Phonological processing in first‐degree relatives of individuals with autism: An fMRI study

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders. Twin studies have provided heritability estimates as high as 90% for idiopathic ASD. Further evidence for the spectrum's heritability is provided by the presence of the broad autism phenotype (BAP) in unaffected first‐degree relatives. Language ability, specifically phonological processing, is proposed to be a core BAP trait. To date, however, no functional neuroimaging investigations of phonological processing in relatives of individuals with ASD have been undertaken. We conducted a functional magnetic resonance imaging (fMRI) study in parents of children with ASD utilizing a priming task probing implicit phonological processing. In our condition that placed heavier demands on phonological recoding, parents exhibited greater hemodynamic responses than controls in a network of cortical regions involved in phonological processing. Across conditions, parents exhibited enhanced priming‐induced response suppression suggesting compensatory neural processing. A nonword repetition test used in previous studies of relatives was also administered. Correlations between this measure and our functional measures also suggested compensatory processing in parents. Regions exhibiting atypical responses in parents included regions previously implicated in the spectrum's language impairments and found to exhibit structural abnormalities in a parent study. These results suggest a possible neurobiological substrate of the phonological deficits proposed to be a core BAP trait. However, these results should be considered preliminary. No previous fMRI study has investigated phonological processing in ASD, so replication is required. Furthermore, interpretation of our fMRI results is limited by the fact that the parent group failed to exhibit behavioral evidence of phonological impairments. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.

[1]  Karl J. Friston,et al.  Unified segmentation , 2005, NeuroImage.

[2]  W. McMahon,et al.  Superior Temporal Gyrus, Language Function, and Autism , 2007, Developmental neuropsychology.

[3]  B. Pennington,et al.  Impairments in phonological processing and nonverbal intellectual function in parents of children with autism , 2008, Journal of clinical and experimental neuropsychology.

[4]  J. Piven,et al.  Cognitive deficits in parents from multiple-incidence autism families. , 1996, Journal of child psychology and psychiatry, and allied disciplines.

[5]  Otto Muzik,et al.  Impairment of dentato-thalamo-cortical pathway in autistic men: language activation data from positron emission tomography , 1998, Neuroscience Letters.

[6]  Kristen A. Lindgren,et al.  Language and reading abilities of children with autism spectrum disorders and specific language impairment and their first‐degree relatives , 2009, Autism research : official journal of the International Society for Autism Research.

[7]  M. Joanisse,et al.  Modulation of brain regions involved in word recognition by homophonous stimuli: An fMRI study , 2011, Brain Research.

[8]  J. Mitchell Comprehensive Test of Phonological Processing , 2001 .

[9]  S. Folstein,et al.  Predictors of cognitive test patterns in autism families. , 1999, Journal of child psychology and psychiatry, and allied disciplines.

[10]  E. T. Possing,et al.  Language lateralization in left-handed and ambidextrous people: fMRI data , 2002, Neurology.

[11]  J. Hurst,et al.  An extended Family with a Dominantly Inherited Speech Disorder , 1990, Developmental medicine and child neurology.

[12]  A. Song,et al.  Linking Sight and Sound: fMRI Evidence of Primary Auditory Cortex Activation during Visual Word Recognition , 2001, Brain and Language.

[13]  D. Bishop,et al.  Further defining the language impairment of autism: is there a specific language impairment subtype? , 2008, Journal of communication disorders.

[14]  Kim M. Dalton,et al.  Gaze-Fixation, Brain Activation, and Amygdala Volume in Unaffected Siblings of Individuals with Autism , 2007, Biological Psychiatry.

[15]  M. D’Esposito Working memory. , 2008, Handbook of clinical neurology.

[16]  M. Stevens,et al.  Subtypes of Language Disorders in School-Age Children With Autism , 2009, Developmental neuropsychology.

[17]  K. Reddy Cytogenetic abnormalities and fragile-x syndrome in Autism Spectrum Disorder , 2005, BMC Medical Genetics.

[18]  Alan C. Evans,et al.  Neuroanatomical differences in brain areas implicated in perceptual and other core features of autism revealed by cortical thickness analysis and voxel‐based morphometry , 2009, Human brain mapping.

[19]  Stanislas Dehaene,et al.  Cerebral bases of subliminal and supraliminal priming during reading. , 2007, Cerebral cortex.

[20]  Emmanuel Dupoux,et al.  Cerebral bases of subliminal speech priming , 2010, NeuroImage.

[21]  Hermann Ackermann,et al.  The contribution(s) of the insula to speech production: a review of the clinical and functional imaging literature , 2010, Brain Structure and Function.

[22]  J. Constantino,et al.  Familial aggregation of quantitative autistic traits in multiplex versus simplex autism , 2009, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[23]  Paul C. Locasto,et al.  A systematic investigation of the functional neuroanatomy of auditory and visual phonological processing , 2005, NeuroImage.

[24]  M. Mintun,et al.  Regional cerebral blood flow during word and nonword reading , 1997, Human brain mapping.

[25]  E. Ringelstein,et al.  Handedness and hemispheric language dominance in healthy humans. , 2000, Brain : a journal of neurology.

[26]  A. Meltzoff,et al.  Early Social, Imitation, Play, and Language Abilities of Young Non-Autistic Siblings of Children with Autism , 2007, Journal of autism and developmental disorders.

[27]  S. Folstein,et al.  Incorporating language phenotypes strengthens evidence of linkage to autism. , 2001, American journal of medical genetics.

[28]  Cheryl Smith Gabig Verbal working memory and story retelling in school-age children with autism. , 2008, Language, speech, and hearing services in schools.

[29]  H. Tager-Flusberg Brief report: Current theory and research on language and communication in autism , 1996, Journal of autism and developmental disorders.

[30]  Rebecca Treiman,et al.  The English Lexicon Project , 2007, Behavior research methods.

[31]  T. Hashimoto,et al.  Brainstem and Cerebellar Vermis Involvement in Autistic Children , 1993, Journal of child neurology.

[32]  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.

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

[34]  P. Szatmari,et al.  Prolongation of brainstem auditory-evoked responses in autistic probands and their unaffected relatives. , 2000, Archives of general psychiatry.

[35]  Joseph K. Torgesen,et al.  Comprehensive Test of Phonological Processing , 1997 .

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

[37]  Jason Adams,et al.  Abnormal brain size effect on the thalamus in autism , 2006, Psychiatry Research: Neuroimaging.

[38]  S. Baron-Cohen Social and pragmatic deficits in autism: Cognitive or affective? , 1988, Journal of autism and developmental disorders.

[39]  P. Strick,et al.  Cerebellum and nonmotor function. , 2009, Annual review of neuroscience.

[40]  M. Reite,et al.  Hippocampus and amygdala volumes in parents of children with autistic disorder. , 2004, The American journal of psychiatry.

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

[42]  J. Piven,et al.  Personality and language characteristics in parents from multiple-incidence autism families. , 1997, American journal of medical genetics.

[43]  A L Alexander,et al.  Decreased Left Posterior Insular Activity during Auditory Language in Autism , 2010, American Journal of Neuroradiology.

[44]  D. Geschwind,et al.  Quantitative genome scan and Ordered-Subsets Analysis of autism endophenotypes support language QTLs , 2005, Molecular Psychiatry.

[45]  A. Mechelli,et al.  Anatomical Traces of Vocabulary Acquisition in the Adolescent Brain , 2007, The Journal of Neuroscience.

[46]  S. Baron-Cohen,et al.  Defining the broader, medium and narrow autism phenotype among parents using the Autism Spectrum Quotient (AQ) , 2010, Molecular autism.

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

[48]  Eric Courchesne,et al.  Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism , 1997, Current Opinion in Neurobiology.

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

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

[51]  John L Bradshaw,et al.  Electrophysiological signs of supplementary‐motor‐area deficits in high‐functioning autism but not Asperger syndrome: an examination of internally cued movement‐related potentials , 2009, Developmental medicine and child neurology.

[52]  Mart Bles,et al.  Phonological processing of ignored distractor pictures, an fMRI investigation , 2008, BMC Neuroscience.

[53]  S. Baron-Cohen,et al.  The Autism-Spectrum Quotient (AQ): Evidence from Asperger Syndrome/High-Functioning Autism, Malesand Females, Scientists and Mathematicians , 2001, Journal of autism and developmental disorders.

[54]  Edward E. Smith,et al.  Dissociation of Storage and Rehearsal in Verbal Working Memory: Evidence From Positron Emission Tomography , 1996 .

[55]  J. Piven,et al.  Chromosomal abnormalities in a clinic sample of individuals with autistic disorder , 2001, Psychiatric genetics.

[56]  Matcheri S. Keshavan,et al.  Enlarged right superior temporal gyrus in children and adolescents with autism , 2010, Brain Research.

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

[58]  B. Shaywitz,et al.  The Role of Functional Magnetic Resonance Imaging in Understanding Reading and Dyslexia , 2006, Developmental neuropsychology.

[59]  H. Wimmer,et al.  Functional abnormalities in the dyslexic brain: A quantitative meta‐analysis of neuroimaging studies , 2009, Human brain mapping.

[60]  Ralph-Axel Müller,et al.  Partially enhanced thalamocortical functional connectivity in autism , 2006, Brain Research.

[61]  D. Geschwind,et al.  Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families. , 2002, American journal of human genetics.

[62]  J. Sebat,et al.  Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. , 2008, American journal of human genetics.

[63]  N. Minshew,et al.  Understanding autism and related disorders: what has imaging taught us? , 2007, Neuroimaging clinics of North America.

[64]  Satrajit S. Ghosh,et al.  A neuroimaging study of premotor lateralization and cerebellar involvement in the production of phonemes and syllables. , 2008, Journal of speech, language, and hearing research : JSLHR.

[65]  P. Skudlarski,et al.  The cerebellum's role in reading: a functional MR imaging study. , 1999, AJNR. American journal of neuroradiology.

[66]  Elizabeth Redcay,et al.  Deviant Functional Magnetic Resonance Imaging Patterns of Brain Activity to Speech in 2–3-Year-Old Children with Autism Spectrum Disorder , 2008, Biological Psychiatry.

[67]  Jason Adams,et al.  Brief Report: Abnormal Association Between the Thalamus and Brain Size in Asperger’s Disorder , 2008, Journal of autism and developmental disorders.

[68]  Jeffrey A. Stanley,et al.  An MRI and proton spectroscopy study of the thalamus in children with autism , 2008, Psychiatry Research: Neuroimaging.

[69]  James R. Booth,et al.  Phonological Priming in Visual Word Recognition for English Words: An Event-Related Functional MRI Study , 2006 .

[70]  S. Folstein,et al.  Infantile autism: a genetic study of 21 twin pairs. , 1977, Journal of child psychology and psychiatry, and allied disciplines.

[71]  U. Frith,et al.  Explicit and implicit processing of words and pseudowords by adult developmental dyslexics: A search for Wernicke's Wortschatz? , 1999, Brain : a journal of neurology.

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

[73]  Thomas J. Grabowski,et al.  The Left Posterior Superior Temporal Gyrus Participates Specifically in Accessing Lexical Phonology , 2008, Journal of Cognitive Neuroscience.

[74]  Ami Klin,et al.  Reduced thalamic volume in high-functioning individuals with autism , 2003, Biological Psychiatry.

[75]  A. Liberman,et al.  Functional disruption in the organization of the brain for reading in dyslexia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[76]  H. Coslett,et al.  Localization of sublexical speech perception components , 2010, Brain and Language.

[77]  B. Shaywitz,et al.  Paying attention to reading: The neurobiology of reading and dyslexia , 2008, Development and Psychopathology.

[78]  J. Desmond,et al.  Functional Specialization for Semantic and Phonological Processing in the Left Inferior Prefrontal Cortex , 1999, NeuroImage.

[79]  N. Tzourio-Mazoyer,et al.  Automated Anatomical Labeling of Activations in SPM Using a Macroscopic Anatomical Parcellation of the MNI MRI Single-Subject Brain , 2002, NeuroImage.

[80]  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.

[81]  James R. Booth,et al.  Functional Anatomy of Intra- and Cross-Modal Lexical Tasks , 2002, NeuroImage.

[82]  G. B. Schaefer,et al.  Diagnostic yield in the clinical genetic evaluation of autism spectrum disorders , 2006, Genetics in medicine : official journal of the American College of Medical Genetics.

[83]  Yi Zhang,et al.  Sibling recurrence and the genetic epidemiology of autism. , 2010, The American journal of psychiatry.

[84]  Joseph Piven,et al.  Defining key features of the broad autism phenotype: A comparison across parents of multiple‐ and single‐incidence autism families , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[85]  Tanya M. Teslovich,et al.  A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. , 2008, American journal of human genetics.

[86]  C. Lord,et al.  Language and Communication in Autism , 2014 .

[87]  D. Geschwind,et al.  A functional genetic link between distinct developmental language disorders. , 2008, The New England journal of medicine.

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

[89]  Gregory Hickok,et al.  Phonological repetition-suppression in bilateral superior temporal sulci , 2010, NeuroImage.

[90]  P. Deyn,et al.  The Lateralized Linguistic Cerebellum: A Review and a New Hypothesis , 2001, Brain and Language.

[91]  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.

[92]  Ying-Fang Sun,et al.  Brain imaging findings in dyslexia. , 2010, Pediatrics and neonatology.

[93]  E. Walker,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[94]  G. Dawson,et al.  Defining the broader phenotype of autism: Genetic, brain, and behavioral perspectives , 2002, Development and Psychopathology.

[95]  Jason R. Tregellas,et al.  Implicit phonological priming during visual word recognition , 2011, NeuroImage.

[96]  Bruce E. Murdoch,et al.  The cerebellum and language: Historical perspective and review , 2010, Cortex.

[97]  W. Roberts,et al.  Language lateralization development in children with autism: Insights from the late field magnetoencephalogram , 2005, Neuroscience Letters.

[98]  Jason R Tregellas,et al.  A voxel-based morphometry study of gray matter in parents of children with autism , 2006, Neuroreport.

[99]  C Donlan,et al.  Nonword repetition as a behavioural marker for inherited language impairment: evidence from a twin study. , 1996, Journal of child psychology and psychiatry, and allied disciplines.

[100]  D. Poeppel,et al.  The cortical organization of speech processing , 2007, Nature Reviews Neuroscience.

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

[102]  John E. Desmond,et al.  Temporal dynamics of cerebro-cerebellar network recruitment during a cognitive task , 2005, Neuropsychologia.

[103]  Peter Teale,et al.  BMC Psychiatry BioMed Central Research article Use of antipsychotics and benzodiazepines in patients with psychiatric emergencies: Results of an observational trial , 2008 .

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

[105]  D. Amaral,et al.  Neuroanatomy of autism , 2008, Trends in Neurosciences.

[106]  G Jobard,et al.  Evaluation of the dual route theory of reading: a metanalysis of 35 neuroimaging studies , 2003, NeuroImage.

[107]  S. Petersen,et al.  The “Task B problem” and other considerations in developmental functional neuroimaging , 2010, Human brain mapping.

[108]  J. Schmahmann From movement to thought: Anatomic substrates of the cerebellar contribution to cognitive processing , 1996, Human brain mapping.

[109]  Bruce D. McCandliss,et al.  Development of neural systems for reading. , 2007, Annual review of neuroscience.

[110]  Mark H Johnson,et al.  Neuroimaging of typical and atypical development: A perspective from multiple levels of analysis , 2002, Development and Psychopathology.

[111]  I. Moilanen,et al.  Associated Medical Disorders and Disabilities in Children with Autistic Disorder , 2004, Autism : the international journal of research and practice.

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

[113]  P. Skudlarski,et al.  Disruption of posterior brain systems for reading in children with developmental dyslexia , 2002, Biological Psychiatry.

[114]  H Stanislaw,et al.  Calculation of signal detection theory measures , 1999, Behavior research methods, instruments, & computers : a journal of the Psychonomic Society, Inc.

[115]  Joseph T. Devlin,et al.  Supramarginal gyrus involvement in visual word recognition , 2009, Cortex.

[116]  H. Tager-Flusberg,et al.  Language disorders: autism and other pervasive developmental disorders. , 2007, Pediatric clinics of North America.

[117]  Tony Charman,et al.  Neural Correlates of Eye Gaze Processing in the Infant Broader Autism Phenotype , 2009, Biological Psychiatry.

[118]  Robert W Thatcher,et al.  Autism and EEG Phase Reset: Deficient GABA Mediated Inhibition in Thalamo-Cortical Circuits , 2009, Developmental neuropsychology.

[119]  A. Liberman,et al.  Parametrically Dissociating Speech and Nonspeech Perception in the Brain Using fMRI , 2001, Brain and Language.

[120]  S. Kuperman,et al.  Cerebellar structure in autism. , 1987, American journal of diseases of children.

[121]  Marko Wilke,et al.  LI-tool: A new toolbox to assess lateralization in functional MR-data , 2007, Journal of Neuroscience Methods.

[122]  H. Tager-Flusberg A psychological approach to understanding the social and language impairments in autism. , 1999, International review of psychiatry.

[123]  J. Pujol,et al.  Cerebral lateralization of language in normal left-handed people studied by functional MRI , 1999, Neurology.

[124]  H. Engeland,et al.  Review on structural neuroimaging findings in autism , 2004, Journal of Neural Transmission.

[125]  E. Bullmore,et al.  fMRI of parents of children with Asperger Syndrome: A pilot study , 2006, Brain and Cognition.

[126]  H. Tager-Flusberg,et al.  An investigation of language impairment in autism: Implications for genetic subgroups , 2001, Language and cognitive processes.

[127]  J. Hallmayer,et al.  Are phonological processing deficits part of the broad autism phenotype? , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[128]  Geraldine Dawson,et al.  Neurocognitive and electrophysiological evidence of altered face processing in parents of children with autism: Implications for a model of abnormal development of social brain circuitry in autism , 2005, Development and Psychopathology.

[129]  C. Gillberg,et al.  A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. , 1989, Journal of child psychology and psychiatry, and allied disciplines.

[130]  E. Ringelstein,et al.  Language lateralization in healthy right-handers. , 2000, Brain : a journal of neurology.

[131]  M. Annett Left, right, hand and brain : the right shift theory , 1985 .

[132]  Nouchine Hadjikhani,et al.  fMRI activation during a language task in adolescents with ASD , 2008, Journal of the International Neuropsychological Society.

[133]  Richard S. Frackowiak,et al.  Superior temporal sulcus anatomical abnormalities in childhood autism: a voxel-based morphometry MRI study , 2004, NeuroImage.

[134]  R. Tuchman,et al.  Autistic and dysphasic children. I: Clinical characteristics. , 1991, Pediatrics.

[135]  Lieven Lagae,et al.  Neuroimaging of autism , 2009, Neuroradiology.

[136]  Karl J. Friston,et al.  Scanning patients with tasks they can perform , 1999, Human brain mapping.

[137]  J. Fletcher,et al.  Specific reading disability (dyslexia): what have we learned in the past four decades? , 2004, Journal of child psychology and psychiatry, and allied disciplines.

[138]  Frank H. Guenther,et al.  An fMRI investigation of syllable sequence production , 2006, NeuroImage.

[139]  John E. Desmond,et al.  Cerebrocerebellar networks during articulatory rehearsal and verbal working memory tasks , 2005, NeuroImage.

[140]  Helen Tager-Flusberg,et al.  Language laterality in autism spectrum disorder and typical controls: A functional, volumetric, and diffusion tensor MRI study , 2010, Brain and Language.

[141]  Hermann Ackermann,et al.  The contribution of the cerebellum to speech production and speech perception: Clinical and functional imaging data , 2008, The Cerebellum.

[142]  Ralph-Axel Müller,et al.  Atypical functional lateralization of language in autism spectrum disorders , 2008, Brain Research.