Qualitative Impairment in Social Interactions

The criteria in this domain refer to a qualitative impairment in reciprocal social interactions, not to the absolute lack of social behaviors. Behaviors range from total lack of awareness of another person to the presence of eye contact that is not used to modulate social interactions. The qualitative nature of this and the communication domains were first included in the DSM-IV [1994].

As infants, some autistic children do not lift up their arms or change posture in anticipation of being held. They may or may not cuddle, or even stiffen when held, and often do not look or smile when making a social approach. The characteristic give-and-take in lap play that is seen in typically developing infants and toddlers is often missing. Typically developing infants and toddlers often take great delight in using their newfound “pointer” finger to request or to show; those with ASD usually do not point to request or show/share. Older children often do not point things out or use eye contact to share the pleasure of seeing something with another person, which is called joint attention or social referencing.

Some children do make eye contact, often only in brief glances, but the eye contact is usually not used to get someone’s attention. Others may make inappropriate eye contact by turning someone else’s head to gaze into their eyes. Autistic children may appear to ignore a familiar or unfamiliar person because of a lack of social interest. Some children do make social approaches, although their conversational turn-taking or modulation of eye contact is often grossly impaired. At the opposite extreme of social interactions, some children may make indiscriminate approaches to strangers (e.g., climb into the examiner’s lap before the parent has entered the room, be unaware of psychologic barriers, or be described as a child that continuously and inappropriately “gets in your face”).

Some children with autism indicate little or no interest in other children or adults and prefer to play alone, away from others. Others play with adults nearby or sit on the outskirts of other children’s play and engage in parallel play or simply watch the other children. Some children involve other children in designated, often repetitive play, but often only as “assistants,” without heeding any suggestions from the other children. Some prefer to serve in the passive role in other children’s play, such as the infant in a game of house, and follow others’ directions. Other children may seek out one specific child with whom there is a limited solitary interest that dominates the entire relationship.

Autistic children may also have no age-appropriate friends, and older children often are teased or bullied. A child may “want friends” but usually does not understand the concept of the reciprocity and sharing of interests and ideas inherent in friendship. They may refer to all classmates as friends; one telling example is the child who said, “Oh, I have many, many, 29 friends, but none of them likes me.” Verbal children may have one friend, but the relationship may be limited or may focus only on a similar circumscribed interest, such as a particular computer game. Often, children gravitate to either older peers, in which case they play the role of followers, or to much younger peers, in which case they become the leaders.

Qualitative Impairment in (Verbal and Nonverbal) Communication

The communication deficits seen in the autistic spectrum are far more complex than presumed by simple speech delay, and they are similar to the deficits seen in children with developmental language disorders or specific language impairments [Allen and Rapin, 1992]. Expressive language function across the autistic spectrum ranges from complete mutism to verbal fluency, although fluency is often accompanied by many semantic (i.e., word meaning) and verbal pragmatic (i.e., use of language to communicate) errors. Some mute autistic children do not respond to their names, and often, they are initially presumed to be severely hearing-impaired.

In early infancy, some children with ASD do not babble or use any other communicative vocalizations, and they are described as quiet babies. Some children have absolutely no spoken language when speech should be developing, and they fail to compensate with facial expressions or gestures. A typically developing infant or toddler may pull his or her mother over to a desired object and then will clearly point to the object they request. In contrast, a characteristic behavior of many autistic children is to use another person’s hand mechanically to point to the desired object, an action called hand-over-hand “pointing.” Other “independent” children make no demands or requests of the parents but learn to climb at a young age and acquire the desired object for themselves.

A common feature of verbally fluent children is their inability to initiate or sustain a conversation, which requires two or more parties communicating in a give-and-take fashion on a mutually agreed topic. Although they may be able to respond relatively well to, ask questions of, or talk “at” another person, the reciprocity inherent in a conversation is often difficult for individuals with ASD.

A hallmark of autistic speech is immediate or delayed echolalia. Immediate echolalia refers to immediate noncommunicative repetition of words or phrases – the child is simply repeating exactly what was heard without synthesizing the intrinsic language. This ability is a crucial aspect of normal language development in infants under the age of 2 years, but it becomes pathologic when still present as the sole and predominant expressive language after the age of about 18–24 months.

Delayed echolalia or scripts refers to the use of highly ritualized phrases that have been memorized, such as from videos, television, commercials, or overheard conversations. The origin of this stereotypic language does not necessarily have to be clearly identifiable. Many older autistic children incorporate the scripts in an appropriate conversational context, which can give much of their speech a rehearsed and often more fluent quality relative to the rest of their spoken language. Children also demonstrate difficulties with pronouns or other words that change in meaning with context and they often reverse pronouns or refer to themselves in the third person or by name. Others may use literal idiosyncratic phrases or neologisms. Verbal autistic children may speak in detailed and grammatically correct phrases, which are none the less repetitive, concrete, and pedantic. If a child’s answers to questions seem to “miss the point,” further history and conversation with the child should be elicited because this is also a hallmark of autistic language deficits.

Some autistic children do not appropriately use miniature objects, animals, or dolls in pretend play. Others use the miniatures in a repetitive, mechanical fashion without evidence of representational play. Some highly verbal children may invent a fantasy world that becomes the sole focus of repetitive play. A classic example of the lack of appropriate play is the fluent autistic preschooler who “plays” by repeatedly reciting a soliloquy of the old witch scene verbatim from Beauty and the Beast while manipulating dollhouse characters in sequence precisely according to the script. When given the same miniature figures and dollhouse but instructed to play something other than Beauty and the Beast, this child is incapable of synthesizing any other play scenario.

Restricted, Repetitive, and Stereotypic Patterns of Behaviors, Interests, and Activities

Some verbal autistic children ask the same question repeatedly, regardless of what reply is given, or they engage in highly repetitive, perseverative play. Others are preoccupied with special interests that are highly unusual. For example, many children are fascinated with dinosaurs, but autistic children may amass exhaustive facts about every conceivable type of dinosaur and about which museums house which particular fossils; these children often repeatedly “share” their knowledge with others, regardless of the others’ interest or suggestions to the contrary.

Many autistic children are so preoccupied with “sameness” in their home and school environments or routines that little can be changed without prompting a tantrum or other emotional disturbance. For example, some insist that all home furnishings remain in the same position, that all clothing to be a particular color, or that only one specific set of favored sheets be used on the bed. Others may eat only from a specific plate when sitting in a specific chair in a specific room, which may not necessarily be the kitchen or dining room. Some children may insist on being naked while in the home but insist on wearing shoes to the dinner table. This inflexibility may also pertain to familiar routines, such as taking only a certain route to school, entering the grocery store only by one specific door, or never stopping or turning around after the car starts moving. Many parents may not be aware that they are following certain rituals to avoid the emotional upheaval, or they may be aware but are too embarrassed to volunteer such information. Within this context, some children have distinct behavioral repertoires that they use to sustain sameness, even when not imposed externally. By adulthood, many of these rituals may evolve to more classic obsessive-compulsive symptoms.

Some children have obvious stereotypical movements, such as florid hand-clapping or arm-flapping whenever excited or upset, which is pathologic if it occurs after the age of about 18–24 months. Running aimlessly, rocking, spinning, bruxism (teeth grinding), toe-walking, or other odd postures are commonly seen in autistic children. Others may repetitively tap the back of the hand in a less obtrusive manner, or touch or smell items. In higher-functioning youngsters, the stereotypic movements may become “miniaturized” as they get older into more socially acceptable behaviors, such as pill rolling [Bauman, 1992; Rapin, 1996].

Many children demonstrate the classic behavior of lining up toys, videotapes, or other favored objects, but others may simply collect things for no apparent purpose. Many are preoccupied with repetitive actions, such as opening and closing doors, drawers, to flipping the tops of trash cans, or turning light switches repetitively off and on. Others repetitively flick string, elastic bands, measuring tapes, or electric cords. Younger autistic children love spinning objects or themselves. Others are often particularly fascinated with water, and they especially enjoy transferring water repetitively from one vessel into another.

Asperger’s Disorder

The validity of Asperger’s disorder as an entity separate from high-functioning (verbal) children with ASD remains controversial [Ariella Ritvo et al., 2008; Frith, 2004; Howlin, 2003; Macintosh and Dissanayake, 2004; Sanders, 2009; Schopler, 1996; Witwer and Lecavalier, 2008; Woodbury-Smith and Volkmar, 2009], and Asperger’s disorder will most likely not be included as a separate entity under the ASD umbrella in DSM-V [in press]. Clinically, the diagnosis of Asperger’s disorder is often inappropriately given as an alternative, more acceptable, “A-word” to high-functioning autistic children [Bishop, 1989]. The similarity and overlap of signs and symptoms of Asperger’s disorder with nonverbal learning disabilities (NLD) additionally expand the spectrum of these developmental disorders [Harnadek and Rourke, 1994; Klin et al., 1995; Rourke, 1989]; a recent report, however, demonstrates a lack of difficulty with spatial- or problem-solving tasks – a main principle in the NLD model – in a small cohort of children with Asperger’s disorder [Ryburn et al., 2009].

In sharp contrast to autistic disorder, DSM-IV-TR Asperger’s criteria state that “there are no clinically significant delays in early language (e.g., single words are used by age 2, communicative phrases by age 3)” [2000, p. 81]. Normal or near-normal cognitive function is also the rule, including self-help skills, “adaptive behavior (other than in social interaction), and curiosity about the environment in childhood” [1994, p. 77]. Although absence of language delay is required for diagnosis, the DSM-IV definition of single words by age 2 and communicative phrases by age 3 is none the less considerably outside the recognized norm for language development [Coplan and Gleason, 1993; Rossetti, 1990; Sanders, 2009; Zimmerman et al., 2002]. Asperger’s criteria for the qualitative impairments in social interaction and restrictive and repetitive patterns of behaviors and activities are identical to those for autistic disorder (for a recent review, see Woodbury-Smith and Volkmar [2009]).

High verbal skills are the rule in Asperger’s disorder, which typically leads to later clinical recognition than with autistic disorder [Volkmar and Cohen, 1991; Woodbury-Smith and Volkmar, 2009]. Despite the DSM-IV definition [1994, 2000], language in Asperger’s disorder is clearly not typical or normal. For example, there usually is pedantic and poorly intoned speech, poor nonverbal pragmatic or communication skills, and intense preoccupation with circumscribed topics, such as the weather or railway timetables [Ghaziuddin and Gerstein, 1996; Klin et al., 1995; Wing, 1981]. Individuals with Asperger’s use fewer personal pronouns, temporal expressions, and referential expressions [Colle et al., 2008]. They often exhibit deficits in the semantics and verbal pragmatics of language, resulting in concrete and literal speech; their answers often miss the point. They also demonstrate deficits in general receptive language [Koning and Magill-Evans, 2001; Noterdaeme et al., 2009; Saalasti et al., 2008] and in prosodic comprehension [Jarvinen-Pasley et al., 2008]. Szatmari et al. [1995] further define this disorder by the complete lack of delayed echolalia, pronoun reversal, or neologisms in language production.

Socially, individuals with Asperger’s disorder are usually unable to form true friendships. Because of their naive, inappropriate, one-sided social interactions and lack of empathy, they may be ridiculed by their peers. Often, they cease their attempts to develop friendships because of the cruel ridicule and then remain extremely socially isolated. Fine and gross motor deficits have been described, including clumsy and uncoordinated movements and odd postures [Jansiewicz et al., 2006; Klin et al., 1995; Nishitani et al., 2004; Rinehart et al., 2006; Wing, 1981]. However, frank motor apraxia is an inconsistent finding [Dziuk et al., 2007; Mostofsky et al., 2006].

Autistic Regression and Childhood Disintegrative Disorder

Approximately 22–35 percent of autistic children initially appear to develop normally until at least 12 months of age, followed by loss of language and/or social skills [Baird et al., 2008; Meilleur and Fombonne, 2009; Rogers, 2004; Tuchman and Rapin, 1997; Wiggins et al., 2009]. Loss of language skills has been found to be specific for ASD [Kurita, 1996; Pickles et al., 2009]. Parents usually report that infants were socially responsive, smiled, waved bye-bye, and said some words, but they then suddenly or gradually stopped speaking and seemed to withdraw. In an on-going surveillance program, Wiggins et al. [2009] found that, not surprisingly, children with a known ASD diagnosis had a higher rate of parentally reported regression than those identified with ASD through the retrospective record review (26 percent vs. 17 percent, respectively). Regression occurred at a median age of 24 months; boys were more likely to demonstrate regression than girls, and at earlier ages. Children who experienced regression were diagnosed with ASD much earlier (mean age 4.2 years) than those without regression (mean age 6.2 years) [Shattuck et al., 2009].

One difficulty hindering a better understanding of autistic regression involves the disentangling of age at onset from age at recognition [Chawarska et al., 2007; Volkmar et al., 1985]. Many children thought by parents to be normal in the first 18 months may indeed show signs or symptoms on retrospective evaluation of home movies and videotapes by as early as 12 months of age [Baranek, 1999; Goldberg et al., 2003; Maestro et al., 2005; Osterling and Dawson, 1994, 1999; Ozonoff et al., 2005; Werner and Dawson, 2005]. Goldberg et al. [2008] found significant concordance between parental report and retrospective analysis of home videotapes of regression only in the language domains.

As recently reviewed by Tuchman [2006, 2009], there is considerable controversy surrounding the relation between autistic regression and epilepsy, with regression associated with an epileptiform electroencephalogram (EEG) approximately 20 percent of the time. Studies report both higher [Hrdlicka, 2008; Kobayashi and Murata, 1998] and lower rates [Baird et al., 2008; Tuchman et al., 1991] of epilepsy in regression. The behavioral phenotypes of autistic regression, Landau–Kleffner syndrome (LKS), and continuous spike-wave during slow-wave sleep (CSWS) overlap considerably, and may represent distinct syndromes based on age of regression, degree and type of regression, and frequency of epilepsy and EEG abnormalities [Tuchman, 2009]. Children with LKS and isolated language regression are more likely to have epileptiform EEGs and seizures than those with an autistic regression [McVicar et al., 2005].

Mitochondrial disorders have recently been reported to be associated with autism, and with regression in particular [Poling et al., 2006]. In a cohort of 25 patients with ASD and definite or probable mitochondrial disease by the Modified Walker and Mitochondrial Disease Criteria [Bernier et al., 2002; Wolf and Smeitink, 2002], Weissman found that 56 percent experienced regression of previously acquired skills; 64 percent of the regressions were multiple, and 43 percent had the regression(s) after 3 years of age [Weissman et al., 2008]. Shoffner et al. [2009] found that 61 percent of children with ASD and mitochondial disease experienced a regression, 71 percent associated with and 29 percent without fever.

By DSM-IV definition, childhood disintegrative disorder (CDD) refers to the rare phenomenon of normal early development until at least age 24 months, followed by the loss of language, social, play, or motor skills which culminate most often in symptoms of autism. Previously called Heller’s syndrome, dementia infantalis, or disintegrative psychosis, CDD usually occurs between 36 and 48 months of age but may occur up to age 10 years [American Psychiatric Association, 1994, 2000]. There is, therefore, much overlap between CDD and autistic regression, which has led to significant controversy [Hendry, 2000; Malhotra and Gupta, 2002]. The category of CDD will most likely be retained in DSM-V [in press] under the umbrella of ASD; however, the diagnostic criteria may be changed to reflect the increased understanding of the phenomenon of regression in autism. The lower age limit of CDD will most likely be increased to age 3 years, with autistic regression occurring prior to age 3 years remaining under autism.

CDD is considered rare, with recent epidemiological data suggesting a prevalence estimate of 2 per 100,000 [Fombonne, 2002b, 2009]. It is usually associated with more severe autistic symptoms than is early-onset autism, including profound loss of cognitive skills resulting in mental retardation. There is a 4:1 male predominance and a mean age of onset of 29 ± 16 months; more than 95 percent demonstrate symptoms of speech loss, social disturbances, stereotyped behaviors, resistance to change, anxiety, and deterioration of self-help skills [Kurita et al., 2004a, b; Mouridsen, 2003; Volkmar and Rutter, 1995]. The risk of epilepsy may be as high as 70 percent [Mouridsen et al., 1999]. Children with CDD after age 3 years are more likely to have seizures than those who regress before age 24 months [Klein et al., 2000; Shinnar et al., 2001; Wilson et al., 2003]. Treatment experience in CDD has been generally limited to anticonvulsant therapy for seizures, although Mordekar et al. [2009] recently reported amelioration of behavior, language, and motor regression after corticosteroid treatment in two children with CDD, seizures, and/or epileptiform EEG patterns.

Pervasive Developmental Disorder – Not Otherwise Specified and Atypical Autism

The diagnosis of atypical autism or PDD-NOS is used when clinically significant autistic symptoms are present involving reciprocal social interactions, verbal or nonverbal communication, or stereotyped behavior, interests, and activities, but criteria are not met for a specific diagnostic category under the umbrella of autistic spectrum or pervasive developmental disorders (e.g., a child who does not meet the required 6 of 12 criteria for the diagnosis of autistic disorder) [American Psychiatric Association, 1994, 2000]. Children whose symptoms are atypical or not as severe are coded under this diagnosis. It should be noted that the DSM-IV definition of PDD-NOS required that a child meet only 1 of the 12 criteria in any of the three core domains; in DSM-IV-TR, the definition was changed to require impairment in the development of reciprocal social interaction and either impairment in verbal and nonverbal communication skills or the presence of stereotyped behavior, interests, and activities. It is expected that this diagnostic category will be eliminated in the DSM-V [in press, Box 48-3].

Box 48-3 Proposed Revision to 299.00 in DSM-V: Autism Spectrum Disorder

Must meet criteria 1, 2, and 3:

1. Clinically significant, persistent deficits in social communication and interactions, as manifest by all of the following:

a. Marked deficits in nonverbal and verbal communication used for social interaction

b. Lack of social reciprocity

c. Failure to develop and maintain peer relationships appropriate to developmental level

2. Restricted, repetitive patterns of behavior, interests, and activities, as manifested by at least TWO of the following:

a. Stereotyped motor or verbal behaviors, or unusual sensory behaviors

b. Excessive adherence to routines and ritualized patterns of behavior

c. Restricted, fixated interests

3. Symptoms must be present in early childhood (but may not become fully manifest until social demands exceed limited capacities)

Rationale

New name for category, autism spectrum disorder, which includes autistic disorder (autism), Asperger’s disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified

Differentiation of autism spectrum disorder from typical development and other “nonspectrum” disorders is done reliably and with validity, while distinctions among disorders have been found to be inconsistent over time, variable across sites, and often associated with severity, language level, or intelligence, rather than features of the disorder

Since autism is defined by a common set of behaviors, it is best represented as a single diagnostic category that is adapted to the individual’s clinical presentation by inclusion of clinical specifiers (e.g., severity, verbal abilities, and others) and associated features (e.g., known genetic disorders, epilepsy, intellectual disability, and others.) A single-spectrum disorder is a better reflection of the state of knowledge about pathology and clinical presentation; previously, the criteria were equivalent to trying to “cleave meatloaf at the joints”

Three domains become two:

1. Social/communication deficits

2. Fixated interests and repetitive behaviors

Deficits in communication and social behaviors are inseparable and more accurately considered as a single set of symptoms with contextual and environmental specificities

Delays in language are not unique nor universal in autism spectrum disorder and are more accurately considered as a factor that influences the clinical symptoms of autism spectrum disorder, rather than defining the autism spectrum disorder diagnosis

Requiring both criteria to be completely fulfilled improves specificity of diagnosis without impairing sensitivity

Providing examples for subdomains for a range of chronological ages and language levels increases sensitivity across severity levels from mild to more severe, while maintaining specificity with just two domains

Decision based on literature review, expert consultations, and workgroup discussions; confirmed by the results of secondary analyses of data from Collaborative Programs of Excellence in Autism (CPEA) and Studies to Advance Autism Research and Treatment (STAART), University of Michigan, Simons Simplex Collection databases

Several social/communication criteria were merged and streamlined to clarify diagnostic requirements

In DSM-IV, multiple criteria assess the same symptom and therefore carry excessive weight in making diagnosis

Merging social and communication domains requires a new approach to criteria

Secondary data analyses were conducted on social/communication symptoms to determine the most sensitive and specific clusters of symptoms and criteria descriptions for a range of ages and language levels

Requiring two symptom manifestations for repetitive behavior and fixated interests improves specificity of the criterion without significant decrements in sensitivity. The necessity for multiple sources of information, including skilled clinical observation and reports from parents/caregivers/teachers, is highlighted by the need to meet a higher proportion of criteria

The presence, via clinical observation and caregiver report, of a history of fixated interests, routines, or rituals and repetitive behaviors considerably increases the stability of autism spectrum diagnoses over time and the differentiation between autism spectrum disorder and other disorders

Reorganization of subdomains increases clarity and continues to provide adequate sensitivity while improving specificity through provision of examples from different age ranges and language levels

Unusual sensory behaviors are explicitly included within a subdomain of stereotyped motor and verbal behaviors, expanding the specification of different behaviors that can be coded within this domain, with examples particularly relevant for younger children

Autism spectrum disorder is a neurodevelopmental disorder and must be present from infancy or early childhood, but may not be detected until later because of minimal social demands and support from parents or caregivers in early years

(American Psychiatric Association. Proposed Revisions to 299.00 Autistic Disorder in DSM-V, 2010. Retrieved 28 February 2010, from http://www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=94#.)

Risk Factors

Animal Models

No single animal model exists for autism, but several animal models that exhibit some of the major features of autism have provided an opportunity to understand the neural substrates of functional impairments. In the macaque monkey, social behavior is mediated by the amygdala, temporal cortex, orbitofrontal cortex, and superior temporal gyrus [Lord et al., 2000]. In another monkey model (rhesus), bilateral removal of the medial temporal lobes leads to abnormal social behavior during maturation that resolves in adults [Bachevalier, 1994; Machado and Bachevalier, 2003]. Symptoms include abnormal social interaction, absence of facial and body expression, and stereotypic behaviors. Social anxiety and fear have been studied in primates [Amaral, 2002] and in rats [Wolterink et al., 2001], and are related to amygdaloid circuitry.

A behavioral syndrome in Lewis rats with analogies to autism is the result of Borna disease virus infection in neonates [Pletnikov et al., 2003; Weissenbock et al., 2000]. Neonatal infection produces specific behavioral abnormalities, with disturbances in sensorineural development, lower startle responsiveness, and abnormal social play. Proprioceptive systems were abnormal that involved use of hind-limbs and balance. Pathologically, Borna disease virus induces regional neuronal loss in the cerebellum. This model provides some insights into mechanisms of pre- and perinatal infection causing damage to the developing brain, but it does not indicate that Borna disease virus is an etiologic agent in autism.

Other animal models have been developed by knocking out different candidate genes [Lijam et al., 1997], by oxytocin and vasopressin administration [Insel et al., 1999], and by exposing embryos to teratogens such as valproic acid [Ingram et al., 2000]. Behavioral studies have focused on social interaction and memory deficits. Because the neurexin 1-alpha gene has been linked to ASD phenotypes, a knockout mouse model has been developed with analogies to at least one core domain of ASD [Etherton et al., 2009].

Neuropathology

Abnormalities in major cortical and subcortical brain structures have been found through postmortem and magnetic resonance imaging (MRI) studies of autistic subjects. Comprehensive examination of nine autistic postmortem brains was carried out by Kemper and Bauman [1994]. They described three major findings: curtailment of normal development in forebrain neurons, which were smaller and more densely distributed than normal; an apparent congenital decrease in the number of Purkinje cells; and age-related changes in cell size and the number of neurons in the diagonal band of Broca, the cerebellar nuclei, and the inferior olive.

These neuropathologic findings may account for many clinical features of autism. Perinatally acquired lesions in limbic system structures could lead to disruption in memory processes involved in the ability to learn new information. In contrast, striatal and cortical areas involved in habitual memory were spared, potentially relating to the need for sameness, narrow interests, and capacity for rote memory. Disruption of cerebellar function may lead to a number of motor and sensory system deficiencies, including mental imagery, anticipatory planning, and timing and integration of sensory and motor information [Kemper and Bauman, 1998]. Support of brain-tissue banking is critical to continued research into the neuropathologic underpinnings of autism [Pickett, 2001].

Another approach to determining the neuropathologic underpinnings of autism has been suggested by Rodier [2002]. She found that children exposed to thalidomide in the first trimester developed autism at an increased rate, supporting the idea that the brain abnormality originates at the time of closure of the neural tube [Rodier et al., 1996]. This finding was corroborated by postmortem examination of a brain from a subject with autism not exposed to thalidomide, but whose mother was an alcoholic, showing near-complete absence of the facial nucleus and superior olive and narrowing of the brainstem between the trapezoid body and inferior olive. This deficit was reproduced in an HOXA1-knockout mouse model and by exposing rat embryos to valproic acid on the day of neural tube closure [Ingram et al., 2000]. The investigators concluded that central nervous system injuries occurring during or just after neural tube closure can lead to selective loss of neurons derived from the basal plate of the rhombencephalon, and this finding may indicate that the initiating injury in some individuals with autism takes place around the time of neural tube closure.

Additional supporting evidence for this theory comes from a Nova Scotia cohort of 61 autistic children [Rodier et al., 1997]. Forty-two percent of these children with autism had posterior rotation of the external ears, compared with 18 percent of controls. They postulated that this could have been associated with a disruption of otic disc formation in the fourth week of embryonic life and that ear anomalies found in some children with autism could possibly be a marker for initiating events in utero.

An important additional neuropathologic finding described by Casanova et al. [2008, 2002] is the finding of abnormalities in the structure of minicolumns in the brain of autistic individuals. Minicolumns consist of 80–100 neurons, and they are believed to be the smallest unit of functional organization in the cortex. In autistic individuals, the minicolumns were described as more numerous but smaller than those of controls and with less space in between. This structural difference may cause the firing of too many processing units at once and prohibit the units from coherently responding to signals. Over-arousal or under-arousal could easily result. This abnormality could also be responsible for the increased incidence of seizures in individuals with autism.