Articles

Article

Review Article

Exp Neurobiol 2016; 25(1): 1-13

Published online February 29, 2016

https://doi.org/10.5607/en.2016.25.1.1

© The Korean Society for Brain and Neural Sciences

A Short Review on the Current Understanding of Autism Spectrum Disorders

Hye Ran Park1, Jae Meen Lee1, Hyo Eun Moon1, Dong Soo Lee2, Bung-Nyun Kim3, Jinhyun Kim4, Dong Gyu Kim1 and Sun Ha Paek1*

1Department of Neurosurgery, Seoul National University Hospital, Seoul 03080, 2Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, 3Division of Child and Adolescent Psychiatry, Department of Psychiatry, Seoul National University College of Medicine, Seoul 03080, 4Center for Functional Connectomics, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea

Correspondence to: *To whom correspondence should be addressed.
TEL: 82-2-2072-3993, 82-2-2072-3957, FAX: 82-2-744-8459, 82-2-747-3799
e-mail: paeksh@snu.ac.kr

Received: November 23, 2015; Revised: December 18, 2015; Accepted: December 30, 2015

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.

Keywords: Autistic Disorders, Review, Neurobiology, Amygdala

Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders characterized by a lack of social interaction, verbal and nonverbal communication in the first 3 years of life. The distinctive social behaviors include an avoidance of eye contact, problems with emotional control or understanding the emotions of others, and a markedly restricted range of activities and interests [1]. The current prevalence of ASD in the latest large-scale surveys is about 1%~2% [2,3]. The prevalence of ASD has increased in the past two decades [4]. Although the increase in prevalence is partially the result of changes in DSM diagnostic criteria and younger age of diagnosis, an increase in risk factors cannot be ruled out [5,6]. Studies have shown a male predominance; ASD affects 2~3 times more males than females [2,3,7]. This diagnostic bias towards males might result from under-recognition of females with ASD [8]. Also, some researchers have suggested the possibility that the female-specific protective effects against ASD might exist [9].

A Swiss psychiatrist, Paul Eugen Bleuler used the term "autism" to define the symptoms of schizophrenia for the first time in 1912 [10]. He derived it from the Greek word αὐτὀς (autos), which means self. Hans Asperger adopted Bleuler's terminology "autistic" in its modern sense to describe child psychology in 1938. Afterwards, he reported about four boys who did not mix with their peer group and did not understand the meaning of the terms 'respect' and 'polite', and regard for the authority of an adult. The boys also showed specific unnatural stereotypic movement and habits. Asperger describe this pattern of behaviors as "autistic psychopathy", which is now called as Asperger's Syndrome [11]. The person who first used autism in its modern sense is Leo Kanner. In 1943, he reported about 8 boys and 3 girls who had "an innate inability to form the usual, biologically provided affective contact with people", and introduced the label early infantile autism [12]. Hans Asperger and Leo Kanner have been considered as those who designed the basis of the modern study of autism.

Most recently, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) adopted the term ASD with a dyadic definition of core symptoms: early-onset of difficulties in social interaction and communication, and repetitive, restricted behaviors, interests, or activities [13]. Atypical language development, which had been included into the triad of ASD, is now regarded as a co-occurring condition.

As stated earlier, the development of the brain in individuals with ASD is complex and is mediated by many genetic and environmental factors, and their interactions. 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. Also, the resultant microstructural, macrostructural, and functional abnormalities that emerge during brain development create a pattern of dysfunctional neural networks involved in socioemotional processing. Microstructurally, an altered ratio of short- to long-diameter axons and disorganization of cortical layers are observed. Macrostructurally, MRI studies assessing brain volume in individuals with ASD have consistently shown cortical and subcortical gray matter overgrowth in early brain development. Functionally, resting-state fMRI studies show a narrative of widespread global underconnectivity in socioemotional networks, and task-based fMRI studies show decreased activation of networks involved in socioemotional processing. Moreover, electrophysiological studies demonstrate alterations in both resting-state and stimulus-induced oscillatory activities in patients with ASD [14].

The well-conserved sets of genes and genetic pathways were implicated in ASD, many of which contribute toward the formation, stabilization, and maintenance of functional synapses. Therefore, these genetic aspects coupled with an in-depth phenotypic analysis of the cellular and behavioral characteristics are essential to unraveling the pathogenesis of ASD. The number of genes already discovered in ASD holds the promise to translate the knowledge into designing new therapeutic interventions. Also, the fundamental research using animal models is providing key insights into the various facets of human ASD. However, a better understanding of the genetic, molecular, and circuit level aberrations in ASD is still needed [15].

Neuroimaging studies have provided many important insights into the pathological changes that occur in the brain of patients with ASD in vivo. Importantly, ASD is accompanied by an atypical path of brain maturation, which gives rise to differences in neuroanatomy, functioning, and connectivity. Although considerable progress has been made in the development of animal models and cellular assays, neuroimaging approaches allow us to directly examine the brain in vivo, and to probably facilitate the development of a more personalized approach to the treatment of ASD [16].

ASD is not a single disorder. It is now broadly considered to be a multi-factorial disorder resulting from genetic and non-genetic risk factors and their interaction.

Genetic causes including gene defects and chromosomal anomalies have been found in 10%~20% of individuals with ASD [17,18]. Siblings born in families with an ASD subject have a 50 times greater risk of ASD, with a recurrence rate of 5%~8% [19]. The concordance rate reaches up to 82%~92% in monozygotic twins, compared with 1%~10% in dizygotic twins. Genetic studies suggested that single gene mutations alter developmental pathways of neuronal and axonal structures involved in synaptogenesis [20,21,22]. In the cases of related with fragile X syndrome and tuberous sclerosis, hyperexcitability of neocortical circuits caused by alterations in the neocortical excitatory/inhibitory balance and abnormal neural synchronization is thought to be the most probable mechanisms [23,24]. Genome-wide linkage studies suggested linkages on chromosomes 2q, 7q, 15q, and 16p as the location of susceptibility genes, although it has not been fully elucidated [25,26]. These chromosomal abnormalities have been implicated in the disruption of neural connections, brain growth, and synaptic/dendritic morphology [27,28,29]. Metabolic errors including phenylketonuria, creatine deficiency syndromes, adenylosuccinate lyase deficiency, and metabolic purine disorders are also account for less than 5% of individuals with ASD [30]. Recently, the correlation between cerebellar developmental patterning gene ENGRAILED 2 and autism was reported [31]. It is the first genetic allele that contributes to ASD susceptibility in as many as 40% of ASD cases. Other genes such as UBE3A locus, GABA system genes, and serotonin transporter genes have also been considered as the genetic factors for ASD [18].

Diverse environmental causative elements including pre-natal, peri-natal, and post-natal factors also contribute to ASD [32]. Prenatal factors related with ASD include exposure to teratogens such as thalidomide, certain viral infections (congenital rubella syndrome), and maternal anticonvulsants such as valproic acid [33,34]. Low birth weight, abnormally short gestation length, and birth asphyxia are the peri-natal factors [34]. Reported post-natal factors associated with ASD include autoimmune disease, viral infection, hypoxia, mercury toxicity, and others [33,35,36]. Table 1 summarizes the known and putative ASD-related genes and environmental factors contributing to the ASD.

In recent years, some researchers suggest that ASD is the result of complex interactions between genetic and environmental risk factors [37]. Understanding the interaction between genetic and environmental factors in the pathogenesis of ASD will lead to optimal treatment strategy.

ASD is typically noticed in the first 3 years of life, with deficits in social behaviors and nonverbal interactions such as reduced eye contact, facial expression, and body gestures [1]. Children also manifest with non-specific symptoms such as unusual sensory perception skills and experiences, motor clumsiness, and insomnia. Associated phenomena include mental retardation, emotional indifference, hyperactivity, aggression, self-injury, and repetitive behaviors such as body rocking or hand flapping. Repetitive, stereotyped behaviors are often accompanied by cognitive impairment, seizures or epilepsy, gastrointestinal complaints, disturbedd sleep, and other problems. Differential diagnosis includes childhood schizophrenia, learning disability, and deafness [38,39].

ASD is diagnosed clinically based on the presence of core symptoms. However, caution is required when diagnosing ASD because of non-specific manifestations in different age groups and individual abilities in intelligence and verbal domains. The earliest nonspecific signs recognized in infancy or toddlers include irritability, passivity, and difficulties with sleeping and eating, followed by delays in language and social engagement. In the first year of age, infants later diagnosed with ASD cannot be easily distinguished from control infants. However, some authors report that about 50% of infants show behavioral abnormalities including extremes of temperament, poor eye contact, and lack of response to parental voices or interaction. At 12 months of age, individuals with ASD show atypical behaviors, across the domains of visual attention, imitation, social responses, motor control, and reactivity [40]. There is also report about atypical language trajectories, with mild delays at 12 months progressing to more severe delays by 24 months [40]. By 3 years of age, the typical core symptoms such as lack of social communication and restricted/repetitive behaviors and interests are manifested. ASD can be easily differentiated from other psychosocial disorders in late preschool and early school years.

The frontal and temporal lobes are the markedly affected brain areas in the individuals with ASD. In particular, the role of amygdala in cognition and ASD has been proved in numerous neuropathological and neuroimaging studies. The amygdala located the medial temporal lobe anterior to the hippocampal formation has been thought to have a strong association with social and aggressive behaviors in patients with ASD [41,42]. The amygdala is a major component of the limbic system and affective loop of the cortico-striato-thalamo-cortical circuit [43].

The amygdala has 2 specific functions including eye gaze and face processing [44]. The lesion of the amygdala results in fear-processing, modulation of memory with emotional content, and eye gaze when looking at human face [45,46,47]. The findings in individuals with amygdala lesion are similar to the phenomena in ASD. The amygdala receives highly processed somatosensory, visual, auditory, and all types of visceral inputs. It sends efferents through two major pathways, the stria terminalis and the ventral amygdalofugal pathway.

The amygdala comprises a collection of 13 nuclei. Based on histochemical analyses, these 13 nuclei are divided into three primary subgroups: the basolateral (BL), centromedial (CM), and superficial groups [42]. The BL group attributes amygdala to have a role as a node connecting sensory stimuli to higher social cognition level. It links the CM and superficial groups, and it has reciprocal connection with the orbitofrontal cortex, anterior cingulate cortex (ACC), and the medial prefrontal cortex (mPFC) [48]. The BL group contains neurons responsive to faces and actions of others, which is not found in the other two groups of amygdala [49,50]. The CM group consists of the central, medial, cortical nuclei, and the periamygdaloid complex. It innervates many of the visceral and autonomic effector regions of the brain stem, and provides a major output to the hypothalamus, thalamus, ventral tegmental area, and reticular formation [51]. The superficial group includes the nucleus of the lateral olfactory tract [42].

Neurochemistrial studies revealed high density of benzodiazepine/GABAa receptors and a substantial set of opiate receptors in the amygdala. It also includes serotonergic, dopaminergic, cholinergic, and noradrenergic cell bodies and pathways [52]. Since some patients with temporal epilepsy and aggressive behavior experienced improvement in aggressiveness after bilateral stereotactic ablation of basal and corticomedial amygdaloid nuclei, the role of amygdala in emotional processing, especially rage processing has been investigated [53,54,55,56]. Some evidences for the amygdala deficit in patients with ASD have been suggested. Post-mortem studies found the pathology in the amygdala of individuals with ASD compared to age- and sex-matched controls [57,58,59]. Small neuronal size and increased cell density in the cortical, medial, and central nuclei of the amygdala were detected in ASD patients.

Several studies proposed the use of an animal model to confirm the evidence for the association between amygdala and ASD [60,61]. Despite the limitation which stems from the need to prove higher order cognitive disorder, the studies suggested that disease-associated alterations in the temporal lobes during experimental manipulations of the amygdala in animals have produced some symptoms of ASD [62]. Especially, the Kluver-Bucy syndrome, which is caused by bilateral damage to the anterior temporal lobes in monkeys, has characteristic manifestations similar to ASD [63,64]. Monkeys with the Kluver-Bucy syndrome shows absence of social chattering, lack of facial expression, absence of emotional reactions, repetitive abnormal movement patterns, and increased aggression. Sajdyk et al. performed experiments on rats and discovered that physiological activation of the BL nucleus of the amygdala by blocking tonic GABAergic inhibition or enhancing glutamate or the stress-associated peptide corticotropin-releasing factor (CRF)-mediated excitation caused reduction in social behaviors [65]. On the contrary, lesioning of the amygdala or blocking amygdala excitability with glutamate antagonist increased dyadic social interactions [60]. Besides animals, humans who underwent lesioning of the amygdala showed impairments in social judgment. This phenomenon is called acquired ASD [66,67,68]. The pattern of social deficits was similar in idiopathic and acquired ASD [69]. Felix-Ortiz and Tye sought to understand the role of projections from the BL amygdala to the ventral hippocampus in relation to behavior. Their study using mice showed that the BLS-ventral hippocampus pathway involved in anxiety plays a role in the mediation of social behavior as well [70].

The individuals with temporal lobe tumors involving the amygdala and hippocampus provide another evidence of the correlation between the amygdala and ASD. Some authors reported that patients experienced autistic symptoms after temporal lobe was damaged by a tumor [71,72]. Also, individuals with tuberous sclerosis experienced similar symptoms including facial expression due to a temporal lobe hamartoma [73].

Although other researchers failed to find structural abnormalities in the mesial temporal lobe of autistic subjects by performing magnetic resonance imaging (MRI) studies [74,75,76], recent development in neuroimaging has facilitated the investigation of amygdala pathology in ASD. Studies using structural MRI estimated volumes of the amygdala and related structures in individuals with ASD and age-, gender, and verbal IQ-matched healthy controls [77]. Increase in bilateral amygdala volume and reduction in hippocampal and parahippocampal gyrus volumes were noted in individuals with ASD. Also, the lateral ventricles and intracranial volumes were significantly increased in the autistic subjects; however, overall temporal lobe volumes were similar between the ASD and control groups.

There was a significant difference in the whole brain voxel-based scans of individuals with ASD and control groups [78]. Individuals with ASD showed decreased gray matter volume in the right paracingulate sulcus, the left occipito-temporal cortex, and the left inferior frontal sulcus. On the contrary, the gray matter volume in the bilateral cerebellum was increased. Otherwise, they showed increased volume in the left amygdala/periamygdaloid cortex, the right inferior temporal gyrus, and the middle temporal gyrus.

Recently, the development of functional neuroimaging also provided some evidence for the correlation between amygdala deficit and ASD. A study using Technetium-99m (Tc-99m) single-photon emission computed tomography (SPECT) found that regional cerebral blood flow (rCBF) was decreased in the bilateral insula, superior temporal gyri, and left prefrontal cortices in individuals with ASD compared to age- and gender-matched controls with mental retardation [79]. Also, the authors found that rCBF in both the right hippocampus and amygdala was correlated with a behavioral rating subscale.

On proton magnetic resonance spectroscopy (MRS) in the right hippocampal-amygdala region and the left cerebellar hemisphere, autistic subjects showed decreased level of N-acetyl aspartate (NAA) in both areas [80]. There was no difference in the level of the other metabolites, such as creatine and choline. This study implies that a decreased level of NAA might be associated with neuronal hypofunction or immature neurons.

These findings support the claim that amygdala might be a key structure in the development of ASD and a target for the management of the disease.

Frontal lobe has been considered as playing an important role in higher-level control and a key structure associated with autism. Individuals with frontal lobe deficit demonstrate higher-order cognitive, language, social, and emotion dysfunction, which is deficient in autism [81]. Recently, neuroimaging and neuropsychological studies have attempted to delineate distinct regions of prefrontal cortex supporting different aspects of executive function. Some authors have reported that the excessive rates of brain growth in infants with ASD, which is mainly contributed by the increase of frontal cortex volume [82,83]. Especially, the PFC including Brodmann areas 8, 9, 10, 11, 44, 45, 46, and 47 has been noted for the structure related with ASD [84]. The PFC is cytoarchitectonically defined as the presence of a cortical granular layer IV [85], and anatomically refers to the regions of the cerebral cortex that are anterior to premotor cortex and the supplementary motor area [86]. The PFC has extensive connections with other cortical, subcortical and brain stem sites [87]. It receives inputs from the brainstem arousal systems, and its function is particularly dependent on its neurochemical environment [88].

The PFC is broadly divided into the medial PFC (mPFC) and the lateral PFC (lPFC). The mPFC is further divided into four distinct regions: medial precentral cortex, anterior cingulate cortex, prelimbic and infralimbic prefrontal cortex [89]. While the lPFC is thought to support cognitive control process [90], the mPFC has reciprocal connections with brain regions involved in emotional processing (amygdala), memory (hippocampus) and higher-order sensory regions (within temporal cortex) [91]. This involvement of mPFC in social cognition and interaction implies that mPFC might be a key region in understanding self and others [92].

The mPFC involves in fear learning and extinction by reciprocal synaptic connections with the basolateral amygdala [93,94]. It is believed that the mPFC regulates and controls amygdala output and the accompanying behavioral phenomena [95,96]. Previous authors investigated how memory processing is regulated by interactions between BLA and mPFC by means of functional disconnection [97,98]. Disturbed communication within amygdala-mPFC circuitry caused deficits in memory processing. These informations provide support for a role of the mPFC in the development of ASD.

Besides amygdala, nucleus accumbens (NAc) is also considered as the key structure which is related with the social reward response in ASD. NAc borders ventrally on the anterior limb of the internal capsule, and the lateral subventricular fundus of the NAc is permeated in rostral sections by internal capsule fiber bundles. The rationale for NAc to be considered as the potential target of DBS for ASD is its predominant role in modulating the processing of reward and pleasure [99]. Anticipation of rewarding stimuli recruits the NAc as well as other limbic structures, and the experience of pleasure activates the NAc as well as the caudate, putamen, amygdala, and VMPFC [100,101,102]. It is well known that dysfunction of NAc regarding rewarding stimuli in subjects with depression. Bewernick et al. demonstrated antidepressant effects of NAc-DBS in 5 of the 10 patients suffering from severe treatment-resistant depression [103].

Two groups reported about the neural basis of social reward processing in ASD. Schmitz et al. examined responses to a task that involved monetary reward. They investigated the neural substrates of reward feedback in the context of a sustained attention task, and found increased activation in the left anterior cingulate gyrus and left mid-frontal gyrus on rewarded trials in ASD [104]. Scott-Van Zeeland et al. investigated the neural correlates of rewarded implicit learning in children with ASD using both social and monetary rewards. They found diminished ventral striatal response during social, but not monetary, rewarded learning [105]. According to them, activity within the ventral striatum predicted social reciprocity within the control group, but not within the ASD group.

Anticipation of pleasurable stimuli recruits the NAc, whereas the experience of pleasure activates VMPFC [106]. NAc is activated by incentive motivation to reach salient goals [106]. Increased activation in the left anterior cingulate gyrus and left mid-frontal gyrus was noted during both the anticipatory and consummatory phase of the reward response [104,107,108]. However, the activity within the ventral striatum was decreased in autistic subjects, which caused impairment in social reciprocity [105].

These findings indicate that reward network function in ASD is contingent on both the temporal phase of the response and the type of reward processed, suggesting that it is critical to assess the temporal chronometry of responses in a study of reward processing in ASD. NAc might be one of the candidates as a target of DBS which is introduced as below.

Various educational and behavioral treatments have been the mainstay of the management of ASD. Most experts agree that the treatment for ASD should be individualized. Treatment of disabling symptoms such as aggression, agitation, hyperactivity, inattention, irritability, repetitive and self-injurious behavior may allow educational and behavioral interventions to proceed more effectively [109].

Increasing interest is being shown in the role of various pharmacological treatments. Medical management includes typical antipsychotics, atypical antipsychotics, antidepressants, selective serotonin reuptake inhibitors, α2-adrenergic agonists, β-adrenergic antagonist, mood stabilizers, and anticonvulsants [110,111]. So far, there has been no agent which has been proved effective in social communication [112]. A major factor in the choice of pharmacologic treatment is awareness of specific individual physical, behavioral or psychiatric conditions comorbid with ASD, such as obsessive-compulsive disorder, schizophrenia, mood disorder, and intellectual disability [113]. Antidepressants were the most commonly used agents followed by stimulants and antipsychotics. The high prevalence of comorbidities is reflected in the rates of psychotropic medication use in people with ASD. Antipsychotics were effective in treating the repetitive behaviors in children with ASD; however, there was not sufficient evidence on the efficacy and safety in adolescents and adults [114]. There are also alternative options including opiate antagonist, immunotherapy, hormonal agents, megavitamins and other dietary supplements [109,113].

However, the autistic symptoms remain refractory to medication therapy in some patients [115]. These individuals have severely progressed disease and multiple comorbidities causing decreased quality of life [44,110]. Interventional therapy such as deep brain stimulation (DBS) may be an alternative therapeutic option for these patients.

Two kinds of interventions have been used for treating ASD; focused intervention practices and comprehensive treatments [116]. The focused intervention practices include prompting, reinforcement, discrete trial teaching, social stories, or peer-mediated interventions. These are designed to produce specific behavioral or developmental outcomes for individual children with ASD, and used for a limited time period with the intent of demonstrating a change in the targeted behaviors. The comprehensive treatment models are a set of practices performed over an extended period of time and are intense in their application, and usually have multiple components [116].

Since it was approved by the FDA in 1997, DBS has been used to send electrical impulses to specific parts of the brain [117,118]. In recent years, the spectrum for which therapeutic benefit is provided by DBS has widely been expanded from movement disorders such as Parkinson's disease, essential tremor, and dystonia to psychiatric disorders. Some authors have demonstrated the efficacy of DBS for psychiatric disorders including refractory obsessive-compulsive disorder, depression, Tourette syndrome, and others for the past few years [119,120,121].

To the best of our knowledge, there have been 2 published articles of 3 patients who underwent DBS for ASD accompanied by life-threatening self-injurious behaviors not alleviated by antipsychotic medication [122,123]. The targets were anterior limb of the internal capsule and globus pallidus internus, only globus pallidus, and BL nucleus of the amygdala, respectively. All patients obtained some benefit from DBS. Although the first patient showed gradual re-deterioration after temporary improvement, the patient who underwent DBS of the BL nucleus experienced substantial improvement in self-injurious behavior and social communication. These experiences suggested the possibility of DBS for the treatment of ASD. For patients who did not obtain benefit from other treatments, DBS may be a viable therapeutic option. Understanding the structures which contribute to the occurrence of ASD might open a new horizon for management of ASD, particularly DBS. Accompanying development of neuroimaging technique enables more accurate targeting and heightens the efficacy of DBS. However, the optimal DBS target and stimulation parameters are still unknown, and prospective controlled trials of DBS for various possible targets are required to determine optimal target and stimulation parameters for the safety and efficacy of DBS.

ASD should be considered as a complex disorder. It has many etiologies involving genetic and environmental factors, and further evidence for the role of amygdala and NA in the pathophysiology of ASD has been obtained from numerous studies. However, 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.

Table. 1. The known and putative ASD-related genes and environmental factors contributing to the ASD
  1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd ed. Arlington, VA: American Psychiatric Association, 1980.
  2. Mattila ML, Kielinen M, Linna SL, Jussila K, Ebeling H, Bloigu R, Joseph RM, Moilanen I. Autism spectrum disorders according to DSM-IV-TR and comparison with DSM-5 draft criteria: an epidemiological study. J Am Acad Child Adolesc Psychiatry 2011;50:583-592.e11.
    Pubmed
  3. Kim YS, Leventhal BL, Koh YJ, Fombonne E, Laska E, Lim EC, Cheon KA, Kim SJ, Kim YK, Lee H, Song DH, Grinker RR. Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatry 2011;168:904-912.
    Pubmed
  4. Fisch GS. Nosology and epidemiology in autism: classification counts. Am J Med Genet C Semin Med Genet 2012;160C:91-103.
    Pubmed
  5. Elsabbagh M, Divan G, Koh YJ, Kim YS, Kauchali S, Marcín C, Montiel-Nava C, Patel V, Paula CS, Wang C, Yasamy MT, Fombonne E. Global prevalence of autism and other pervasive developmental disorders. Autism Res 2012;5:160-179.
    Pubmed
  6. Fombonne E. In: Hollander E, Kolevzon A, Coyle JT. Textbook of autism spectrum disorders. Washington, D.C: American Psychiatric Publishing, Inc., 2011; 2011. p. 117-136.
  7. Saemundsen E, Ludvigsson P, Rafnsson V. Autism spectrum disorders in children with a history of infantile spasms: a population-based study. J Child Neurol 2007;22:1102-1107.
    Pubmed
  8. Baron-Cohen S, Lombardo MV, Auyeung B, Ashwin E, Chakrabarti B, Knickmeyer R. Why are autism spectrum conditions more prevalent in males?. PLoS Biol 2011;9:e1001081.
    Pubmed
  9. Robinson EB, Lichtenstein P, Anckarsäter H, Happé F, Ronald A. Examining and interpreting the female protective effect against autistic behavior. Proc Natl Acad Sci U S A 2013;110:5258-5262.
    Pubmed
  10. Bleuler E. The theory of schizophrenic negativism. New York, NY: The Journal of Nervous and Mental Disease Publishing Company, 1912.
  11. Asperger H. Die "Autistischen Psychopathen" im Kindesalter. Arch Psychiatr Nervenkr 1944;117:76-136.
  12. Kanner L. Autistic disturbances of affective contact. Nerv Child 1943;2:217-250.
  13. American Psychiatric Publishing. Diagnostic and statistical manual of mental disorders: DSM-5. 5th ed. Arlington, VA: American Psychiatric Publishing, 2013.
  14. Sinha S, McGovern RA, Sheth SA. Deep brain stimulation for severe autism: from pathophysiology to procedure. Neurosurg Focus 2015;38:E3.
    Pubmed
  15. Banerjee S, Riordan M, Bhat MA. Genetic aspects of autism spectrum disorders: insights from animal models. Front Cell Neurosci 2014;8:58.
    Pubmed
  16. Ecker C, Bookheimer SY, Murphy DG. Neuroimaging in autism spectrum disorder: brain structure and function across the lifespan. Lancet Neurol 2015;14:1121-1134.
    Pubmed
  17. Herman GE, Henninger N, Ratliff-Schaub K, Pastore M, Fitzgerald S, McBride KL. Genetic testing in autism: how much is enough?. Genet Med 2007;9:268-274.
    Pubmed
  18. Miles JH. Autism spectrum disorders--a genetics review. Genet Med 2011;13:278-294.
    Pubmed
  19. Szatmari P, Jones MB, Zwaigenbaum L, MacLean JE. Genetics of autism: overview and new directions. J Autism Dev Disord 1998;28:351-368.
    Pubmed
  20. Chang J, Gilman SR, Chiang AH, Sanders SJ, Vitkup D. Genotype to phenotype relationships in autism spectrum disorders. Nat Neurosci 2015;18:191-198.
    Pubmed
  21. Geschwind DH. Genetics of autism spectrum disorders. Trends Cogn Sci 2011;15:409-416.
    Pubmed
  22. Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, Mill J, Cantor RM, Blencowe BJ, Geschwind DH. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 2011;474:380-384.
    Pubmed
  23. Clifford S, Dissanayake C, Bui QM, Huggins R, Taylor AK, Loesch DZ. Autism spectrum phenotype in males and females with fragile X full mutation and premutation. J Autism Dev Disord 2007;37:738-747.
    Pubmed
  24. Curatolo P, Bombardieri R. Tuberous sclerosis. Handb Clin Neurol 2008;87:129-151.
    Pubmed
  25. Wassink TH, Brzustowicz LM, Bartlett CW, Szatmari P. The search for autism disease genes. Ment Retard Dev Disabil Res Rev 2004;10:272-283.
    Pubmed
  26. Xu J, Zwaigenbaum L, Szatmari P, Scherer SW. Molecular cytogenetics of autism. Curr Genomics 2004;5:347-364.
  27. Dykens EM, Sutcliffe JS, Levitt P. Autism and 15q11-q13 disorders: behavioral, genetic, and pathophysiological issues. Ment Retard Dev Disabil Res Rev 2004;10:284-291.
    Pubmed
  28. Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Saemundsen E, Stefansson H, Ferreira MA, Green T, Platt OS, Ruderfer DM, Walsh CA, Altshuler D, Chakravarti A, Tanzi RE, Stefansson K, Santangelo SL, Gusella JF, Sklar P, Wu BL, Daly MJ, Autism Consortium. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 2008;358:667-675.
    Pubmed
  29. Casas KA, Mononen TK, Mikail CN, Hassed SJ, Li S, Mulvihill JJ, Lin HJ, Falk RE. Chromosome 2q terminal deletion: report of 6 new patients and review of phenotype-breakpoint correlations in 66 individuals. Am J Med Genet A 2004;130A:331-339.
    Pubmed
  30. Manzi B, Loizzo AL, Giana G, Curatolo P. Autism and metabolic diseases. J Child Neurol 2008;23:307-314.
    Pubmed
  31. Gharani N, Benayed R, Mancuso V, Brzustowicz LM, Millonig JH. Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder. Mol Psychiatry 2004;9:474-484.
    Pubmed
  32. London EA, Etzel RA. The environment as an etiologic factor in autism: a new direction for research. Environ Health Perspect 2000;108:401-404.
    Pubmed
  33. Kern JK, Jones AM. Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health B Crit Rev 2006;9:485-499.
    Pubmed
  34. Kolevzon A, Gross R, Reichenberg A. Prenatal and perinatal risk factors for autism: a review and integration of findings. Arch Pediatr Adolesc Med 2007;161:326-333.
    Pubmed
  35. Ashwood P, Van de Water J. Is autism an autoimmune disease?. Autoimmun Rev 2004;3:557-562.
    Pubmed
  36. Davidson PW, Myers GJ, Weiss B. Mercury exposure and child development outcomes. Pediatrics 2004;113:1023-1029.
    Pubmed
  37. Kim YS, Leventhal BL. Genetic epidemiology and insights into interactive genetic and environmental effects in autism spectrum disorders. Biol Psychiatry 2015;77:66-74.
    Pubmed
  38. Fombonne E. In: Casanova MF. Recent developments in autism research. New York, NY: Nova Science Publishers Inc., 2005; 2005. p. 1-25.
  39. World Health Organization. International statistical classification of diseases and related health problems. 10th ed. Geneva: World Health Organization, 2004.
  40. Zwaigenbaum L, Bryson S, Rogers T, Roberts W, Brian J, Szatmari P. Behavioral manifestations of autism in the first year of life. Int J Dev Neurosci 2005;23:143-152.
    Pubmed
  41. Aggleton JP. In: Aggleton JP. The amygdala: neurobiological aspects of emotion, memory, and mental dysfunction. New York, NY: Wiley-Liss, 1992; 1992. p. 485-503.
  42. Sah P, Faber ES, Lopez De Armentia M, Power J. The amygdaloid complex: anatomy and physiology. Physiol Rev 2003;83:803-834.
    Pubmed
  43. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 1986;9:357-381.
    Pubmed
  44. Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet 2014;383:896-910.
    Pubmed
  45. Adolphs R, Gosselin F, Buchanan TW, Tranel D, Schyns P, Damasio AR. A mechanism for impaired fear recognition after amygdala damage. Nature 2005;433:68-72.
    Pubmed
  46. Adolphs R, Tranel D, Buchanan TW. Amygdala damage impairs emotional memory for gist but not details of complex stimuli. Nat Neurosci 2005;8:512-518.
    Pubmed
  47. Spezio ML, Huang PY, Castelli F, Adolphs R. Amygdala damage impairs eye contact during conversations with real people. J Neurosci 2007;27:3994-3997.
    Pubmed
  48. Adolphs R. What does the amygdala contribute to social cognition?. Ann N Y Acad Sci 2010;1191:42-61.
    Pubmed
  49. Rolls ET. In: Aggleton JP. The amygdala. New York, NY: Wiley-Liss, 1992; 1992. p. 143-165.
  50. Brothers L, Ring B, Kling A. Response of neurons in the macaque amygdala to complex social stimuli. Behav Brain Res 1990;41:199-213.
    Pubmed
  51. Veinante P, Yalcin I, Barrot M. The amygdala between sensation and affect: a role in pain. J Mol Psychiatry 2013;1:9.
    Pubmed
  52. Nolte J. The human brain: an introduction to its functional anatomy. 5th ed. St. Louis, MO: Mosby, 2002.
  53. Luczywek E, Mempel E. Stereotactic amygdalotomy in the light of neuropsychological investigations. Acta Neurochir (Wien) 1976;23:221-223.
    Pubmed
  54. Mempel E, Witkiewicz B, Stadnicki R, Łuczywek E, Kuciński L, Pawłowski G, Nowak J. The effect of medial amygdalotomy and anterior hippocampotomy on behavior and seizures in epileptic patients. Acta Neurochir Suppl (Wien) 1980;30:161-167.
    Pubmed
  55. Narabayashi H, Nagao T, Saito Y, Yoshida M, Nagahata M. Stereotaxic amygdalotomy for behavior disorders. Arch Neurol 1963;9:1-16.
    Pubmed
  56. Narabayashi H, Uno M. Long range results of stereotaxic amygdalotomy for behavior disorders. Confin Neurol 1966;27:168-171.
    Pubmed
  57. Bauman ML, Kemper TL. The neurobiology of autism. 2nd ed. Baltimore, MD: The Johns Hopkins University Press, 2005.
  58. Rapin I, Katzman R. Neurobiology of autism. Ann Neurol 1998;43:7-14.
    Pubmed
  59. Kemper TL, Bauman M. Neuropathology of infantile autism. J Neuropathol Exp Neurol 1998;57:645-652.
    Pubmed
  60. Sajdyk TJ, Shekhar A. Excitatory amino acid receptor antagonists block the cardiovascular and anxiety responses elicited by γ-aminobutyric acidA receptor blockade in the basolateral amygdala of rats. J Pharmacol Exp Ther 1997;283:969-977.
    Pubmed
  61. Emery NJ, Clayton NS. Effects of experience and social context on prospective caching strategies by scrub jays. Nature 2001;414:443-446.
    Pubmed
  62. Sweeten TL, Posey DJ, Shekhar A, McDougle CJ. The amygdala and related structures in the pathophysiology of autism. Pharmacol Biochem Behav 2002;71:449-455.
    Pubmed
  63. Klüver H, Bucy PC. Preliminary analysis of functions of the temporal lobes in monkeys. Arch Neurol Psychiatry 1939;42:979-1000.
  64. Hetzler BE, Griffin JL. Infantile autism and the temporal lobe of the brain. J Autism Dev Disord 1981;11:317-330.
    Pubmed
  65. Sajdyk TJ, Shekhar A. Sodium lactate elicits anxiety in rats after repeated GABA receptor blockade in the basolateral amygdala. Eur J Pharmacol 2000;394:265-273.
    Pubmed
  66. Adolphs R, Tranel D, Damasio H, Damasio A. Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala. Nature 1994;372:669-672.
    Pubmed
  67. Young AW, Hellawell DJ, Van De Wal C, Johnson M. Facial expression processing after amygdalotomy. Neuropsychologia 1996;34:31-39.
    Pubmed
  68. Stone V. In: Baron-Cohen S, Tager-Flusberg H, Cohen DJ. Understanding other minds: perspectives from autism. 2nd ed. Oxford: Oxford University Press, 2000; 2000. p. 253-273.
  69. Adolphs R, Sears L, Piven J. Abnormal processing of social information from faces in autism. J Cogn Neurosci 2001;13:232-240.
    Pubmed
  70. Felix-Ortiz AC, Tye KM. Amygdala inputs to the ventral hippocampus bidirectionally modulate social behavior. J Neurosci 2014;34:586-595.
    Pubmed
  71. Taylor DC, Neville BG, Cross JH. Autistic spectrum disorders in childhood epilepsy surgery candidates. Eur Child Adolesc Psychiatry 1999;8:189-192.
    Pubmed
  72. Hoon AH, Reiss AL. The mesial-temporal lobe and autism: case report and review. Dev Med Child Neurol 1992;34:252-259.
    Pubmed
  73. Bolton PF, Griffiths PD. Association of tuberous sclerosis of temporal lobes with autism and atypical autism. Lancet 1997;349:392-395.
    Pubmed
  74. Haznedar MM, Buchsbaum MS, Wei TC, Hof PR, Cartwright C, Bienstock CA, Hollander E. Limbic circuitry in patients with autism spectrum disorders studied with positron emission tomography and magnetic resonance imaging. Am J Psychiatry 2000;157:1994-2001.
    Pubmed
  75. Courchesne E, Press GA, Yeung-Courchesne R. Parietal lobe abnormalities detected with MR in patients with infantile autism. AJR Am J Roentgenol 1993;160:387-393.
    Pubmed
  76. Nowell MA, Hackney DB, Muraki AS, Coleman M. Varied MR appearance of autism: fifty-three pediatric patients having the full autistic syndrome. Magn Reson Imaging 1990;8:811-816.
    Pubmed
  77. Howard MA, Cowell PE, Boucher J, Broks P, Mayes A, Farrant A, Roberts N. Convergent neuroanatomical and behavioural evidence of an amygdala hypothesis of autism. Neuroreport 2000;11:2931-2935.
    Pubmed
  78. Abell F, Krams M, Ashburner J, Passingham R, Friston K, Frackowiak R, Happé F, Frith C, Frith U. The neuroanatomy of autism: a voxel-based whole brain analysis of structural scans. Neuroreport 1999;10:1647-1651.
    Pubmed
  79. Ohnishi T, Matsuda H, Hashimoto T, Kunihiro T, Nishikawa M, Uema T, Sasaki M. Abnormal regional cerebral blood flow in childhood autism. Brain 2000;123:1838-1844.
    Pubmed
  80. Otsuka H, Harada M, Mori K, Hisaoka S, Nishitani H. Brain metabolites in the hippocampus-amygdala region and cerebellum in autism: an 1H-MR spectroscopy study. Neuroradiology 1999;41:517-519.
    Pubmed
  81. Stuss DT, Knight RT. Principles of frontal lobe function. Oxford: Oxford University Press, 2013.
  82. Herbert MR, Ziegler DA, Makris N, Filipek PA, Kemper TL, Normandin JJ, Sanders HA, Kennedy DN, Caviness VS. Localization of white matter volume increase in autism and developmental language disorder. Ann Neurol 2004;55:530-540.
    Pubmed
  83. Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, Barnes CC, Pierce K. Neuron number and size in prefrontal cortex of children with autism. JAMA 2011;306:2001-2010.
    Pubmed
  84. Preuss TM. Do rats have prefrontal cortex? The Rose-Woolsey-Akert program reconsidered. J Cogn Neurosci 1995;7:1-24.
    Pubmed
  85. Finger S. Origins of neuroscience: a history of explorations into brain function. New York, NY: Oxford University Press, 1994.
  86. Zelazo PD, Müller U. In: Goswami U. Blackwell handbook of childhood cognitive development. Malden, MA: Blackwell Publishers Ltd., 2002; 2002. p. 445-469.
  87. Alvarez JA, Emory E. Executive function and the frontal lobes: a meta-analytic review. Neuropsychol Rev 2006;16:17-42.
    Pubmed
  88. Robbins TW, Arnsten AF. The neuropsychopharmacology of fronto-executive function: monoaminergic modulation. Annu Rev Neurosci 2009;32:267-287.
    Pubmed
  89. Heidbreder CA, Groenewegen HJ. The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics. Neurosci Biobehav Rev 2003;27:555-579.
    Pubmed
  90. Kim MJ, Whalen PJ. The structural integrity of an amygdala-prefrontal pathway predicts trait anxiety. J Neurosci 2009;29:11614-11618.
    Pubmed
  91. Wood JN, Grafman J. Human prefrontal cortex: processing and representational perspectives. Nat Rev Neurosci 2003;4:139-147.
    Pubmed
  92. Frith CD, Frith U. The neural basis of mentalizing. Neuron 2006;50:531-534.
    Pubmed
  93. Quirk GJ, Mueller D. Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 2008;33:56-72.
    Pubmed
  94. Sotres-Bayon F, Quirk GJ. Prefrontal control of fear: more than just extinction. Curr Opin Neurobiol 2010;20:231-235.
    Pubmed
  95. Bishop SJ. Neurocognitive mechanisms of anxiety: an integrative account. Trends Cogn Sci 2007;11:307-316.
    Pubmed
  96. Quirk GJ, Beer JS. Prefrontal involvement in the regulation of emotion: convergence of rat and human studies. Curr Opin Neurobiol 2006;16:723-727.
    Pubmed
  97. Fuchs RA, Eaddy JL, Su ZI, Bell GH. Interactions of the basolateral amygdala with the dorsal hippocampus and dorsomedial prefrontal cortex regulate drug context-induced reinstatement of cocaine-seeking in rats. Eur J Neurosci 2007;26:487-498.
    Pubmed
  98. Mashhoon Y, Wells AM, Kantak KM. Interaction of the rostral basolateral amygdala and prelimbic prefrontal cortex in regulating reinstatement of cocaine-seeking behavior. Pharmacol Biochem Behav 2010;96:347-353.
    Pubmed
  99. Cohen MX, Axmacher N, Lenartz D, Elger CE, Sturm V, Schlaepfer TE. Neuroelectric signatures of reward learning and decision-making in the human nucleus accumbens. Neuropsychopharmacology 2009;34:1649-1658.
    Pubmed
  100. Knutson B, Adams CM, Fong GW, Hommer D. Anticipation of increasing monetary reward selectively recruits nucleus accumbens. J Neurosci 2001;21:RC159.
    Pubmed
  101. Ernst M, Nelson EE, McClure EB, Monk CS, Munson S, Eshel N, Zarahn E, Leibenluft E, Zametkin A, Towbin K, Blair J, Charney D, Pine DS. Choice selection and reward anticipation: an fMRI study. Neuropsychologia 2004;42:1585-1597.
    Pubmed
  102. Wacker J, Dillon DG, Pizzagalli DA. The role of the nucleus accumbens and rostral anterior cingulate cortex in anhedonia: integration of resting EEG, fMRI, and volumetric techniques. Neuroimage 2009;46:327-337.
    Pubmed
  103. Schlaepfer TE, Cohen MX, Frick C, Kosel M, Brodesser D, Axmacher N, Joe AY, Kreft M, Lenartz D, Sturm V. Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology 2008;33:368-377.
    Pubmed
  104. Schmitz N, Rubia K, van Amelsvoort T, Daly E, Smith A, Murphy DG. Neural correlates of reward in autism. Br J Psychiatry 2008;192:19-24.
    Pubmed
  105. Scott-Van Zeeland AA, Dapretto M, Ghahremani DG, Poldrack RA, Bookheimer SY. Reward processing in autism. Autism Res 2010;3:53-67.
    Pubmed
  106. Knutson B, Cooper JC. Functional magnetic resonance imaging of reward prediction. Curr Opin Neurol 2005;18:411-417.
    Pubmed
  107. Kim H, Shimojo S, O'Doherty JP. Is avoiding an aversive outcome rewarding? Neural substrates of avoidance learning in the human brain. PLoS Biol 2006;4:e233.
    Pubmed
  108. Forbes EE, Hariri AR, Martin SL, Silk JS, Moyles DL, Fisher PM, Brown SM, Ryan ND, Birmaher B, Axelson DA, Dahl RE. Altered striatal activation predicting real-world positive affect in adolescent major depressive disorder. Am J Psychiatry 2009;166:64-73.
    Pubmed
  109. Posey DJ, McDougle CJ. Pharmacotherapeutic management of autism. Expert Opin Pharmacother 2001;2:587-600.
    Pubmed
  110. Adler BA, Wink LK, Early M, Shaffer R, Minshawi N, McDougle CJ, Erickson CA. Drug-refractory aggression, self-injurious behavior, and severe tantrums in autism spectrum disorders: a chart review study. Autism 2015;19:102-106.
    Pubmed
  111. Stigler KA, McDonald BC, Anand A, Saykin AJ, McDougle CJ. Structural and functional magnetic resonance imaging of autism spectrum disorders. Brain Res 2011;1380:146-161.
    Pubmed
  112. Farmer C, Thurm A, Grant P. Pharmacotherapy for the core symptoms in autistic disorder: current status of the research. Drugs 2013;73:303-314.
    Pubmed
  113. Kerbeshian J, Burd L, Avery K. Pharmacotherapy of autism: A review and clinical approach. J Dev Phys Disabil 2001;13:199-228.
  114. McPheeters ML, Warren Z, Sathe N, Bruzek JL, Krishnaswami S, Jerome RN, Veenstra-Vanderweele J. A systematic review of medical treatments for children with autism spectrum disorders. Pediatrics 2011;127:e1312-e1321.
    Pubmed
  115. Richards C, Oliver C, Nelson L, Moss J. Self-injurious behaviour in individuals with autism spectrum disorder and intellectual disability. J Intellect Disabil Res 2012;56:476-489.
    Pubmed
  116. Odom SL, Boyd BA, Hall LJ, Hume K. Evaluation of comprehensive treatment models for individuals with autism spectrum disorders. J Autism Dev Disord 2010;40:425-436.
    Pubmed
  117. Benabid AL. Deep brain stimulation for Parkinson's disease. Curr Opin Neurobiol 2003;13:696-706.
    Pubmed
  118. Lozano AM, Dostrovsky J, Chen R, Ashby P. Deep brain stimulation for Parkinson's disease: disrupting the disruption. Lancet Neurol 2002;1:225-231.
    Pubmed
  119. Hamani C, Pilitsis J, Rughani AI, Rosenow JM, Patil PG, Slavin KS, Abosch A, Eskandar E, Mitchell LS, Kalkanis S, Array. 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 Surgeons. Neurosurgery 2014;75:327-333.
    Pubmed
  120. Taghva AS, Malone DA, Rezai AR. Deep brain stimulation for treatment-resistant depression. World Neurosurg 2013;80:S27.e17-S27.e24.
    Pubmed
  121. Schrock LE, Mink JW, Woods DW, Porta M, Servello D, Visser-Vandewalle V, Silburn PA, Foltynie T, Walker HC, Shahed-Jimenez J, Savica R, Klassen BT, Machado AG, Foote KD, Zhang JG, Hu W, Ackermans L, Temel Y, Mari Z, Changizi BK, Lozano A, Auyeung M, Kaido T, Agid Y, Welter ML, Khandhar SM, Mogilner AY, Pourfar MH, Walter BL, Juncos JL, Gross RE, Kuhn J, Leckman JF, Neimat JA, Okun MS, Tourette Syndrome Association International Deep Brain Stimulation (DBS) Database and Registry Study Group. Tourette syndrome deep brain stimulation: a review and updated recommendations. Mov Disord 2015;30:448-471.
    Pubmed
  122. Sturm V, Fricke O, Bührle CP, Lenartz D, Maarouf M, Treuer H, Mai JK, Lehmkuhl G. 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. Front Hum Neurosci 2012;6:341.
    Pubmed
  123. Stocco A, Baizabal-Carvallo JF. Deep brain stimulation for severe secondary stereotypies. Parkinsonism Relat Disord 2014;20:1035-1036.
    Pubmed
  124. Helsmoortel C, Vulto-van Silfhout AT, Coe BP, Vandeweyer G, Rooms L, van den Ende J, Schuurs-Hoeijmakers JH, Marcelis CL, Willemsen MH, Vissers LE, Yntema HG, Bakshi M, Wilson M, Witherspoon KT, Malmgren H, Nordgren A, Annerén G, Fichera M, Bosco P, Romano C, de Vries BB, Kleefstra T, Kooy RF, Eichler EE, Van der Aa N. A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nat Genet 2014;46:380-384.
    Pubmed
  125. Willsey AJ, Sanders SJ, Li M, Dong S, Tebbenkamp AT, Muhle RA, Reilly SK, Lin L, Fertuzinhos S, Miller JA, Murtha MT, Bichsel C, Niu W, Cotney J, Ercan-Sencicek AG, Gockley J, Gupta AR, Han W, He X, Hoffman EJ, Klei L, Lei J, Liu W, Liu L, Lu C, Xu X, Zhu Y, Mane SM, Lein ES, Wei L, Noonan JP, Roeder K, Devlin B, Sestan N, State MW. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell 2013;155:997-1007.
    Pubmed
  126. Halgren C, Kjaergaard S, Bak M, Hansen C, El-Schich Z, Anderson CM, Henriksen KF, Hjalgrim H, Kirchhoff M, Bijlsma EK, Nielsen M, den Hollander NS, Ruivenkamp CA, Isidor B, Le Caignec C, Zannolli R, Mucciolo M, Renieri A, Mari F, Anderlid BM, Andrieux J, Dieux A, Tommerup N, Bache I. Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Clin Genet 2012;82:248-255.
    Pubmed
  127. Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W, Liu W, Klei L, Lei J, Yin J, Reilly SK, Tebbenkamp AT, Bichsel C, Pletikos M, Sestan N, Roeder K, State MW, Devlin B, Noonan JP. The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nat Commun 2015;6:6404.
    Pubmed
  128. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimäki T, Lin CF, Ma'ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnström K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Rüther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JDDDD, Array. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 2014;515:209-215.
    Pubmed
  129. Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP, Penn O, Witherspoon K, Gerdts J, Baker C, Vulto-van Silfhout AT, Schuurs-Hoeijmakers JH, Fichera M, Bosco P, Buono S, Alberti A, Failla P, Peeters H, Steyaert J, Vissers LE, Francescatto L, Mefford HC, Rosenfeld JA, Bakken T, O'Roak BJ, Pawlus M, Moon R, Shendure J, Amaral DG, Lein E, Rankin J, Romano C, de Vries BB, Katsanis N, Eichler EE. Disruptive CHD8 mutations define a subtype of autism early in development. Cell 2014;158:263-276.
    Pubmed
  130. Van Bon BW, Coe BP, Bernier R, Green C, Gerdts J, Witherspoon K, Kleefstra T, Willemsen MH, Kumar R, Bosco P, Fichera M, Li D, Amaral D, Cristofoli F, Peeters H, Haan E, Romano C, Mefford HC, Scheffer I, Gecz J, de Vries BB, Eichler EE. Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID. Mol Psychiatry 2016;21:126-132
    Pubmed
  131. O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 2012;485:246-250.
    Pubmed
  132. Murdoch JD, State MW. Recent developments in the genetics of autism spectrum disorders. Curr Opin Genet Dev 2013;23:310-315.
    Pubmed
  133. Butler MG, Dasouki MJ, Zhou XP, Talebizadeh Z, Brown M, Takahashi TN, Miles JH, Wang CH, Stratton R, Pilarski R, Eng C. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet 2005;42:318-321.
    Pubmed
  134. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 2012;485:237-241.
    Pubmed
  135. Grozeva D, Carss K, Spasic-Boskovic O, Parker MJ, Archer H, Firth HV, Park SM, Canham N, Holder SE, Wilson M, Hackett A, Field M, Floyd JA, Hurles M, Raymond FL, UK10K Consortium. De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability. Am J Hum Genet 2014;94:618-624.
    Pubmed
  136. Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, Nygren G, Rastam M, Gillberg IC, Anckarsäter H, Sponheim E, Goubran-Botros H, Delorme R, Chabane N, Mouren-Simeoni MC, de Mas P, Bieth E, Rogé B, Héron D, Burglen L, Gillberg C, Leboyer M, Bourgeron T. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 2007;39:25-27.
    Pubmed
  137. Willsey AJ, State MW. Autism spectrum disorders: from genes to neurobiology. Curr Opin Neurobiol 2015;30:92-99.
    Pubmed
  138. Hamdan FF, Daoud H, Piton A, Gauthier J, Dobrzeniecka S, Krebs MO, Joober R, Lacaille JC, Nadeau A, Milunsky JM, Wang Z, Carmant L, Mottron L, Beauchamp MH, Rouleau GA, Michaud JL. De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Biol Psychiatry 2011;69:898-901.
    Pubmed
  139. Deriziotis P, O'Roak BJ, Graham SA, Estruch SB, Dimitropoulou D, Bernier RA, Gerdts J, Shendure J, Eichler EE, Fisher SE. De novo TBR1 mutations in sporadic autism disrupt protein functions. Nat Commun 2014;5:4954.
    Pubmed
  140. Fatemi SH, Earle J, Kanodia R, Kist D, Emamian ES, Patterson PH, Shi L, Sidwell R. Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: implications for genesis of autism and schizophrenia. Cell Mol Neurobiol 2002;22:25-33.
    Pubmed
  141. Fatemi SH, Pearce DA, Brooks AI, Sidwell RW. Prenatal viral infection in mouse causes differential expression of genes in brains of mouse progeny: a potential animal model for schizophrenia and autism. Synapse 2005;57:91-99.
    Pubmed
  142. Libbey JE, Sweeten TL, McMahon WM, Fujinami RS. Autistic disorder and viral infections. J Neurovirol 2005;11:1-10.
    Pubmed
  143. Madsen KM, Hviid A, Vestergaard M, Schendel D, Wohlfahrt J, Thorsen P, Olsen J, Melbye M. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med 2002;347:1477-1482.
    Pubmed
  144. Yasuda H, Yoshida K, Yasuda Y, Tsutsui T. Infantile zinc deficiency: association with autism spectrum disorders. Sci Rep 2011;1:129.
    Pubmed
  145. Grabrucker S, Jannetti L, Eckert M, Gaub S, Chhabra R, et al. Zinc deficiency dysregulates the synaptic ProSAP/Shank scaffold and might contribute to autism spectrum disorders. Brain 2014;137:137-152.
    Pubmed
  146. Melke J, Goubran Botros H, Chaste P, Betancur C, Nygren G, Anckarsäter H, Rastam M, Ståhlberg O, Gillberg IC, Delorme R, Chabane N, Mouren-Simeoni MC, Fauchereau F, Durand CM, Chevalier F, Drouot X, Collet C, Launay JM, Leboyer M, Gillberg C, Bourgeron T. Abnormal melatonin synthesis in autism spectrum disorders. Mol Psychiatry 2008;13:90-98.
    Pubmed
  147. Rossignol DA, Frye RE. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child Neurol 2011;53:783-792.
    Pubmed
  148. Tanne JH. Maternal obesity and diabetes are linked to children's autism and similar disorders. BMJ 2012;344:e2768.
    Pubmed
  149. Kinney DK, Munir KM, Crowley DJ, Miller AM. Prenatal stress and risk for autism. Neurosci Biobehav Rev 2008;32:1519-1532.
    Pubmed
  150. Miyazaki K, Narita N, Narita M. Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism. Int J Dev Neurosci 2005;23:287-297.
    Pubmed
  151. Eskenazi B, Marks AR, Bradman A, Harley K, Barr DB, Johnson C, Morga N, Jewell NP. Organophosphate pesticide exposure and neurodevelopment in young Mexican-American children. Environ Health Perspect 2007;115:792-798.
    Pubmed
  152. Larsson HJ, Eaton WW, Madsen KM, Vestergaard M, Olesen AV, Agerbo E, Schendel D, Thorsen P, Mortensen PB. Risk factors for autism: perinatal factors, parental psychiatric history, and socioeconomic status. Am J Epidemiol 2005;161:916-925.
    Pubmed