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2. Historical Perspectives: What have we learned from research by Michael Rutter

3. SOME RESEARCH ACCOMPLISHMENTS: CLINICAL I Validation of differentiation between autism and other disorders Separateness of autism and schizophrenia Separateness of autism and intellectual disability Demonstration of neurodevelopmental basis of autism (through onset of epilepsy) Identification of low IQ and lack of language as key predictors of outcome

4. SOME RESEARCH ACCOMPLISHMENTS: CLINICAL II Development of reliable and valid interview and observation measures Demonstration that supposedly untestable children could be tested Demonstration of the importance of structure and focus in special education Development of psychological methods of treatment that involve behavioural and developmental principles, and involve partnership with parents

5. SOME RESEARCH ACCOMPLISHMENTS: CLINICAL III Identification of very high rate of autism in siblings relative to the general population Demonstration that the familial loading is strongly genetically influenced Demonstration that the genetic liability extends beyond the traditional diagnosis to include a broader phenotype Demonstration that a minority of cases of autism arise on the basis of a medical condition Demonstration of enlarged brain size developing in early life

6. SOME RESEARCH ACCOMPLISHMENTS: CLINICAL IV Identification of a mentalizing defect (later theory of mind) as basic Demonstration of key social cognition deficits (joint attention) that are evident before the development of ToM Validity of regression shown through home videos Demonstration of the reality of savant skills Discovery of Rett syndrome Demonstration of autistic-like syndrome in institutionalized and congenitally blind children

7. SOME RESEARCH ACCOMPLISHMENTS: USING TECHNOLOGY I 1.Demonstration (using imaging) that autism not due to a localized brain abnormality 2.Demonstration that increased head size reflects increased brain size 3.Demonstration that autism is associated with abnormal neural connectivity 4.Demonstration that individuals with autism solve cognitive tasks using areas of the brain that differ from those used by typically developing individuals

8. SOME RESEARCH ACCOMPLISHMENTS: USING TECHNOLOGY II 5.Demonstration of raised serotonin levels in some individuals with autism 6.Molecular genetic evidence of chromosomal regions likely to contain susceptibility genes 7.Evidence of likely role of copy number variations

9. COMMENTS ON RESEARCH STRATEGIES N.B. Good use made of: longitudinal studies with appropriate comparison groups observation of the unexpected systematic standardized measures knowledge on psychological processes in typically developing child quantitative genetics creative experimental strategies structural and functional imaging molecular genetic strategies

10. SOME INCONCLUSIVE RESEARCH No convincing evidence that the basic deficits are regularly relieved by any form of psychotropic medicine No convincing evidence of any neurochemical abnormality specifically associated with autism No convincing evidence of EEG patterns specifically associated with autism No convincing evidence of any immune abnormality specifically associated with autism No convincing evidence that benefits of psychological interventions contingent on either very early or very intensive application

11. CHALLENGES ON MEANING OF KEY CLINICAL FEATURES 1.Developmental regression 2.Existence and pattern of savant skills 3.Onset of epilepsy in late adolescence 4.Increase in brain size in preschool years 5.Adult outcome of broader phenotype 6.Lack of response to neurleptics

12. CHALLENGES OF MEANING OF OTHER PHENOMENA I 1.Intellectual disability 2.Association with paternal age 3.Association with minor congenital anomalies, chromosome abnormalities and CNVs 4.Male preponderance 5.Association with ADHD and with anxiety disorders 6.Environmental causes 7.Neuropathology 8.Dietary factors 9.Continuing disability of those or normal IQ

13. SOME REMAINING PUZZLES AND CHALLENGES I 1.What is the adult outcome of the broader phenotype? 2.What are the origins of intellectual disability in autism? 3.Why does autism differ from most other psychiatric disorders in showing no substantial response to neuroleptics? Might this be because the basic problem reflects immune mechanisms rather than transmitters? 4.Can the association with high paternal age be confirmed? If it can, what does it mean? 5.What is the meaning of the association with CNVs and a high rate of chromosomal abnormalities?

14. SOME REMAINING PUZZLES AND CHALLENGES II 6.What mechanisms underlie the male preponderance in autism? Are these mechanisms shared with other neurodevelopmental disorders? 7.What is the general population prevalence of the different components of autism? To what extent do they co-occur? 8.Why do so many individuals with normal IQ in autism nevertheless have a poor adult outcome?

15. SOME REMAINING PUZZLES AND CHALLENGES III 9.What are the environmental causes of autism? What mechanisms are involved? 10.What is the neuropathology of autism? Does it vary by degree of intellectual ability? 11.The claims that dietary interventions alleviate autism need evaluating. If effective, what mechanisms are involved?

16. SOME REMAINING PUZZLES AND CHALLENGES III 12.What can the psychological interventions achieve? Does their efficacy depend on their early application at high intensity? What mechanisms mediate efficacy? Do the children apparently relieved of their autism show a normalization of the social/cognitive deficits? 13.What early psychological abnormalities precede the onset of the overt clinical manifestations? What is their meaning in terms of the abnormal psychology involved in autism?

17. SOME GENERAL MESSAGES ON RESEARCH CHALLENGES Need for a greater focus on neglected clinical issues (such as regression or savant skills) Need to use epidemiological methods in a more hypothesis-testing fashion (e.g. in relation to prenatal risk factors or to the possibility that the three main domains of autistic symptomatology are more separate than the diagnosis implies) Need to increase the more searching, hypothesis-testing, creative use of the technologies (such as imaging and molecular genetics) Funding agencies need to recognise that research advances usually derive from creative research that reflects often iconoclastic approaches born out of new ways of looking at old problems.

18. Historical Perspectives: What have we learned from research by Michael Rutter