Autism

McManus, I. C., Murray, B., Doyle, K., & Baron-Cohen, S. (1992). Handedness in childhood autism shows a dissociation of skill and preference. Cortex, 28, 373381. Prior, M. R., & Bradshaw, J. L. (1979). Hemisphere functioning in autistic children. Cortex, 15, 7381. Raczkowski, D., & Kalat, J. W. (1974). Reliability and validity of some handedness questionnaire items. Neuropsychologia, 12, 4347.

543

Rinehart, N. J., Bradshaw, J. L., Brereton, A. V., & Tonge, B. J. (2002). Lateralization in individuals with high-functioning autism and Aspergers disorder: A frontostriatal model. Journal of Autism and Developmental Disorders, 32, 321332. Soper, H. V., Satz, P., Orsini, D. L., Henry, R. R., Zvi, J. C., & Schulman, M. (1986). Handedness patterns in autism suggest subtypes. Journal of Autism and Developmental Disorders, 16, 155167.