Saccade Adaptation Abnormalities Implicate Dysfunction of Cerebellar-Dependent Learning Mechanisms in Autism Spectrum Disorders (ASD)

The cerebellar vermis (lobules VI-VII) has been implicated in both postmortem and neuroimaging studies of autism spectrum disorders (ASD). This region maintains the consistent accuracy of saccadic eye movements and plays an especially important role in correcting systematic errors in saccade amplitudes such as those induced by adaptation paradigms. Saccade adaptation paradigms have not yet been used to study ASD. Fifty-six individuals with ASD and 53 age-matched healthy controls performed an intrasaccadic target displacement task known to elicit saccadic adaptation reflected in an amplitude reduction. The rate of amplitude reduction and the variability of saccade amplitude across 180 adaptation trials were examined. Individuals with ASD adapted slower than healthy controls, and demonstrated more variability of their saccade amplitudes across trials prior to, during and after adaptation. Thirty percent of individuals with ASD did not significantly adapt, whereas only 6% of healthy controls failed to adapt. Adaptation rate and amplitude variability impairments were related to performance on a traditional neuropsychological test of manual motor control. The profile of impaired adaptation and reduced consistency of saccade accuracy indicates reduced neural plasticity within learning circuits of the oculomotor vermis that impedes the fine-tuning of motor behavior in ASD. These data provide functional evidence of abnormality in the cerebellar vermis that converges with previous reports of cellular and gross anatomic dysmorphology of this brain region in ASD.

[1]  N. Minshew,et al.  Oculomotor evidence for neocortical systems but not cerebellar dysfunction in autism , 1999, Neurology.

[2]  Scott T. Grafton,et al.  Genetic dissection of Alzheimer's disease and related dementias: amyloid and its relationship to tau , 1998, Nature Neuroscience.

[3]  D. Zee,et al.  Effects of lesions of the oculomotor vermis on eye movements in primate: saccades. , 1998, Journal of neurophysiology.

[4]  A. Scheibel,et al.  Lower Purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA-NSAC Autopsy Research Report. , 1986, The American journal of psychiatry.

[5]  C Martin-Ruiz,et al.  Nicotinic receptor abnormalities in the cerebellar cortex in autism. , 2002, Brain : a journal of neurology.

[6]  Sarah E. Pekny,et al.  Motor Learning Relies on Integrated Sensory Inputs in ADHD, but Over‐Selectively on Proprioception in Autism Spectrum Conditions , 2012, Autism research : official journal of the International Society for Autism Research.

[7]  M. Ito Cerebellar control of the vestibulo-ocular reflex--around the flocculus hypothesis. , 1982, Annual review of neuroscience.

[8]  E. Courchesne,et al.  Abnormality of cerebellar vermian lobules VI and VII in patients with infantile autism: identification of hypoplastic and hyperplastic subgroups with MR imaging. , 1994, AJR. American journal of roentgenology.

[9]  John O. Willis,et al.  Wechsler Abbreviated Scale of Intelligence , 2014 .

[10]  H. Deubel Separate adaptive mechanisms for the control of reactive and volitional saccadic eye movements , 1995, Vision Research.

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

[12]  R. Landa,et al.  Current Perspectives on Motor Functioning in Infants, Children, and Adults With Autism Spectrum Disorders , 2011, Physical Therapy.

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

[14]  Scott T. Grafton,et al.  Functional adaptation of reactive saccades in humans: a PET study , 2000, Experimental Brain Research.

[15]  Diana L. Robins,et al.  Predictors of Optimal Outcome in Toddlers Diagnosed with Autism Spectrum Disorders , 2007, Journal of autism and developmental disorders.

[16]  Jessica Brian,et al.  A Prospective Case Series of High-risk Infants who Developed Autism , 2007, Journal of autism and developmental disorders.

[17]  C. Scudder,et al.  Comparison of two methods of producing adaptation of saccade size and implications for the site of plasticity. , 1998, Journal of neurophysiology.

[18]  P. Thuras,et al.  Purkinje Cell Size Is Reduced in Cerebellum of Patients with Autism , 2002, Cellular and Molecular Neurobiology.

[19]  S. Mostofsky,et al.  Specificity of Cerebellar Vermian Abnormalities in Autism: A Quantitative Magnetic Resonance Imaging Study , 2003, Journal of child neurology.

[20]  P. Thier,et al.  Saccadic Dysmetria and Adaptation after Lesions of the Cerebellar Cortex , 1999, The Journal of Neuroscience.

[21]  P. Thier,et al.  Encoding of movement time by populations of cerebellar Purkinje cells , 2000, Nature.

[22]  J. Baio,et al.  Prevalence of Autism Spectrum Disorders: Autism and Developmental Disabilities Monitoring Network, United States, 2006. Morbidity and Mortality Weekly Report. Surveillance Summaries. Volume 58, Number SS-10. , 2009 .

[23]  Reza Shadmehr,et al.  Acquisition of internal models of motor tasks in children with autism. , 2008, Brain : a journal of neurology.

[24]  Beatriz Luna,et al.  Maturation of Executive Function in Autism , 2007, Biological Psychiatry.

[25]  R. Wurtz,et al.  Reversible inactivation of monkey superior colliculus. I. Curvature of saccadic trajectory. , 1998, Journal of neurophysiology.

[26]  M Glickstein,et al.  Normal spatial attention but impaired saccades and visual motion perception after lesions of the monkey cerebellum. , 2009, Journal of neurophysiology.

[27]  A. Reiss,et al.  Neuroanatomic alterations and social and communication deficits in monozygotic twins discordant for autism disorder. , 2009, The American journal of psychiatry.

[28]  Sarah E. Criscimagna-Hemminger,et al.  Cerebellar Contributions to Reach Adaptation and Learning Sensory Consequences of Action , 2012, The Journal of Neuroscience.

[29]  U Rosenhall,et al.  Oculomotor findings in autistic children , 1988, The Journal of Laryngology & Otology.

[30]  J. Pekar,et al.  Decreased connectivity and cerebellar activity in autism during motor task performance. , 2009, Brain : a journal of neurology.

[31]  Julia A. Scott,et al.  A comprehensive volumetric analysis of the cerebellum in children and adolescents with autism spectrum disorder , 2009, Autism research : official journal of the International Society for Autism Research.

[32]  Beatriz Luna,et al.  Atypical involvement of frontostriatal systems during sensorimotor control in autism , 2007, Psychiatry Research: Neuroimaging.

[33]  Matthew W. Mosconi,et al.  Consensus Paper: Pathological Role of the Cerebellum in Autism , 2012, The Cerebellum.

[34]  Marja Cantell,et al.  Motor and gestural performance in children with autism spectrum disorders, developmental coordination disorder, and/or attention deficit hyperactivity disorder , 2007, Journal of the International Neuropsychological Society.

[35]  Edward G Freedman,et al.  The Locus of Motor Activity in the Superior Colliculus of the Rhesus Monkey Is Unaltered during Saccadic Adaptation , 2010, The Journal of Neuroscience.

[36]  Artem V. Belopolsky,et al.  I. Curvature of Saccadic Trajectory Reversible Inactivation of Monkey Superior Colliculus. , 2015 .

[37]  Leon Eisenberg,et al.  Autism and Asperger syndrome , 1992, The Lancet.

[38]  Geraldine Dawson,et al.  Cerebellar vermal volumes and behavioral correlates in children with autism spectrum disorder , 2009, Psychiatry Research: Neuroimaging.

[39]  Masao Ito,et al.  Long-term desensitization of quisqualate-specific glutamate receptors in Purkinje cells investigated with wedge recording from rat cerebellar slices , 1989, Neuroscience Research.

[40]  Douglas L. Rosene,et al.  Cerebellar Purkinje Cells are Reduced in a Subpopulation of Autistic Brains: A Stereological Experiment Using Calbindin-D28k , 2008, The Cerebellum.

[41]  E. Courchesne,et al.  Abnormal variability and distribution of functional maps in autism: an FMRI study of visuomotor learning. , 2003, The American journal of psychiatry.

[42]  N. Minshew,et al.  Pursuit eye movement deficits in autism. , 2004, Brain : a journal of neurology.

[43]  L. Kanner Autistic disturbances of affective contact. , 1968, Acta paedopsychiatrica.

[44]  T. Kemper,et al.  Histoanatomic observations of the brain in early infantile autism , 1985, Neurology.

[45]  H. Deubel,et al.  Cerebellar lesions impair rapid saccade amplitude adaptation , 2001, Neurology.

[46]  Eric Courchesne,et al.  Neurologic Abnormalities in Infantile Autism , 1996, Journal of child neurology.

[47]  B. Leventhal,et al.  The Autism Diagnostic Observation Schedule—Generic: A Standard Measure of Social and Communication Deficits Associated with the Spectrum of Autism , 2000, Journal of autism and developmental disorders.

[48]  K. Ohtsuka,et al.  Discharge properties of Purkinje cells in the oculomotor vermis during visually guided saccades in the macaque monkey. , 1995, Journal of neurophysiology.

[49]  N. Minshew,et al.  Oculomotor studies of cerebellar function in autism , 2005, Psychiatry Research.

[50]  D. Marr A theory of cerebellar cortex , 1969, The Journal of physiology.

[51]  Eric Courchesne,et al.  Differential effects of developmental cerebellar abnormality on cognitive and motor functions in the cerebellum: an fMRI study of autism. , 2003, The American journal of psychiatry.

[52]  U. Frith,et al.  Autism and Asperger Syndrome , 1992 .

[53]  T. Kemper,et al.  Neuroanatomic observations of the brain in autism: a review and future directions , 2005, International Journal of Developmental Neuroscience.

[54]  R. Shadmehr,et al.  Cerebellar Contributions to Adaptive Control of Saccades in Humans , 2009, The Journal of Neuroscience.

[55]  N. Minshew,et al.  Oculomotor abnormalities parallel cerebellar histopathology in autism , 2004, Journal of Neurology, Neurosurgery & Psychiatry.

[56]  J. Baio Prevalence of autism spectrum disorders--Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. , 2012, Morbidity and mortality weekly report. Surveillance summaries.

[57]  Albert F. Fuchs,et al.  Effect of inactivation and disinhibition of the oculomotor vermis on saccade adaptation , 2011, Brain Research.

[58]  Richard D. Jones,et al.  Adaptive modification of saccade amplitude in Parkinson's disease. , 2002, Brain : a journal of neurology.

[59]  H. Asperger,et al.  'Autistic psychopathy' in childhood. , 1991 .

[60]  Sally J. Rogers,et al.  Gross Motor Development, Movement Abnormalities, and Early Identification of Autism , 2008, Journal of autism and developmental disorders.

[61]  Ruth A. Carper,et al.  Unusual brain growth patterns in early life in patients with autistic disorder , 2001, Neurology.

[62]  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.

[63]  Michael R. Hunsaker,et al.  Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome , 2011, Molecular autism.

[64]  S. Lawrie,et al.  Towards a neuroanatomy of autism: A systematic review and meta-analysis of structural magnetic resonance imaging studies , 2008, European Psychiatry.

[65]  J. Sweeney,et al.  Pharmacological treatment effects on eye movement control , 2008, Brain and Cognition.

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

[67]  Katharina Havermann,et al.  The influence of the consistency of postsaccadic visual errors on saccadic adaptation. , 2010, Journal of neurophysiology.

[68]  M. Eizenman,et al.  Saccadic Adaptation in Children , 2006, Journal of child neurology.

[69]  B. Provost,et al.  Levels of Gross and Fine Motor Development in Young Children with Autism Spectrum Disorder , 2007, Physical & occupational therapy in pediatrics.

[70]  R. Ivry,et al.  Cerebellar involvement in anticipating the consequences of self-produced actions during bimanual movements. , 2005, Journal of neurophysiology.

[71]  C. Scudder,et al.  Adaptive modification of saccade size produces correlated changes in the discharges of fastigial nucleus neurons. , 2003, Journal of neurophysiology.

[72]  Yoshiko Kojima,et al.  Subthreshold Activation of the Superior Colliculus Drives Saccade Motor Learning , 2009, The Journal of Neuroscience.

[73]  Hiroshi Imamizu,et al.  Human cerebellar activity reflecting an acquired internal model of a new tool , 2000, Nature.

[74]  A. Fuchs,et al.  Characteristics of saccadic gain adaptation in rhesus macaques. , 1997, Journal of neurophysiology.

[75]  Donald Hedeker,et al.  Advances in analysis of longitudinal data. , 2010, Annual review of clinical psychology.

[76]  Anna-Maria D'Cruz,et al.  Neurobehavioral abnormalities in first-degree relatives of individuals with autism. , 2010, Archives of general psychiatry.

[77]  Eric Courchesne,et al.  Outcome classification of preschool children with autism spectrum disorders using MRI brain measures. , 2004, Journal of the American Academy of Child and Adolescent Psychiatry.

[78]  J. Albus A Theory of Cerebellar Function , 1971 .

[79]  A N Bhat,et al.  Infant Behavior and Development Relation between early motor delay and later communication delay in infants at risk for autism , 2012 .

[80]  Denis Pélisson,et al.  Retention of Saccadic Adaptation in Humans , 2005, Annals of the New York Academy of Sciences.

[81]  J. Krakauer,et al.  Sensory prediction errors drive cerebellum-dependent adaptation of reaching. , 2007, Journal of neurophysiology.

[82]  D. Geschwind,et al.  Connecting genes to brain in the autism spectrum disorders. , 2010, Archives of neurology.

[83]  G. Blatt,et al.  Increased GAD67 mRNA expression in cerebellar interneurons in autism: Implications for Purkinje cell dysfunction , 2008, Journal of neuroscience research.

[84]  G. Blatt,et al.  Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications , 2007, Acta Neuropathologica.

[85]  J. Yelnik,et al.  Involvement of the cerebellar thalamus in human saccade adaptation , 2001, The European journal of neuroscience.

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

[87]  S. Mostofsky,et al.  Specificity of dyspraxia in children with autism. , 2012, Neuropsychology.

[88]  G. Baird,et al.  The severity and nature of motor impairment in Asperger's syndrome: a comparison with specific developmental disorder of motor function. , 2002, Journal of child psychology and psychiatry, and allied disciplines.

[89]  S. M. Morton,et al.  Children with Autism Adapt Normally during a Catching Task Requiring the Cerebellum , 2004, Neurocase.

[90]  E. Courchesne,et al.  An MRI study of autism : The cerebellum revisited , 1999, Neurology.

[91]  S. C. Mclaughlin Parametric adjustment in saccadic eye movements , 1967 .

[92]  P. Thier,et al.  Reduced saccadic resilience and impaired saccadic adaptation due to cerebellar disease , 2007, The European journal of neuroscience.