Autistic behaviors have been observed in children with genetic disorders, infections that damage the brain, and prenatal exposure to drugs. For example autistic disorder has been observed in some children exposed to alcohol during gestation. Alcohol affects brainstem nuclei and the cerebellum in a pattern of damage known as Wernicke's encephalopathy. Abnormalities within the brainstem and cerebellum have been observed in brains from individuals with autism.

The auditory system is prominently affected in Wernicke's encephalopathy. Indications that auditory dysfunction underlies the language disorder of children with autism are discussed below. Impairment of metabolism in the auditory system and other brain areas affected in Wernicke's encephalopathy could be shared in common by all of the etiologies of autism.

1. Rubella, phenylketonuria, tuberous sclerosis, fragile-X, and more...

Autistic behavior is observed in children with many diverse medical conditions (Gillberg & Coleman, 1996). Prenatal rubella, phenylketonuria, tuberous sclerosis, and fragile X Syndrome are among the most well known medical predispositions. Following are citations to several case reports: Chess, 1971; Fombonne et al., 1997; Chen & Hsaio, 1989; Lowe et al., 1980; Miladi et al., 1992; Bolton & Griffiths, 1997; Gillberg et al., 1994; Bailey et al., 1998).

Nanson (1992) reported autistic behaviors in six children with fetal alcohol syndrome (FAS), and additional features of autism in children with FAS have since been reported (Harris et al., 1995; Aronson et al., 1997; Church et al., 1997).

Exposure to other drugs during gestation also appears to predispose an infant to development of autism. Davis et al. (1992) observed autistic behaviors in children of mothers who used cocaine during pregnancy; but alcohol and other drugs of abuse may also have been responsible. Christianson et al. (1994) and Williams and Hersch (1997) reported autism in children whose mothers used the anticonvulsant medication valproic acid during pregnancy. Stromland et al. (1994) reported cases of autism among victims of prenatal exposure to thalidomide in the early 1960's.

There have been several recent reports of autistic behaviors in children with disorders of purine metabolism (Page & Coleman, 2000; Stathis et al., 2000; Van den Berghe et al., 1997). Many more genetic, infectious, and environmental factors that lead to autism spectrum disorders are no doubt waiting to be identified.

But the core syndrome of autism is distinctive and cannot be simply dismissed as evidence of damage to wide areas of the brain caused by diverse medical conditions. What is needed is to discover which brain areas are affected in common by virus infections, genetic defects, or prenatal exposure to alcohol, and which of these brain areas are essential for development of social awareness and language.

2. Vulnerable areas of the brain

That autistic behaviors have been observed in children exposed to alcohol during gestation suggests an array of brain areas that might be affected. The effects of alcohol on the mature brain are well known. The mammillary bodies, oculomotor nuclei, inferior colliculi, inferior olives, and cerebellum are consistently listed as part of the neuropathology caused by alcohol abuse in a pattern of brain damage known as Wernicke's encephalopathy (Butterworth, 1993; Cavanagh et al., 1997; Torvik, 1987; Victor et al., 1971).

The brainstem nuclei affected have been found to have the highest rates of blood flow and glucose utilization in the brain (Sokoloff, 1981). Wernicke's encephalopathy is widely believed to be caused by thiamine (vitamin B1) deficiency. This vitamin is an essential cofactor for enzymes of the mitochondrial aerobic energy system (Hakim & Pappius, 1981). It should be noted, however, that Wernicke encephalopthy type patterns of brain damage have been observed in disorders of energy metabolism caused by defects of the mitochondrial enzymes themselves (Cavanagh & Harding, 1994).

3. Prenatal exposure to alcohol

The effects of alcohol on the developing fetus are much less predictable than in the adult brain; there may be no visible damage in some cases but in others major structural deformities have been reported (Roebuck, et al., 1998). Vingan, et al. (1986) used the deoxyglucose method of Sokoloff (1981) to determine the effects of prenatal exposure to alcohol on brain metabolism in laboratory rats and found significant reductions of metabolic activity throughout the brain without visible signs of damage.

Impairment of function within the brainstem nuclei of high metabolic rate could be linked with many features of the core syndrome of autism. Oculomotor signs are among the earliest clinical manifestations of Wernicke's encephalopathy (Cogan et al., 1985). Varying degrees of oculomotor dysfunction are evident in children with autism (Miller et al., 1998). Lack of eye contact, a vacant look, and even decreased blink reactions may be subtle signs of eye movement disturbance. Cranio-facial abnormalities are common in fetal alcohol syndrome, but not in children with autism. However, facial immobility and lack of facial expression may be the result of a lesser degree of involvement of the cranial nerve system in autistic children.

Developmental language disorder and hearing impairments are complications of fetal alcohol syndrome (Church & Abel, 1998; Steinhausen et al., 1994). The auditory system is conspicuously affected in Wernicke's encephalopathy, and impaired auditory function could affect comprehension of speech sounds in children exposed to alcohol during gestation.

4. Developmental language disorder

For children with autism the most serious impediment to development is failure to learn language. Rapin (1997) proposed that the language disorder of some children with autism is the result of verbal auditory agnosia, an inability to decode rapid streams of speech. Hopefully this view will stimulate more research on auditory dysfunction in autism. Agnosia, an impairment of recognition without sensory loss, seems particularly relevant to the problems of echolalic children. An echolalic child may be able to recite a large repertoire of phrases, but does not reword what has been heard to fit new contexts. This suggests an inability to recognize individual words in streams of speech and to put them together in different combinations appropriate to new situations.

Verbal auditory agnosia may afflict us all in later life. After adolescence most people have difficulty learning a foreign language and few learn a new language without accent. With maturation we seem to lose awareness of acoustic features essential for learning a language through hearing. What is especially difficult is trying to follow streams of speech in a foreign language. This is a common experience for adult learners of a new language and in no way viewed as an impairment of auditory function. That we do not recognize this loss of acuity as we mature may partly explain why we fail to see it as disabling when it occurs in a young child.

5. Sound onset, noise, and stressed syllables

Caspary et al. (1995) found changes with aging in the inhibitory neurotransmitter gamma amino butyric acid (GABA) in the inferior colliculus of laboratory rats. GABA neurons appear to damp propagation of sounds that are ongoing, thus providing a distinction between sound onset and those we can relegate as background noise. This may be a capability needed to recognize beginnings of new words in streams of speech. Presbyacusis of the elderly includes an inability to focus on speech in noisy environments, which may indicate loss of function in inhibitory neurons.

Brown and Bellugi (1964) determined that young children extract basic units of meaning (morphemes) from speech through recognition of stressed syllables. The child then uses these morphemic units to create original speech in other contexts. At first a normal child's speech tends to be telegraphic and primitive, but it is tailored to fit each new situation.

The autistic child may not comprehend the significance of stressed syllables, and may not even hear stress accentuation. The closest the echolalic child comes to using morphemic units is what Prizant (1982) calls gestalt forms, or unanalyzed clauses taken from the speech of others. Gestalt forms are verbatim recitations not modified to fit new contexts; what Kanner (1946) termed irrelevant and metaphorical speech.

6. Gestalt, echolalic, and metaphorical speech

A normally developing young child might say, "Truck, dat mine", derived from having heard adult expressions such as, "That's mine", "That's your truck", or "That book is mine". The child selects what he needs and constructs an expression that is different than anything a fluent adult speaker might say.

Brown (1975) contrasted the telegraphic speech of normal children with echolalia in an autistic child. The autistic child might assert that the truck is his by saying, "That's your truck", the exact sentence an adult used to tell him that the truck is his toy. The echolalic child does this without changing either the pronoun "your" to "my" or the intonation.

Research on how children extract meaning from what they hear continues to be based on the findings of Brown and Bellugi (1964), and is sometimes extended by data from sound spectrograms as in the work of Swanson et al. (1992) and Jusczyk (1997). Stages of development are estimated in terms of mean length of utterance (Brown 1973). But in analyzing the speech of autistic children it should be kept in mind that echoed phrases cannot be considered multi-word utterances (Tager-Flusberg & Calkins, 1990). Brown (1975) quoted an autistic child's repeated expression of exasperation, "What's the matter, your truck stuck?" and pointed out that this statement was more or less equivalent to "Damn!" (This child was Conrad).

The intended meaning of phrases used by autistic children can also be easily missed, even by those who are well acquainted with echolalic speech (Simon, 1975). On a visit to a swim class I was asked by one little girl, "You don't want to go swimming?" I told her I did but hadn't brought my bathing suit. She repeated this question persistently; only when efforts to coax her into the pool revealed her fear of water did I realize that her question was in fact a statement meaning that she did not want to go swimming.

7. The inferior colliculus

The inferior colliculi of the midbrain auditory system are the first and most severely affected nuclei in cases of severe thiamine deficiency (Chen et al., 1997; Vortmeyer et al., 1992). Of the brainstem nuclei of high metabolic rate, the inferior colliculus consistently proves to be at the top of the rank order; Sokoloff (1981) remarked, "the inferior colliculus is clearly the most metabolically active structure in the brain."

The inferior colliculus is also the earliest structure to become myelinated and fully functional in the human brain (Yakovlev & Lecours, 1967; Moore et al., 1995). In laboratory animals, the inferior and superior colliculi have been found to generate trophic substances important for development of later maturing areas of the brain (vonHungen et al., 1975; Kungel & Friauf 1995). Pre- or perinatal damage of the inferior colliculi could then lead to abnormal development and hypometabolism in the language receptive areas of the temporal lobes.

8. Toxic substances

Toxic substances such as lead, mercury, and poisonous fumes affect the brain in Wernicke-like patterns of damage (Bertoni & Sprenkle, 1989; Bini & Bollea, 1947; Oyanagi et al., 1989; Cavanagh & Nolan, 1993; Goulon et al., 1975; Squier et al., 1992). Of the three cases reported by Wernicke (1881) one was a woman who had ingested sulfuric acid. Anti-tumor and anti-microbial drugs can have a toxic effect and produce Wernicke-type patterns of brain damage (DeKlippel et al., 1991; Rogulja et al., 1973).

Toxic substances impair mitochondrial enzymes of aerobic metabolism and damage mitochondrial DNA, which may lead to matrilineal heritable disorders (Schapira, 1998). The auditory system is especially vulnerable to damage in mitochondrial disorders (Jacobs, 1997; Lestienne & Bataille, 1994; Warner & Schapira, 1997).

9. Asphyxia at birth

Asphyxia at birth also can produce a Wernicke-type pattern of brain damage (Windle, 1969; Leech & Alvord, 1977; Myers, 1972; Natsume et al., 1995; Roland et al., 1988; Schneider et al., 1975).

Matsuishi et al., (1999) investigated outcome in survivors of a neonatal intensive care unit and diagnosed autistic disorder in 18 of 5,271 infants followed for five years; 57 developed cerebral palsy. Meconium-aspiration syndrome was reported as the most significant factor that distinguished children who developed autistic disorder from those who developed cerebral palsy or who developed normally.

Prolonged partial hypoxia is a perinatal mishap associated with cerebral palsy (Myers, 1972). A brief episode of total oxygen deprivation for a few minutes produces a Wernicke-like pattern of brain damage (Windle, 1969; Myers, 1972). A brief period of total asphyxia can easily go unnoticed, however Matsuishi et al., (1999) found meconium aspiration as a significant factor predisposing infants to autistic disorder. Meconium aspiration is a sign that the infant was gasping for air.

The metabolically active inferior colliculus is the most predictably affected by a brief period of asphyxia at birth (Windle, 1969; Myers, 1972). Myriad environmental sound sources are tracked within the inferior colliculus; it is an active processing center for detection of sound onset and changes of intensity between the ears (Feng 1992). The inferior colliculus is also an alerting center and plays a role in general awareness and maintaining the conscious state (Brandao et al., 1993). This could be the crucial component of the auditory system that is impaired in children with autism even if not visibly damaged.

10. Brain abnormalities in autism

Decreased numbers of Purkinje cells in the cerebellum and abnormalities of the inferior olives have been repeatedly reported in postmortem examination of the brains of individuals with autism (Williams et al., 1980; Ritvo et al., 1986; Bailey et al., 1998; Kemper & Bauman, 1998). Variability of the size of cerebellar lobules in brains from autistic individuals is illustrated in the paper by Kemper and Bauman (1998), and anomalies of the cerebellar vermis are evident on magnetic resonance image (MRI) scans from a much larger group of living subjects (Courchesne, 1997).

On the other hand, Schaefer et al. (1996) compared MRI images from 125 normal and 13 autistic subjects with those from 89 patients with a variety of neurogenetic disorders. In this study, no differences were found in the cerebellar vermis of autistic compared with normal subjects, but hypoplasia was found in patients with other disorders, some with autistic features and some without. Schaefer et al. concluded that cerebellar involvement is a common factor in many neurological conditions and not a specific marker for autism. Cavanagh et al. (1997) discussed vulnerability of the cerebellar vermis as part of the neuropathology caused by chronic alcoholism.

Decreased size of the posterior corpus callosum has also been noted in MRI scans from some individuals with autism (Gillberg & Svendsen, 1983; Piven et al., 1997; Bailey et al. , 1998). But this also is not a specific marker for autism; Levy et al. (1996) noted thinning of the posterior corpus callosum in children born to mothers with untreated phenylketonuria. In their review of neuropathology found in children with prenatal exposure to alcohol Roebuck et al. (1998) cited several reports of agenesis or thinning of the corpus callosum. The corpus callosum may be a structure that is especially vulnerable to teratogenic substances, of which many more are likely to be found as etiologic factors in autism.

11. Brain size

Brains from individuals with autism are mostly of normal to larger than normal size, but measurements of MRI scans indicate the brainstem tends to be reduced in size (Gaffney et al., 1988; Hashimoto et al., 1995). Kemper and Bauman noted defects in cell size and migration patterns in the limbic system and pointed out that prenatal damage of the inferior olives could prevent normal proliferation of Purkinje cells during development.

Early damage to other brainstem structures might likewise interfere with trophic influences required for maturation of the temporal lobes and corpus callosum. Bailey et al. (1998) found ectopic groups of neurons in four of the brains they examined from autistic individuals. Ectopic neurons represent a severe form of cell migration abnormality, and this is a common finding in brains from children with fetal alcohol syndrome (Roebuck et al., 1998).

Hypometabolism in the temporal lobes is observable in positron emission (PET) scans of children with infantile spasms and autistic behaviors (Chugani et al. , 1996). Bolton and Griffiths (1997) found tubers in the temporal lobes of children with tuberous sclerosis who were also autistic. Impairment of the temporal lobes could be expected to severely impede language development.

12. The temporal lobes

Coleman et al. (1985) examined the brain of a 21-year old woman with autism for signs of damage in areas of the cerebral cortex involved in language, the primary auditory cortex, auditory association cortex, and Broca's speech area. No significant differences could be found in comparisons of her brain, including counts of neurons in tissue from both left and right sides, with two brains from age-and-sex-matched individuals who had not been mentally disabled.

Rodier et al. (1996) examined the brainstem in the same case and found abnormalities from the inferior olive in the medulla to the superior olive and facial nucleus in the pons. They could not discern the usually distinctive spindle-shaped cells or the pattern of fibers that should surround them in the superior olive. The brainstem appeared shortened between the inferior olive and trapezoid body, and there was a severe reduction of facial motor neurons. Deformity of this magnitude, involving brainstem auditory nuclei and their connections from trapezoid body to superior olive, could be expected to interfere with transmission of auditory signals to the temporal lobes and result in agnosia for acoustic features. Although no visible signs of damage in the temporal lobes were found, brainstem trophic factors needed for functional maturation of the temporal lobes may have been missing during development.

Prenatal exposure to alcohol is likely to have played a role in the neuropathology of the case investigated by Coleman et al. (1985) and Rodier et al. (1996). The mother became a chronic abuser of alcohol and Dexedrine during the patient's infancy, but could not remember whether her addiction problems arose before or after the birth of her child. Alcohol use during pregnancy should be investigated in every case of autistic disorder and especially in research studies of families with two or more siblings with broader autism phenotype.

13. Metabolic impairment

Visible or microscopic abnormalities of the brainstem, limbic system, temporal lobes, corpus callosum, and cerebellum, represent the most severe manifestations of their etiologies, because none is a consistent finding in children with autism.

The difficulty in locating a particular site in the brain by traditional neuropathology or on MRI and PET scans suggests that a metabolic rather than structural anomaly within the brain is responsible for the core syndrome of autism. Preservation of islands of intelligence in children with autism suggests further that this metabolic anomaly is not a widespread affliction of the brain, but affects function in areas of the brain required for joint attention and other components of human social interactions including language.

The effect of alcohol on the brain is better understood than that of genetic metabolic disorders or infections. Wernicke's encephalopathy is an affliction of brainstem nuclei of high metabolic rate. It is reasonable to assume that these same brainstem areas are also vulnerable to the effects of abnormal metabolites generated in infectious processes and genetic conditions like phenylketonuria.

Wernicke (1881) referred to the pathology caused by alcohol abuse as hemorrhagic poliencephalitis superior, and he compared the appearance of the lesions to those of the spinal cord and lower brainstem in infantile poliomyelitis. A symmetric pattern of brainstem lesions caused by the poliovirus was later reported (Barnhart et al., 1948; Bodian, 1949).

14. Brainstem nuclei of high metabolic rate

Autistic disorder is observed as part of many medical conditions. This indicates that the brain areas impaired in children with autism are vulnerable to many damaging influences. The brainstem nuclei of high metabolic rate are affected by many adverse conditions because of their need for uninterrupted energy production.

The auditory system is metabolically the most active within the brain, and auditory dysfunction is a prominent feature of the core syndrome of autism. Autism spectrum disorders have multiple etiologies, but one common pattern of brain impairment is responsible for the characteristic incapacity for social interaction and language development.

Kemper and Bauman (1998) pointed out that it is important to know not only what area of the brain is damaged, but how and when this happens. The brainstem nuclei of high metabolic rate should be considered candidates, not only based on their function in the mature brain but also for the consequences of deranged influence on development of cortical structures like the temporal lobes.

15. Deficits of awareness in laboratory animals

Lack of social responsiveness and disinterest in communication are thought by many researchers to be the primary problem of children with autism, and that the language disorder is secondary. But damage to the inferior colliculus may diminish environmental awareness. Denny-Brown (1962) proposed this for the superior (visual) colliculi. He described profound losses of awareness, responsiveness, and drive in monkeys after ablation of the superior colliculi, and proposed that this might be the most essential structure for unitary function of the brain. Denny-Brown used suction to remove the inferior colliculi, and careful reading of his method indicates he may also have removed portions of the inferior colliculi, or their connections with the superior colliculi in his experiments.

Experimental disconnection of nerve pathways into or out of the inferior colliculi suggests that auditory processing within the midbrain may be as important as visual functions for unitary function and responsiveness to environmental stimuli. Sprague et al. (1961) observed a dramatic loss of attention, affect, and motivation in cats after severing the lateral lemniscal tracts between the superior olive and inferior colliculus. They described the altered behavior they observed as reminiscent of autistic children, and compared their findings with those of Klver and Bucy (1939) who obtained a similar alteration of behavior after removing the temporal lobes of monkeys. Jane et al. (1965) described loss of attention and behavioral changes in cats with lesions of the brachium of the inferior colliculus that went far beyond the auditory functions they set out to investigate. The brachium connects the inferior colliculus with the medial geniculate body of the thalamus and is contiguous with the superior colliculus.

16. Evolution of the auditory system

Evolution of the auditory system in higher vertebrate species can be traced back to the lateral line organs of fish (Ariens Kappers et al. 1936, Sarnat & Netsky 1974, Butler & Hodos 1996). The lateral line system evolved from neural mechanisms for orientation. Later elaborations provided functions for the vestibular system of animals adapted to living on land. The inferior colliculus of higher vertebrate species has analogous functions to the vestibular organ (torus semicircularis) in the brain of lower vertebrates (Heiligenberg & Rose 1985). In mammals, the vestibular sense organs reside in the inner ear and there are neural connections from auditory nuclei to subcortical components of the vestibular system. Thus auditory function remains closely linked to vestibular function, and signs of vestibular dysfunction have been reported in autistic children Ornitz (1983).

Orientation and response to vibrations transmitted through water may be the earliest precursors of auditory function in primitive species of fishes. However, the inferior colliculi evolved as a posterior extension of the optic lobe in amphibian species. The anterior part of the optic lobe evolved into the superior colliculi in higher vertebrates. The superior and inferior pairs together are known as the corpora quadrigeminae, and are situated in the tectum (roof) of the midbrain above the third ventricle of the brainstem, just forward of the cerebellum.

The superior colliculi detect change in the peripheral visual fields. Detection of motion in the visual field has long been recognized as important for survival (Lettvin et al. 1959), and the inferior colliculi added acoustic stimulation as an alerting mechanism for visual and motor orientation. The auditory system is the most recent evolutionary extension of senses that provide environmental awareness. With extensive connections to other sensory and motor systems of the brain, the inferior colliculi may be, along with the superior pair, locus of the conscious state.

17. High metabolic rate in the inferior colliculus

Why should the inferior colliculus have a higher metabolic rate than the superior colliculus? Perhaps this is because, as an accessory to the primary visual alerting system, the inferior colliculus provides not just a new set of functions for hearing but also mechanisms that make use of auditory and visual signals simultaneously and in a way that the two systems can interact.

Hearing is an accessory to vision in the species familiar to most of us. It would be interesting to find a species in which hearing evolved first with the visual system as the later-developing elaboration. The auditory system may have more work to do thus require more energy than if it evolved without any relationship to the visual system. We turn our heads and look for things that make noises but rarely try to hear something that happens to pass by our field of vision.

Impairment of auditory alerting is part of the attention deficit disorder of many children with autism. A child with autism at times appears deaf and fails to orient to sounds that normally attract attention. Startle and blink reactions may be lacking. These are some of the functions of the inferior colliculus. Lack of facial expression or eye contact as well as global deficits in awareness could be the result of impaired function in this most active nucleus of the brain.

18. Vulnerability of the inferior colliculus

The inferior colliculus is vulnerable to any factor that disrupts energy metabolism, but its position in the brain makes it susceptible to traumatic injury as well.

Denny-Brown (1962) presented a case of a young woman who suffered damage to the midbrain tectum after being thrown from a horse and lapsed into coma. Denny-Brown pointed out the susceptibility to damage of the brain structures just forward of the tentorium connection of the cerebellum to the midbrain. The superior and inferior colliculi form the midbrain tectum and are in proximity to the posterior fossa structures that appear damaged in MRI scans of individuals with autism.

Gellner (1959) suggested that damage to these structures can occur from trauma experienced during prolonged labor or difficult birth, especially in cases in which passage of an infant's head through the maternal pelvis was impeded by malpresentation. She also proposed that damage to the inferior or superior colliculi might underlie auditory or visual impairments that lead to mental retardation, and that psychological stress caused by these defects could lead to the disorder defined by Kanner (1943).

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