A Short Review on the Current Understanding of Autism Spectrum Disorders

Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders characterized by a deficit in social behaviors and nonverbal interactions such as reduced eye contact, facial expression, and body gestures in the first 3 years of life. It is not a single disorder, and it is broadly considered to be a multi-factorial disorder resulting from genetic and non-genetic risk factors and their interaction. Genetic studies of ASD have identified mutations that interfere with typical neurodevelopment in utero through childhood. These complexes of genes have been involved in synaptogenesis and axon motility. Recent developments in neuroimaging studies have provided many important insights into the pathological changes that occur in the brain of patients with ASD in vivo. Especially, the role of amygdala, a major component of the limbic system and the affective loop of the cortico-striatothalamo-cortical circuit, in cognition and ASD has been proved in numerous neuropathological and neuroimaging studies. Besides the amygdala, the nucleus accumbens is also considered as the key structure which is related with the social reward response in ASD. Although educational and behavioral treatments have been the mainstay of the management of ASD, pharmacological and interventional treatments have also shown some benefit in subjects with ASD. Also, there have been reports about few patients who experienced improvement after deep brain stimulation, one of the interventional treatments. The key architecture of ASD development which could be a target for treatment is still an uncharted territory. Further work is needed to broaden the horizons on the understanding of ASD.

[1]  Matthew W State,et al.  Autism spectrum disorders: from genes to neurobiology , 2015, Current Opinion in Neurobiology.

[2]  Rebecca C. Knickmeyer,et al.  Why Are Autism Spectrum Conditions More Prevalent in Males? , 2011, PLoS biology.

[3]  Daniel Tranel,et al.  Amygdala damage impairs emotional memory for gist but not details of complex stimuli , 2005, Nature Neuroscience.

[4]  Paul D Griffiths,et al.  Association of tuberous sclerosis of temporal lobes with autism and atypical autism , 1997, The Lancet.

[5]  R. Adolphs,et al.  Annals of the New York Academy of Sciences What Does the Amygdala Contribute to Social Cognition? , 2022 .

[6]  Bennett L. Leventhal,et al.  Genetic Epidemiology and Insights into Interactive Genetic and Environmental Effects in Autism Spectrum Disorders , 2015, Biological Psychiatry.

[7]  P. Whalen,et al.  The Structural Integrity of an Amygdala–Prefrontal Pathway Predicts Trait Anxiety , 2009, The Journal of Neuroscience.

[8]  Stephan J Sanders,et al.  The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment , 2015, Nature Communications.

[9]  T. Bourgeron,et al.  Abnormal melatonin synthesis in autism spectrum disorders , 2008, Molecular Psychiatry.

[10]  D. Rossignol,et al.  Melatonin in autism spectrum disorders: a systematic review and meta‐analysis , 2011, Developmental medicine and child neurology.

[11]  C. McDougle,et al.  Drug-refractory aggression, self-injurious behavior, and severe tantrums in autism spectrum disorders: A chart review study , 2015, Autism : the international journal of research and practice.

[12]  Kazuya Yoshida,et al.  Infantile zinc deficiency: Association with autism spectrum disorders , 2011, Scientific reports.

[13]  M. Hurles,et al.  De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability. , 2014, American journal of human genetics.

[14]  T. Robbins,et al.  The neuropsychopharmacology of fronto-executive function: monoaminergic modulation. , 2009, Annual review of neuroscience.

[15]  E. London The environment as an etiologic factor in autism: a new direction for research. , 2000, Environmental health perspectives.

[16]  E Courchesne,et al.  Parietal lobe abnormalities detected with MR in patients with infantile autism. , 1993, AJR. American journal of roentgenology.

[17]  Hanna Ebeling,et al.  Autism spectrum disorders according to DSM-IV-TR and comparison with DSM-5 draft criteria: an epidemiological study. , 2011, Journal of the American Academy of Child and Adolescent Psychiatry.

[18]  K. Tye,et al.  Amygdala Inputs to the Ventral Hippocampus Bidirectionally Modulate Social Behavior , 2014, The Journal of Neuroscience.

[19]  N. Emery,et al.  Effects of experience and social context on prospective caching strategies by scrub jays , 2001, Nature.

[20]  C. McDougle,et al.  Pharmacotherapeutic management of autism , 2001, Expert opinion on pharmacotherapy.

[21]  Francisco Sotres-Bayon,et al.  Prefrontal control of fear: more than just extinction , 2010, Current Opinion in Neurobiology.

[22]  Kali T. Witherspoon,et al.  A SWI/SNF related autism syndrome caused by de novo mutations in ADNP , 2014, Nature Genetics.

[23]  G. Pawlowski,et al.  The effect of medial amygdalotomy and anterior hippocampotomy on behavior and seizures in epileptic patients. , 1980, Acta neurochirurgica. Supplementum.

[24]  J. O'Doherty,et al.  Is Avoiding an Aversive Outcome Rewarding? Neural Substrates of Avoidance Learning in the Human Brain , 2006, PLoS biology.

[25]  J. Brian,et al.  Behavioral manifestations of autism in the first year of life , 2005, International Journal of Developmental Neuroscience.

[26]  R. Zannolli,et al.  Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B , 2012, Clinical genetics.

[27]  J. Aggleton The functional effects of amygdala lesions in humans: A comparison with findings from monkeys. , 1992 .

[28]  R. Adolphs,et al.  Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala , 1994, Nature.

[29]  K. Kantak,et al.  Interaction of the rostral basolateral amygdala and prelimbic prefrontal cortex in regulating reinstatement of cocaine-seeking behavior , 2010, Pharmacology Biochemistry and Behavior.

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

[31]  Janet B W Williams,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[32]  Gene S Fisch,et al.  Nosology and epidemiology in autism: Classification counts , 2012, American journal of medical genetics. Part C, Seminars in medical genetics.

[33]  D. Loesch,et al.  Autism Spectrum Phenotype in Males and Females with Fragile X Full Mutation and Premutation , 2007, Journal of autism and developmental disorders.

[34]  B. Neville,et al.  Autistic spectrum disorders in childhood epilepsy surgery candidates , 1999, European Child & Adolescent Psychiatry.

[35]  Christine Ecker,et al.  Neuroimaging in autism spectrum disorder: brain structure and function across the lifespan , 2015, The Lancet Neurology.

[36]  Paolo Curatolo,et al.  Autism and Metabolic Diseases , 2008, Journal of child neurology.

[37]  Zachary Warren,et al.  A Systematic Review of Medical Treatments for Children With Autism Spectrum Disorders , 2011, Pediatrics.

[38]  H. Narabayashi,et al.  Long range results of stereotaxic amygdalotomy for behavior disorders. , 1966, Confinia neurologica.

[39]  Swati Banerjee,et al.  Genetic aspects of autism spectrum disorders: insights from animal models , 2014, Front. Cell. Neurosci..

[40]  D. Kwiatkowski,et al.  Tuberous sclerosis. , 1994, Archives of dermatology.

[41]  G. Arbanas Diagnostic and Statistical Manual of Mental Disorders (DSM-5) , 2015 .

[42]  R. Benayed,et al.  Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder , 2004, Molecular Psychiatry.

[43]  J. Miles Autism spectrum disorders—A genetics review , 2011, Genetics in Medicine.

[44]  L. Burd,et al.  Pharmacotherapy of Autism: A Review and Clinical Approach , 2001 .

[45]  P. Tanguay,et al.  The Neurobiology of Autism, 2nd ed , 2006 .

[46]  M. Gelabert-González,et al.  [Deep brain stimulation in Parkinson's disease]. , 2013, Revista de neurologia.

[47]  Jeffrey C. Cooper,et al.  Functional magnetic resonance imaging of reward prediction , 2005, Current opinion in neurology.

[48]  W. McMahon,et al.  Autistic disorder and viral infections , 2005, Journal of NeuroVirology.

[49]  H. Groenewegen,et al.  The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics , 2003, Neuroscience & Biobehavioral Reviews.

[50]  S. Baron-Cohen,et al.  Understanding other minds : perspectives from autism , 1994 .

[51]  T. van Amelsvoort,et al.  Neural correlates of reward in autism , 2008, British Journal of Psychiatry.

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

[53]  E. Luczywek,et al.  Stereotactic amygdalotomy in the light of neuropsychological investigations. , 1976, Acta neurochirurgica.

[54]  Angelica Ronald,et al.  Examining and interpreting the female protective effect against autistic behavior , 2013, Proceedings of the National Academy of Sciences.

[55]  P. Ashwood,et al.  Is autism an autoimmune disease? , 2004, Autoimmunity reviews.

[56]  A. Lozano,et al.  Deep Brain Stimulation for Treatment-Resistant Depression , 2005, Neuron.

[57]  K. Munir,et al.  Prenatal stress and risk for autism , 2008, Neuroscience & Biobehavioral Reviews.

[58]  C. Frith,et al.  The Neural Basis of Mentalizing , 2006, Neuron.

[59]  Keiji Tanaka,et al.  Functional Division Among Monkey Prefrontal Areas in Goal-Directed Behavior , 2010 .

[60]  A. Koeppen,et al.  Principles of Frontal Lobe Function, second ed., Donald T. Stuss, Robert T. Knight (Eds.). Oxford University Press, New York NY (2013), 800, pages, ISBN: 978-0-19-983775-5 , 2014 .

[61]  U. Goswami Blackwell handbook of childhood cognitive development , 2002 .

[62]  A. Hariri,et al.  Altered striatal activation predicting real-world positive affect in adolescent major depressive disorder. , 2009, The American journal of psychiatry.

[63]  John J. Connolly,et al.  The Genetics of Autism Spectrum Disorders , 2011 .

[64]  A. Reiss,et al.  The Mesial‐temporal Lobe and Autism: Case Report and Review , 1992 .

[65]  T. Wassink,et al.  The search for autism disease genes. , 2004, Mental retardation and developmental disabilities research reviews.

[66]  J. Alvarez,et al.  Executive Function and the Frontal Lobes: A Meta-Analytic Review , 2006, Neuropsychology Review.

[67]  A. Reiss,et al.  The mesial-temporal lobe and autism: case report and review. , 1995, Developmental medicine and child neurology.

[68]  J. Lacaille,et al.  De Novo SYNGAP1 Mutations in Nonsyndromic Intellectual Disability and Autism , 2011, Biological Psychiatry.

[69]  J. Shendure,et al.  De novo TBR1 mutations in sporadic autism disrupt protein functions , 2014, Nature Communications.

[70]  Bradley P. Coe,et al.  Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations , 2012, Nature.

[71]  T. Boeckers,et al.  Zinc deficiency dysregulates the synaptic ProSAP/Shank scaffold and might contribute to autism spectrum disorders. , 2014, Brain : a journal of neurology.

[72]  J. Power,et al.  The amygdaloid complex: anatomy and physiology. , 2003, Physiological reviews.

[73]  Esben Agerbo,et al.  Risk factors for autism: perinatal factors, parental psychiatric history, and socioeconomic status. , 2005, American journal of epidemiology.

[74]  Parag G. Patil,et al.  Deep brain stimulation for obsessive-compulsive disorder: systematic review and evidence-based guideline sponsored by the American Society for Stereotactic and Functional Neurosurgery and the Congress of Neurological Surgeons (CNS) and endorsed by the CNS and American Association of Neurological Sur , 2014, Neurosurgery.

[75]  J. Fryns,et al.  The neurobiology of autism. , 1999, Genetic counseling.

[76]  Manuel F. Casanova,et al.  Recent developments in autism research , 2005 .

[77]  Jay Shendure,et al.  Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development , 2014, Cell.

[78]  P. O. Franklin,et al.  American Society for Stereotactic and Functional Neurosurgery , 2015 .

[79]  Janet K. Kern,et al.  Evidence of Toxicity, Oxidative Stress, and Neuronal Insult in Autism , 2006, Journal of toxicology and environmental health. Part B, Critical reviews.

[80]  P. Schyns,et al.  A mechanism for impaired fear recognition after amygdala damage , 2005, Nature.

[81]  Stephan J. Sanders,et al.  Genotype to phenotype relationships in autism spectrum disorders , 2014, Nature Neuroscience.

[82]  H. Narabayashi,et al.  Stereotaxic amygdalotomy for behavior disorders. , 1963, Archives of neurology.

[83]  Sonia J. Bishop,et al.  Neurocognitive mechanisms of anxiety: an integrative account , 2007, Trends in Cognitive Sciences.

[84]  P. Zelazo,et al.  Executive Function in Typical and Atypical Development , 2010 .

[85]  Limin Shi,et al.  Prenatal Viral Infection Leads to Pyramidal Cell Atrophy and Macrocephaly in Adulthood: Implications for Genesis of Autism and Schizophrenia , 2002, Cellular and Molecular Neurobiology.

[86]  T. Kemper,et al.  Neuropathology of infantile autism , 1998, Molecular Psychiatry.

[87]  H. Asperger,et al.  Die „Autistischen Psychopathen” im Kindesalter , 1944, Archiv für Psychiatrie und Nervenkrankheiten.

[88]  B. Weiss,et al.  Mercury exposure and child development outcomes. , 2004, Pediatrics.

[89]  Joshua M. Korn,et al.  Association between microdeletion and microduplication at 16p11.2 and autism. , 2008, The New England journal of medicine.

[90]  S. Scherer,et al.  Molecular Cytogenetics of Autism , 2004 .

[91]  Katherine E Henson,et al.  Risk of Suicide After Cancer Diagnosis in England , 2018, JAMA psychiatry.

[92]  M. Narita,et al.  Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism , 2005, International Journal of Developmental Neuroscience.

[93]  Michael F. Walker,et al.  De novo mutations revealed by whole-exome sequencing are strongly associated with autism , 2012, Nature.

[94]  T. Preuss Do Rats Have Prefrontal Cortex? The Rose-Woolsey-Akert Program Reconsidered , 1995, Journal of Cognitive Neuroscience.

[95]  K. McBride,et al.  Genetic testing in autism: how much is enough? , 2007, Genetics in Medicine.

[96]  J. Griffin,et al.  Infantile autism and the temporal lobe of the brain , 1981, Journal of autism and developmental disorders.

[97]  Wei Niu,et al.  Coexpression Networks Implicate Human Midfetal Deep Cortical Projection Neurons in the Pathogenesis of Autism , 2013, Cell.

[98]  Anantha Shekhar,et al.  The amygdala and related structures in the pathophysiology of autism , 2002, Pharmacology Biochemistry and Behavior.

[99]  L. Brothers,et al.  Response of neurons in the macaque amygdala to complex social stimuli , 1990, Behavioural Brain Research.

[100]  R. A. Fuchs,et al.  Interactions of the basolateral amygdala with the dorsal hippocampus and dorsomedial prefrontal cortex regulate drug context‐induced reinstatement of cocaine‐seeking in rats , 2007, The European journal of neuroscience.

[101]  Ralph Adolphs,et al.  Amygdala Damage Impairs Eye Contact During Conversations with Real People , 2007, The Journal of Neuroscience.

[102]  Kara Hume,et al.  Evaluation of Comprehensive Treatment Models for Individuals with Autism Spectrum Disorders , 2010, Journal of autism and developmental disorders.

[103]  R. Poldrack,et al.  Reward processing in autism , 2010, Autism research : official journal of the International Society for Autism Research.

[104]  T. Uema,et al.  Abnormal regional cerebral blood flow in childhood autism. , 2000, Brain : a journal of neurology.

[105]  Michael X. Cohen,et al.  Deep Brain Stimulation to Reward Circuitry Alleviates Anhedonia in Refractory Major Depression , 2008, Neuropsychopharmacology.

[106]  Alexander Kolevzon,et al.  Prenatal and perinatal risk factors for autism: a review and integration of findings. , 2007, Archives of pediatrics & adolescent medicine.

[107]  K Reesten M Eldgaard,et al.  A Population-Based Study of Measles, Mumps, and Rubella Vaccination and Autism , 2002 .

[108]  H. Klüver,et al.  PRELIMINARY ANALYSIS OF FUNCTIONS OF THE TEMPORAL LOBES IN MONKEYS , 1939 .

[109]  P. Veinante,et al.  The amygdala between sensation and affect: a role in pain , 2013, Journal of molecular psychiatry.

[110]  Thomas Foltynie,et al.  Tourette syndrome deep brain stimulation: A review and updated recommendations , 2015, Movement disorders : official journal of the Movement Disorder Society.

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

[112]  Jan Wacker,et al.  The role of the nucleus accumbens and rostral anterior cingulate cortex in anhedonia: Integration of resting EEG, fMRI, and volumetric techniques , 2009, NeuroImage.

[113]  Y. S. Kim,et al.  Global Prevalence of Autism and Other Pervasive Developmental Disorders , 2012, Autism research : official journal of the International Society for Autism Research.

[114]  Deborah J. Hellawell,et al.  Facial expression processing after amygdalotomy , 1996, Neuropsychologia.

[115]  J. Piven,et al.  Abnormal Processing of Social Information from Faces in Autism , 2001, Journal of Cognitive Neuroscience.

[116]  Edmund T. Rolls,et al.  Neurophysiology and functions of the primate amygdala. , 1992 .

[117]  E. Courchesne,et al.  Neuron number and size in prefrontal cortex of children with autism. , 2011, JAMA.

[118]  E. Hollander Textbook of Autism Spectrum Disorders , 2010 .

[119]  Y. S. Kim,et al.  Prevalence of autism spectrum disorders in a total population sample. , 2011, The American journal of psychiatry.

[120]  Christopher S. Monk,et al.  Choice selection and reward anticipation: an fMRI study , 2004, Neuropsychologia.

[121]  M B Jones,et al.  Genetics of Autism: Overview and New Directions , 1998, Journal of autism and developmental disorders.

[122]  Mogens Vestergaard,et al.  A population-based study of measles, mumps, and rubella vaccination and autism. , 2002, The New England journal of medicine.

[123]  A. Brooks,et al.  Prenatal viral infection in mouse causes differential expression of genes in brains of mouse progeny: A potential animal model for schizophrenia and autism , 2005, Synapse.

[124]  Christopher S. Poultney,et al.  Synaptic, transcriptional, and chromatin genes disrupted in autism , 2014, Nature.

[125]  John P. Aggleton,et al.  The amygdala: Neurobiological aspects of emotion, memory, and mental dysfunction. , 1992 .

[126]  Michael X. Cohen,et al.  Neuroelectric Signatures of Reward Learning and Decision-Making in the Human Nucleus Accumbens , 2009, Neuropsychopharmacology.

[127]  C. McDougle,et al.  Structural and functional magnetic resonance imaging of autism spectrum disorders , 2011, Brain Research.

[128]  H. Nishitani,et al.  Brain metabolites in the hippocampus-amygdala region and cerebellum in autism: an 1H-MR spectroscopy study , 1999, Neuroradiology.

[129]  E. Saemundsen,et al.  Autism Spectrum Disorders in Children With a History of Infantile Spasms: A Population-Based Study , 2007, Journal of child neurology.

[130]  Robert Chen,et al.  Deep brain stimulation for Parkinson's disease: disrupting the disruption , 2002, The Lancet Neurology.

[131]  D. Hackney,et al.  Varied MR appearance of autism: fifty-three pediatric patients having the full autistic syndrome. , 1990, Magnetic resonance imaging.

[132]  S. Horvath,et al.  Transcriptomic Analysis of Autistic Brain Reveals Convergent Molecular Pathology , 2011, Nature.

[133]  C Eng,et al.  Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations , 2005, Journal of Medical Genetics.

[134]  A. Shekhar,et al.  Excitatory amino acid receptor antagonists block the cardiovascular and anxiety responses elicited by gamma-aminobutyric acidA receptor blockade in the basolateral amygdala of rats. , 1997, The Journal of pharmacology and experimental therapeutics.

[135]  R. Michels,et al.  Diagnostic and Statistical Manual of Mental Disorders, 3rd ed , 1981 .

[136]  J. Moss,et al.  Self-injurious behaviour in individuals with autism spectrum disorder and intellectual disability. , 2012, Journal of intellectual disability research : JIDR.

[137]  J. Grafman,et al.  Human prefrontal cortex: processing and representational perspectives , 2003, Nature Reviews Neuroscience.

[138]  A. Thurm,et al.  Pharmacotherapy for the Core Symptoms in Autistic Disorder: Current Status of the Research , 2013, Drugs.

[139]  A. Shekhar,et al.  Sodium lactate elicits anxiety in rats after repeated GABA receptor blockade in the basolateral amygdala. , 2000, European journal of pharmacology.

[140]  M. State,et al.  Recent developments in the genetics of autism spectrum disorders. , 2013, Current opinion in genetics & development.

[141]  Kali T. Witherspoon,et al.  Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID , 2016, Molecular Psychiatry.

[142]  Brian Knutson,et al.  Anticipation of Increasing Monetary Reward Selectively Recruits Nucleus Accumbens , 2001, The Journal of Neuroscience.

[143]  V. Sturm,et al.  DBS in the basolateral amygdala improves symptoms of autism and related self-injurious behavior: a case report and hypothesis on the pathogenesis of the disorder , 2013, Front. Hum. Neurosci..

[144]  J. Tanne Maternal obesity and diabetes are linked to children’s autism and similar disorders , 2012, BMJ : British Medical Journal.

[145]  Sameer A Sheth,et al.  Deep brain stimulation for severe autism: from pathophysiology to procedure. , 2015, Neurosurgical focus.

[146]  Thomas Bourgeron,et al.  Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders , 2007, Nature Genetics.

[147]  G. E. Alexander,et al.  Parallel organization of functionally segregated circuits linking basal ganglia and cortex. , 1986, Annual review of neuroscience.

[148]  Stanley Finger,et al.  Origins of neuroscience: A history of explorations into brain function. , 1994 .

[149]  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.

[150]  Pat Levitt,et al.  Autism and 15q11-q13 disorders: behavioral, genetic, and pathophysiological issues. , 2004, Mental retardation and developmental disabilities research reviews.

[151]  G. Quirk,et al.  Neural Mechanisms of Extinction Learning and Retrieval , 2008, Neuropsychopharmacology.

[152]  Jennifer S. Beer,et al.  Prefrontal involvement in the regulation of emotion: convergence of rat and human studies , 2006, Current Opinion in Neurobiology.

[153]  David A. Ziegler,et al.  Localization of white matter volume increase in autism and developmental language disorder , 2004, Annals of neurology.

[154]  J. Mulvihill,et al.  Chromosome 2q terminal deletion: Report of 6 new patients and review of phenotype‐breakpoint correlations in 66 individuals , 2004, American journal of medical genetics. Part A.

[155]  J. Baizabal-Carvallo,et al.  Deep brain stimulation for severe secondary stereotypies. , 2014, Parkinsonism & related disorders.