A systems neuroscience approach to autism: biological, cognitive, and clinical perspectives.

Autism is a behaviorally defined disorder characterized by a broad constellation of symptoms. Numerous studies directed to the biological substrate demonstrate clear effects of neurodevelopmental differences that will likely point to the etiology, course, and long-term outcomes of the disorder. Consistently replicated research on the neural underpinnings of autism is reviewed. In general, results suggest several main conclusions: First, autism is a heterogeneous disorder and is likely to have multiple possible etiologies; second, structural brain studies have indicated a variety of diffuse anatomical differences, reflective of an early developmental change in the growth or pruning of neural tissue, rather than localized lesions; similarly, neurochemical studies suggest early, neuromodulatory discrepancies rather than gross or localized abnormalities; and finally, there are a number of limitations on studies of brain activity that to date preclude definitive answers to questions of how the brain functions differently in autism. The large number of active research programs investigating the cognitive neuroscience of autism spectrum disorders, in combination with the exciting development of new methodologies and tools in this area, indicates the drama and excitement of work in this area.

[1]  T. Frey,et al.  Neurological aspects of rubella virus infection. , 1997, Intervirology.

[2]  R. Rothermel,et al.  Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children , 1999, Annals of neurology.

[3]  C. Gillberg,et al.  Childhood psychosis and computed tomographic brain scan findings , 1983, Journal of autism and developmental disorders.

[4]  Andrew E. Switala,et al.  Minicolumnar pathology in autism , 2002, Neurology.

[5]  R. Hobson The autistic child's appraisal of expressions of emotion. , 1986, Journal of child psychology and psychiatry, and allied disciplines.

[6]  A Pickles,et al.  Language level and nonverbal social-communicative behaviors in autistic and language-delayed children. , 1996, Journal of the American Academy of Child and Adolescent Psychiatry.

[7]  S. Folstein,et al.  The etiology of autism: pre-, peri- and neonatal factors. , 1993, Journal of the American Academy of Child and Adolescent Psychiatry.

[8]  B. J. Casey,et al.  Imaging the developing brain with fMRI. , 2003, Mental retardation and developmental disabilities research reviews.

[9]  N. Minshew,et al.  Speech and language in high-functioning autistic individuals. , 1995 .

[10]  P. Rodier,et al.  Vulnerable periods and processes during central nervous system development. , 1994, Environmental health perspectives.

[11]  M. Smith,et al.  Brief report: Facilitated communication with adults with autism , 1993, Journal of Autism and Developmental Disorders.

[12]  E. Fombonne,et al.  No evidence for a new variant of measles-mumps-rubella-induced autism. , 2001, Pediatrics.

[13]  S. Folstein,et al.  Social language use in parents of autistic individuals , 1992, Psychological Medicine.

[14]  P. Mundy,et al.  A longitudinal study of joint attention and language development in autistic children , 1990, Journal of autism and developmental disorders.

[15]  P. Howlin The acquisition of grammatical morphemes in autistic children: A critique and replication of the findings of Bartolucci, Pierce, and Streiner, 1980 , 1984, Journal of autism and developmental disorders.

[16]  Dante Cicchetti,et al.  Equifinality and multifinality in developmental psychopathology , 1996, Development and Psychopathology.

[17]  J B Poline,et al.  Temporal lobe dysfunction in childhood autism: a PET study. Positron emission tomography. , 2000, The American journal of psychiatry.

[18]  Hypoplasia of the cerebellar vermis in neurogenetic syndromes , 1996, Annals of neurology.

[19]  D. Skuse,et al.  Imprinting, the X-Chromosome, and the Male Brain: Explaining Sex Differences in the Liability to Autism , 2000, Pediatric Research.

[20]  Eric Courchesne,et al.  Cerebral Lobes in Autism: Early Hyperplasia and Abnormal Age Effects , 2002, NeuroImage.

[21]  L. Lotspeich,et al.  Lack of association between HoxA1 and HoxB1 gene variants and autism in 110 multiplex families. , 2002, American journal of medical genetics.

[22]  C. Gillberg,et al.  Auditory Integration Training in Children with Autism , 1997 .

[23]  K. Reichelt,et al.  Dietary intervention in autistic syndromes. , 1990 .

[24]  A. Bailey,et al.  A clinicopathological study of autism. , 1998, Brain : a journal of neurology.

[25]  U. Frith,et al.  Autism: beyond “theory of mind” , 1994, Cognition.

[26]  A Pickles,et al.  Autism screening questionnaire: Diagnostic validity , 1999, British Journal of Psychiatry.

[27]  K. Reichelt,et al.  Autistic syndromes and diet : a follow-up study , 1995 .

[28]  F. Sallee,et al.  Platelet serotonin transporter in depressed children and adolescents: 3H-paroxetine platelet binding before and after sertraline. , 1998, Journal of the American Academy of Child and Adolescent Psychiatry.

[29]  P Bolton,et al.  Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism. , 1995, American journal of human genetics.

[30]  C. Lord Facilitating Social Inclusion , 1995 .

[31]  S. Chess Follow-up report on autism in congenital rubella , 1977, Journal of autism and childhood schizophrenia.

[32]  G. Anderson,et al.  Autism research. Bringing together approaches to pull apart the disorder. , 1996, Archives of general psychiatry.

[33]  E. Orrbine,et al.  Effect of secretin on children with autism: a randomized controlled trial , 2000, Developmental medicine and child neurology.

[34]  C. Liston,et al.  Fiber tracking using magnetic resonance diffusion tensor imaging and its applications to human brain development. , 2003, Mental retardation and developmental disabilities research reviews.

[35]  Sudhir Gupta Immunological Treatments for Autism , 2000, Journal of autism and developmental disorders.

[36]  Masahito Miyazaki,et al.  Reduced brainstem size in children with autism , 1992, Brain and Development.

[37]  J. Russell,et al.  Working memory in children with autism and with moderate learning difficulties. , 1996, Journal of child psychology and psychiatry, and allied disciplines.

[38]  S Arndt,et al.  Regional brain enlargement in autism: a magnetic resonance imaging study. , 1996, Journal of the American Academy of Child and Adolescent Psychiatry.

[39]  S. Baron-Cohen,et al.  Does the autistic child have a “theory of mind” ? , 1985, Cognition.

[40]  A. Meltzoff Infant imitation and memory: nine-month-olds in immediate and deferred tests. , 1988, Child development.

[41]  C. Gillberg,et al.  AUTISM IN THALIDOMIDE EMBRYOPATHY: A POPULATION STUDY , 1994, Developmental medicine and child neurology.

[42]  C. Lord,et al.  Austism diagnostic observation schedule: A standardized observation of communicative and social behavior , 1989, Journal of autism and developmental disorders.

[43]  I. Cohen,et al.  A comparison of haloperidol and behavior therapy and their interaction in autistic children. , 1978, Journal of the American Academy of Child Psychiatry.

[44]  B. J. Casey,et al.  Evidence for a mechanistic model of cognitive control , 2001, Clinical Neuroscience Research.

[45]  M. Leboyer,et al.  Towards a cognitive phenotype for autism: increased prevalence of executive dysfunction and superior spatial span amongst siblings of children with autism. , 1999, Journal of child psychology and psychiatry, and allied disciplines.

[46]  M. Rutter,et al.  Quasi-autistic patterns following severe early global privation. English and Romanian Adoptees (ERA) Study Team. , 1999, Journal of child psychology and psychiatry, and allied disciplines.

[47]  I M Smith,et al.  First report of a Canadian epidemiological study of autistic syndromes. , 1988, Journal of child psychology and psychiatry, and allied disciplines.

[48]  M. Leboyer,et al.  Executive function in parents of children with autism , 1997, Psychological Medicine.

[49]  T. Sigmundsson,et al.  Brain anatomy and sensorimotor gating in Asperger's syndrome. , 2002, Brain : a journal of neurology.

[50]  P Bolton,et al.  Variable expression of the autism broader phenotype: findings from extended pedigrees. , 2000, Journal of child psychology and psychiatry, and allied disciplines.

[51]  G. Dawson,et al.  Practice parameter: Screening and diagnosis of autism , 2000, Neurology.

[52]  J. Bregman,et al.  Field trial for autistic disorder in DSM-IV. , 1994, The American journal of psychiatry.

[53]  B. Pennington,et al.  Executive functions in young children with autism. , 1999, Child development.

[54]  A. Zimmerman Commentary: Immunological Treatments for Autism: In Search of Reasons for Promising Approaches , 2000, Journal of autism and developmental disorders.

[55]  R. Müller,et al.  Brain Mapping of Language and Auditory Perception in High-Functioning Autistic Adults: A PET Study , 1999, Journal of autism and developmental disorders.

[56]  L. Adamson,et al.  Joint attention in preverbal children: Autism and developmental language disorder , 1996, Journal of autism and developmental disorders.

[57]  C. Zeanah,et al.  The clinical assessment of attachment in children under five. , 1997, Journal of the American Academy of Child and Adolescent Psychiatry.

[58]  S. Folstein,et al.  Spontaneous narrative-discourse performance of parents of autistic individuals. , 1991, Journal of speech and hearing research.

[59]  F. Macciardi,et al.  Genetically determined low maternal serum dopamine beta-hydroxylase levels and the etiology of autism spectrum disorders. , 2001, American journal of medical genetics.

[60]  M. Garvey,et al.  Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. , 1998, The American journal of psychiatry.

[61]  B. Pennington,et al.  A theoretical approach to the deficits in infantile autism , 1991, Development and Psychopathology.

[62]  A. Mayes,et al.  Convergent neuroanatomical and behavioural evidence of an amygdala hypothesis of autism , 2000, Neuroreport.

[63]  E. Courchesne,et al.  Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism , 2001, Biological Psychiatry.

[64]  D. Holmes,et al.  Evaluating the impact of facilitated communication on the communicative competence of fourteen students with autism , 1996, Journal of autism and developmental disorders.

[65]  J. Piven,et al.  Psychiatric disorder and the broad autism phenotype: evidence from a family study of multiple-incidence autism families. , 1999, The American journal of psychiatry.

[66]  S. Folstein,et al.  Macrocephaly in children and adults with autism. , 1997, Journal of the American Academy of Child and Adolescent Psychiatry.

[67]  D. Amaral,et al.  Increased social fear and decreased fear of objects in monkeys with neonatal amygdala lesions , 2001, Neuroscience.

[68]  B. Dalgleish Cognitive processing and linguistic reference in autistic children , 1975, Journal of autism and childhood schizophrenia.

[69]  D. Cohen,et al.  The Hyperserotonemia of Autism a , 1990, Annals of the New York Academy of Sciences.

[70]  Genetics of autism , 1998 .

[71]  M. Rutter Autistic children: infancy to adulthood. , 1970, Seminars in psychiatry.

[72]  J. Overall,et al.  Tardive and withdrawal dyskinesia in autistic children: a prospective study. , 1988, Psychopharmacology bulletin.

[73]  P. Rodier,et al.  Embryological origin for autism: Developmental anomalies of the cranial nerve motor nuclei , 1996, The Journal of comparative neurology.

[74]  G. Bartolucci,et al.  Cross-sectional studies of grammatical morphemes in autistic and mentally retarded children , 1980, Journal of autism and developmental disorders.

[75]  B J Freeman,et al.  The UCLA-University of Utah Epidemiologic Survey of Autism: Genealogical Analysis of Familial , 1990 .

[76]  S. Kuperman,et al.  Morphological evidence for brainstem involvement in infantile autism , 1988, Biological Psychiatry.

[77]  W. Lipkin,et al.  Infectious and immune factors in the pathogenesis of neurodevelopmental disorders: epidemiology, hypotheses, and animal models. , 2001, Mental retardation and developmental disabilities research reviews.

[78]  E. Ritvo,et al.  Examination of circadian rhythmicity of blood serotonin and platelets in autistic and non-autistic children , 1971, Journal of autism and childhood schizophrenia.

[79]  R. Koegel,et al.  Self-Management of Problematic Social Behavior , 1994 .

[80]  E. Fombonne,et al.  The epidemiology of autism: a review , 1999, Psychological Medicine.

[81]  D. Cohen,et al.  Effects of diagnosis, race, and puberty on platelet serotonin levels in autism and mental retardation. , 1998, Journal of the American Academy of Child and Adolescent Psychiatry.

[82]  M. Rutter,et al.  Autism and developmental receptive language disorder--a comparative follow-up in early adult life. I: Cognitive and language outcomes. , 2000, Journal of child psychology and psychiatry, and allied disciplines.

[83]  J. Rumsey,et al.  Autonomic nervous system activity in autistic, schizophrenic, and normal men: effects of stimulus significance. , 1987, Journal of abnormal psychology.

[84]  B. Pennington,et al.  Imitation and pantomime in high-functioning adolescents with autism spectrum disorders. , 1996, Child development.

[85]  V. Ramachandran,et al.  Autonomic responses of autistic children to people and objects , 2001, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[86]  E. Bullmore,et al.  Social intelligence in the normal and autistic brain: an fMRI study , 1999, The European journal of neuroscience.

[87]  P. Bolton,et al.  A family study of autism: cognitive patterns and levels in parents and siblings. , 1997, Journal of child psychology and psychiatry, and allied disciplines.

[88]  J. Bachevalier Medial temporal lobe structures and autism: A review of clinical and experimental findings , 1994, Neuropsychologia.

[89]  S. Wolff,et al.  Personality characteristics of parents of autistic children: a controlled study. , 1988, Journal of child psychology and psychiatry, and allied disciplines.

[90]  J. Piven,et al.  An MRI study of autism: The cerebellum revisited , 1997, Neurology.

[91]  A. Damasio,et al.  Computerized tomographic scan findings in patients with autistic behavior. , 1980, Archives of neurology.

[92]  H. Ellis,et al.  A preliminary study of right hemisphere cognitive deficits and impaired social judgments among young people with Asperger syndrome , 1994, European Child & Adolescent Psychiatry.

[93]  Dong Ik Kim,et al.  Perfusion impairments in infantile autism on technetium-99m ethyl cysteinate dimer brain single-photon emission tomography: comparison with findings on magnetic resonance imaging , 1999, European Journal of Nuclear Medicine.

[94]  A. Couteur,et al.  Autism Diagnostic Interview-Revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders , 1994, Journal of autism and developmental disorders.

[95]  C. Gillberg,et al.  AUTISTIC BEHAVIOUR AND ATTENTION DEFICITS IN TUBEROUS SCLEROSIS: A POPULATION‐BASED STUDY , 1994, Developmental medicine and child neurology.

[96]  Dominique Bondoux,et al.  Whole blood serotonin and plasma beta-endorphin in autistic probands and their first-degree relatives , 1999, Biological Psychiatry.

[97]  Patricia Howlin,et al.  Diagnosis in Autism , 1997 .

[98]  J. Mountz,et al.  Functional deficits in autistic disorder: characterization by technetium-99m-HMPAO and SPECT. , 1995, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[99]  F. Volkmar At the Threshold: The Developing Adolescent , 1994 .

[100]  P. Mundy,et al.  On the nature of communication and language impairment in autism , 1997 .

[101]  E. Courchesne A Neurophysiological View of Autism , 1987 .

[102]  F. Volkmar Pharmacological Interventions in Autism: Theoretical and Practical Issues , 2001, Journal of clinical child psychology.

[103]  M. Ernst,et al.  Low medial prefrontal dopaminergic activity in autistic children , 1997, The Lancet.

[104]  M. Leboyer,et al.  SPECT OF THE BRAIN IN CHILDHOOD AUTISM: EVIDENCE FOR A LACK OF NORMAL HEMISPHERIC ASYMMETRY , 1995, Developmental medicine and child neurology.

[105]  Nancy J. Minshew,et al.  Magnetic resonance imaging of the posterior fossa in autism , 1992, Biological Psychiatry.

[106]  U. Frith,et al.  The neuropsychology of autism. , 1996, Brain : a journal of neurology.

[107]  E. Schopler,et al.  Preschool issues in autism , 1993 .

[108]  E. Courchesne,et al.  Atypical patterns of cerebral motor activation in autism: a functional magnetic resonance study , 2001, Biological Psychiatry.

[109]  M S Buchsbaum,et al.  Limbic circuitry in patients with autism spectrum disorders studied with positron emission tomography and magnetic resonance imaging. , 2000, The American journal of psychiatry.

[110]  N. Minshew,et al.  Neocortical system abnormalities in autism: An fMRI study of spatial working memory , 2002, Neurology.

[111]  N. Minshew,et al.  Brain Volume in Autism , 2001, Journal of child neurology.

[112]  J W Murakami,et al.  Reduced cerebellar hemisphere size and its relationship to vermal hypoplasia in autism. , 1989, Archives of neurology.

[113]  J. Kralovánszky,et al.  Putative Role of Dihydropyrimidine Dehydrogenase in the Toxic Side Effect of 5-Fluorouracil in Colorectal Cancer Patients , 1998, Oncology.

[114]  L. Eisenberg,et al.  The fathers of autistic children. , 1957, The American journal of orthopsychiatry.

[115]  B. Pennington,et al.  Intact and impaired memory functions in autism. , 1996, Child development.

[116]  B. Leventhal,et al.  Clinical and neurochemical effects of fenfluramine in children with autism. , 1993, The Journal of neuropsychiatry and clinical neurosciences.

[117]  B. Leventhal,et al.  Multisite, double-blind, placebo-controlled trial of porcine secretin in autism. , 2001, Journal of the American Academy of Child and Adolescent Psychiatry.

[118]  M S Buchsbaum,et al.  Anterior cingulate gyrus volume and glucose metabolism in autistic disorder. , 1997, The American journal of psychiatry.

[119]  A. Bailey,et al.  Prevalence of the fragile X anomaly amongst autistic twins and singletons. , 1993, Journal of child psychology and psychiatry, and allied disciplines.

[120]  Susan E. Bryson,et al.  Brief report: Epidemiology of autism , 1996, Journal of autism and developmental disorders.

[121]  H. Garber,et al.  Magnetic resonance imaging of the posterior fossa in autistic adults. , 1992, The American journal of psychiatry.

[122]  B. Rimland Controversies in the Treatment of Autistic Children: Vitamin and Drug Therapy , 1988, Journal of child neurology.

[123]  J. Bemporad,et al.  Brief report: Open trial effects of beta-blockers on speech and social behaviors in 8 autistic adults , 1987, Journal of autism and developmental disorders.

[124]  C. Gillberg,et al.  Symptoms in the first two years of life , 1989, European archives of psychiatry and neurological sciences.

[125]  J. Rapoport,et al.  A double-blind comparison of clomipramine, desipramine, and placebo in the treatment of autistic disorder. , 1993, Archives of general psychiatry.

[126]  A. Bailey,et al.  Autism as a strongly genetic disorder: evidence from a British twin study , 1995, Psychological Medicine.

[127]  E. Schopler,et al.  Treatment of autistic disorder. , 1996, Journal of the American Academy of Child and Adolescent Psychiatry.

[128]  E. Courchesne,et al.  Reduced size of corpus callosum in autism. , 1995, Archives of neurology.

[129]  S Arndt,et al.  An MRI study of the corpus callosum in autism. , 1997, The American journal of psychiatry.

[130]  S. Peroutka,et al.  The Neuropharmacology of Serotonin , 1990 .

[131]  R. Platt,et al.  Reducing antibiotic use in children: a randomized trial in 12 practices. , 2001, Pediatrics.

[132]  J. Overall,et al.  Efficacy and safety of fenfluramine in autistic children. , 1988, Journal of the American Academy of Child and Adolescent Psychiatry.

[133]  Sally J. Rogers,et al.  Diagnosis of autism before the age of 3 , 2000 .

[134]  R. Palkovitz,et al.  Differential autonomic responses of autistic and normal children , 1980, Journal of autism and developmental disorders.

[135]  O. I. Lovaas,et al.  Long-term outcome for children with autism who received early intensive behavioral treatment. , 1993, American journal of mental retardation : AJMR.

[136]  M. Rutter,et al.  A Comparative Study of Infantile Autism and Specific Developmental Receptive Language Disorder , 1975, British Journal of Psychiatry.

[137]  Paola Visconti,et al.  EEG features and epilepsy in patients with autism , 1995, Brain and Development.

[138]  G. Bartolucci,et al.  Deictic categories in the language of autistic children , 1974, Journal of autism and childhood schizophrenia.

[139]  N. Minshew,et al.  MRI volumes of amygdala and hippocampus in non–mentally retarded autistic adolescents and adults , 1999, Neurology.

[140]  C. McDougle,et al.  Risperidone in children with autism and serious behavioral problems. , 2002, The New England journal of medicine.

[141]  T. Shapiro,et al.  The quest for a linguistic model to study the speech of autistic children. Studies on echoing. , 1977, Journal of the American Academy of Child Psychiatry.

[142]  Ira L. Cohen,et al.  An artificial neural network analogue of learning in autism , 1994, Biological Psychiatry.

[143]  P. Rodier,et al.  Linking etiologies in humans and animal models: studies of autism. , 1997, Reproductive toxicology.

[144]  J Townsend,et al.  Visual attention abnormalities in autism: Delayed orienting to location , 1996, Journal of the International Neuropsychological Society.

[145]  E. Courchesne,et al.  Hypoplasia of cerebellar vermal lobules VI and VII in autism. , 1988, The New England journal of medicine.

[146]  A. Meltzoff,et al.  Neuropsychological correlates of early symptoms of autism. , 1998, Child development.

[147]  N. Minshew,et al.  Posterior fossa magnetic resonance imaging in autism. , 2001, Journal of the American Academy of Child and Adolescent Psychiatry.

[148]  A L Reiss,et al.  Neuroanatomical and neurocognitive differences in a pair of monozygous twins discordant for strictly defined autism , 1998, Annals of neurology.

[149]  Karl J. Friston,et al.  The neuroanatomy of autism: a voxel-based whole brain analysis of structural scans. , 1999, Neuroreport.

[150]  S. Kuperman,et al.  Midsagittal Magnetic Resonance Imaging of Autism , 1987, British Journal of Psychiatry.

[151]  Dc Washington Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. , 1994 .

[152]  M. Reite,et al.  Smaller left hemisphere planum temporale in adults with autistic disorder , 2002, Neuroscience Letters.

[153]  Tony Charman,et al.  Psychological Markers in the Detection of Autism in Infancy in a Large Population , 1996, British Journal of Psychiatry.

[154]  N. Rosman,et al.  Pneumographic findings in the infantile autism syndrome. A correlation with temporal lobe disease. , 1975, Brain : a journal of neurology.

[155]  T. Shapiro,et al.  Response to triiodothyronine and dextroamphetamine: A study of preschool schizophrenic children , 1972, Journal of autism and childhood schizophrenia.

[156]  C. Gillberg,et al.  Fenfluramine treatment of twenty children with autism , 1989, Journal of autism and developmental disorders.

[157]  W. Stone,et al.  A structured parent interview for identifying young children with autism , 1993, Journal of autism and developmental disorders.

[158]  H. Pearson Human genetics: Dual identities , 2002, Nature.

[159]  David A. Ziegler,et al.  Abnormal asymmetry in language association cortex in autism , 2002, Annals of neurology.

[160]  C. Haselgrove,et al.  MRI‐based morphometric analysis of typical and atypical brain development , 2003 .