Lets Talk About Autism (Part II)

How is autism classified?

Autism is one of five pervasive developmental disorders (PDD)1 , which are characterized by widespread abnormalities of social interaction and communication, as well as severely restricted interests and highly repetitive behavior. It should be noted, however, that these symptoms are not indicative of sickness, fragility, or emotional disturbance.

Another PDD, Asperger syndrome , is closest to autism both in signs and likely causes; Rett syndrome and childhood disintegrative disorder also share several signs with autism, but may have unrelated causes; PDD not otherwise specified (PDD-NOS) is the diagnosis used when the criteria are not met for a more specific disorder. Unlike persons with Autism, people with Asperger’s do not experience the substantial delay in language development.

The manifestations of autism cover a wide-spectrum ranging from individuals with severe impairments – who may be silent, mentally disabled, and locked into hand-flapping and rocking – to high-functioning individuals who may have active but distinctly odd social approaches, narrowly focused interest, and verbose, pedantic communication. Because the behavior spectrum is continuous, boundaries between diagnostic categories are somewhat arbitrary. Sometimes the syndrome is divided into low-functioning, medium-functioning, or high-functioning autism (LFA, MFA, or HFA), based on established IQ thresholds or on how much support an individual requires in daily life; these subdivisions are not standardized and, therefore, considered controversial. Autism can also be divided into syndromal and non-syndromal; syndromal autism is normally associated with severe or profound mental retardation or a congenital syndrome with physical symptoms such as tuberous sclerosis .

Research into causes has been hampered because of the inability to identify biologically meaningful sub-populations as well as the traditional boundaries between the disciplines of psychiatry, psychology, neurology, and pediatrics. Newer techniques such as functional magnetic resonance imaging (f-MRI) and diffusion tensor imaging can help to identify biologically relevant phenotypes (observable traits) that can be viewed on brain scans to help further neurogenetic studies of autism; one such example is lowered activity in the fusiform face area of the brain, which is associated with impaired perception of people versus object.

What are the causes of autism?

I t has long been presumed that there is a common cause at the genetic, cognitive, and neural levels for autism’s characteristic triad of symptoms2 . However, there is increasing suspicion that autism is, instead, a complex disorder whose core aspects have distinct causes that often co-occur.

Autism has been found to have a strong genetic basis, although they are complex and, therefore, it is unclear whether ASD is explained more by rare mutations with major effects, or by rare muti-gene interactions among multiple genes, the environment, and epigenetic factors which do not change DNA but are heritable and influence gene expression. Studies conducted with twins suggest that the heritability is 0.7 for autism and as high as 0.9 for ASD. Additionally, siblings of those with autism are approximately 25 times more likely to be autistic than the general population. It should be noted that, while there is some information, most of the mutations that increased the risk of autism haven’t been identified.

Several lines of evidence point to synaptic dysfunction as a cause of autism. Some rare mutations may lead to autism by disrupting some synaptic pathways, such as those involved with cell adhesion. Gene replacement studies in mice suggest that autistic symptoms are closely related to later developmental steps that depend on activity in synapses as well as activity-dependent changes. All known teratogens (agents that cause birth defects) related to the risk of autism appear to act during the first eight (8) weeks from conception; and, though this does not exclude the possibility that autism can be initiated or affected later, there is strong evidence that autism arises very early in development.

Although evidence for other environmental causes is anecdotal and has not been confirmed by reliable studies, extensive searches are currently underway. Environmental factors that have been claimed to either contribute to or exacerbate autism, or that could be important to future research, include certain foods, infectious disease, heavy metals, solvents, diesel exhaust, PCBs, phthalates and phenols used in plastic products, pesticides, brominated flame retardants, alcohol, smoking, illicit drugs, vaccines, and prenatal stress. Currently, however, no links have been established and some of these have been completely disproved.

Parents may first become aware of autistic symptoms around the time of a routine vaccination. This has led to unsupported theories blaming vaccine “overload”, a vaccine preservative, or the measles-mumps-rubella (MMR) vaccine for causing autism. The latter theory was supported by a litigation-funded study that has since been shown to have been “an elaborate fraud”. Although these theories lack convincing scientific evidence and, are biologically implausible, parental concerns about a potential vaccine link with autism has led to lower rates of childhood immunizations, outbreaks of previously controlled childhood diseases in some countries, as well as the preventable deaths of several children.

What is the mechanism of autism?

Autism symptoms are the result of maturation-related changes in various systems of the brain, however, exactly how autism occurs is not well understood. Research has shown that the mechanism can be divided into two (2) areas: 1) The pathophysiology of brain structures and processes associated with autism; and 2) the neuropsychological linkage between brain structures and behaviors.


Unlike many other diseases which affect the brain, such as Parkinson’s, autism does not have a clear unifying mechanism at either the molecular, cellular, or systems level; it is not known whether autism is a few disorders caused by mutations converging on a few common molecular pathways or a large set of disorders with diverse mechanisms. Autism appears to be the result of developmental factors that affect many or all functional brain systems and which disturb the timing of brain development more than the final product. Neuroanatomical studies as well as the associations with teratogens strongly suggest that the mechanisms of autism include alteration of brain development soon after conception. This anomaly appears to start a cascade of pathological events in the brain which are significantly influenced by environmental factors. Just after birth, the brain of an autistic child tends to grow faster than usual, followed by either normal or relatively slower growth during childhood. What is not known is whether this early overgrowth occurs in all children affected by autism. Hypotheses for the cellular and molecular bases of pathological early overgrowth include the following: 1) An excess of neurons that causes local over connectivity in key brain regions; 2) Disturbed neuronal migration during early gestation; 3) Unbalanced excitation-inhibitory networks; 4) Abnormal formation of synapses and dendritic spines.

Interaction between the immune system and the nervous system begin early during the embryonic stage of life, and successful neuro-development depends on a balance immune response. Aberrant immune activity during critical periods of neuro-development is possibly part of the mechanism of some forms of ASD. Although some abnormalities in the immune system have been found in specific sub-groups of autistic individuals, it is not known whether these abnormalities are relevant to or secondary to autism’s disease processes. As auto-antibodies are found in conditions other than ASD, and are not always present in ASD, the relationship between immune disturbances and autism remains unclear and controversial.

The relationship of neuron-chemicals to autism is not well understood; several of these have been investigated, with the most evidence for the role of serotonin and of genetic differences in its transport. Still others have pointed to a role for group I metabotropic glutamate receptors (mGluR) in the pathogenesis of one type of autism – fragile X. There is some data which suggest an increase in several growth factor hormones (pictured at right) while other data seem to indicate that autism could be the result of a decrease in these same growth hormones. In addition, some inborn errors of metabolism have been associated with autism, however, these probably account for less than five percent (5%) of reported cases.

Another possible cause of autism is explained by the mirror neuron system (MNS) theory. It hypothesizes that distortion in the development of the MNS interferes with imitation and leads to autism’s core features of social impairments and communication difficulties. The MNS operates when a person performs an action or observes another person hy perform the same action. It is believed that this may contribute to an individual’s understanding of other people by enabling the modeling of their behavior via embodied simulation of their actions, intentions, and emotions.

ASD-related patterns of low function and aberrant activation in the brain differ depending on whether the brain is doing social or non-social tasks. In autism, there is evidence for reduced functional connectivity of the default network – a large-scale brain network involved in social and emotional processing, with intact connectivity of the task-positive network, used in sustained attention and goal-directed thinking. In a person with autism, these two networks are not negatively correlated in time, which suggest an imbalance in toggling between the two networks, possibly reflecting a disturbance of self-referential thought.

Yet another theory, the “under-connectivity theory of autism “, hypothesizes that autism is marked by under-functioning high-level neural connections and synchronization, along with an excess of low-level processes3 . Evidence in support of this theory has been found in functional neuro-imaging studies of autistic individuals as well as by brainwave studies that suggests that adults with ASD have local over-connectivity in the cortex and weak functional connections between the frontal lobe and the remainder of the cortex. Other evidence seems to suggest that the under-connectivity is mainly localized within each hemisphere of the cortex and that autism is a disorder of the association cortex.

From studies based on event-related potentials, transient changes to the brain’s electrical activity in response to a stimuli, there is considerable evidence for differences in autistic individuals with respect to attention, orientation to both auditory and visual stimuli, novelty detection, language and face processing, and information storage.

In terms of genetics, relations have been found between autism and schizophrenia based on duplications and deletions of chromosomes; the research has shown that schizophrenia and autism are significantly more common in combination with 1q21.1 deletion syndrome . Research on autism/schizophrenia relations for chromosome 15 (15q13.3), chromosome 16 (16p13.1) and chromosome 17 (17p12) are inconclusive.


There are two (2) major categories of cognitive theories which have been proposed regarding the link between the brain of a person with autism and behavior. The first one of these focuses on deficits in social cognition. The empathizing-systemitizing theory contends that an autistic individual can systemize – meaning they can develop internal rules of operation to handle events within the brain – but are less effective at empathizing by handling events generated by other agents.

Both of these theories are somewhat related to the earlier theory of mind approach, which hypothesizes that autistic behavior arises from the inability to ascribe mental states to oneself and others. This theory is supported by an autistic child’s atypical response to the Sally-Anne test for reasoning about others’ motivations, and the mirror neuron system theory described in Pathophysiology maps well to the hypothesis. However, most studies have found no evidence of impairment in an autistic person’s ability to understand other people’s basic intentions or goals; instead, data suggest that the impairments are found in understanding more complex social emotions or in considering others’ viewpoint4 .

The second category focuses on non-social or general processing. Executive dysfunction hypothesizes that autistic behavior is the result, at least in part, of deficits in the working memory, planning, inhibition and other forms of executive function. Test of core executive processes such as eye movement tasks indicate improvement from late childhood to adolescence, but performance never reaches typical adult levels. One of the strengths of this theory is the ability to predict stereotyped behavior and narrow interest; two weaknesses with the theory are that executive function is difficult to measure along with the fact that these functional deficits have not been found in young children with autism.

Yet another theory – the Weak central coherence theory – hypothesizes that a limited ability to see the big picture underlies the central disturbance in autism. This theory has proved well in its ability to predict special talents and peaks in performance of persons with autism. This theory maps well from the under-connectivity theory of autism.

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