Autism and Other Neurodevelopmental Disorders Affecting Cognition
Autism Has Characteristic Behavioral Features
There Is a Strong Genetic Component in Autism
Autism Has Characteristic Neurological Abnormalities
There Are Distinctive Cognitive Abnormalities in Autism
Social Communication Is Impaired: The Mind Blindness Hypothesis
Some Neurodevelopmental Disorders Have a Known Genetic Basis
DURING THE PAST CENTURY “MENTAL RETARDATION” was broadly used to label a variety of cognitive impairments that were linked to prenatal or early postnatal brain abnormalities. Some subgroups with easily identifiable physical features, such as Down syndrome, were recognized early on. In recent years syndromes that result from genetic anomalies but do not express obvious physical features, such as fragile X syndrome, have also been delineated.
Common to all of these disorders are mental impairments that persist throughout life, hampering development and learning, hence the terms “neurodevelopmental disorder” and “learning disability.” Generally speaking, even if all mental functions seem to be affected, some tend to be more affected than others. This differential vulnerability gives interesting clues about the different origins and developmental time course of specific mental functions in normal development.
In this chapter we focus on autism and briefly consider Down syndrome, fragile X, and other neurodevelopmental disorders with a known genetic basis. Autism is especially interesting because it impairs brain functions that are highly sophisticated in human beings: social awareness and communication. Autism is also an exemplar of many psychiatric disorders: there is a striking range in severity of symptoms, an impressive heterogeneity of comorbid conditions, and no clear cut neuropathology. It is likely that autism will ultimately be viewed as a class of disorders each with different etiologies that include genetic and environmental factors and their interaction.
Autism Has Characteristic Behavioral Features
Autism has probably always been with us, but it was identified and labeled only in 1943 by Leo Kanner and by Hans Asperger in 1944. Where were the autistic people in the past? Rare historical documents suggest that some may have been valued as eccentrics or holy fools, but the majority were probably considered to suffer constitutional mental deficiency.
Today clinicians and researchers think of autism as a spectrum of disorders with three common diagnostic features, each showing a great deal of variability among individuals: impaired social interaction, impaired verbal and nonverbal communication, and restricted or circumscribed interests with stereotyped behaviors. The label “Asperger syndrome” is often used for individuals who exhibit the typical features of autism but have high verbal ability and no delay in language acquisition.
Autism and related disorders affect approximately 1% of the population, a far higher frequency than was previously recognized. Whether this reflects a better understanding and recognition of the range of disorders that actually belongs in this category or an actual increase in incidence is not entirely clear. The possibility that this increase is due to immunization or any simple environmental factor has been largely eliminated. Some studies indicate that the sperm of older fathers increases the incidence of autism as it does for schizophrenia. Risk also goes up with the age of the mother. As we shall see below, up to 10% of children with autism carry a genetic defect that results from a copy number variation, a mutation that arises in the germline.
Classification today is based on the three diagnostic criteria described above, which are more inclusive than those used in the earliest descriptions of the disease. Boys outnumber girls by 4 to 1, and by approximately 8 to 1 in cases of autism without intellectual disability. Although autism can occur in people with a high IQ, more than half the individuals with autism suffer from intellectual disability (defined as an IQ below 70). By definition, autism should be detectable before the child is 3 years old. Autism occurs in all countries and cultures and in every socioeconomic group.
Although autism is clearly a disorder that affects the brain, there are as yet no diagnostic biological markers and therefore diagnosis is based on behavioral criteria. Because behavior is highly changeable during development and depends on a number of factors, such as age, environment, social context, and availability and duration of remedial help, no single behavior could ever be diagnostic.
Some parents of an autistic child are aware that something is not quite right with their child from an early age. Other parents report that their babies first developed typically and then regressed in their development during the second year of life. A prospective study of siblings at genetic risk for autism showed that at age 6 months infants at genetic risk and later diagnosed autistic did not differ from those who were typically developing on measures of social interaction, such as gaze to faces, social smile, and vocalizations to others. However, differences from typically developing children increasingly emerged and were significant by 1 year of age. One of the earliest signs, near the end of the first year, is that the baby does not turn when called by name. Other early signs include the lack of preference for people over objects, and repetitive use of objects, such as spinning, and unusual visual exploration.
Beginning at approximately 18 months of age several other signs become clear. Most children with autism do not automatically direct their attention to the person or object that is the focus of other people’s attention. Children with autism often fail to use pointing or other gestures to direct the attention of other people. They also fail to engage in ordinary make-believe play. Later, signs of delayed and abnormal language development are evident, with echoing of other people’s speech (echolalia) and the use of idiosyncratic expressions. By the age of 3, typical cases of autism can be diagnosed reliably on the basis of this constellation of social and communication impairments, and rigid and repetitive behavior and interests. In cases where there is neither intellectual disability nor language delay (Asperger syndrome), diagnosis is typically not made until school age.
Like other neurodevelopmental disorders, autism is a lifelong disorder. Autism is not progressive, however. On the contrary, special educational programs and professional support often lead to marked improvements in behavior with age. The understanding and use of language by people with autism is quite variable. Even in individuals of high ability, language remains literal and conversational skills are lacking, as evident in poor turn-taking and poor understanding of irony. Most people with autism continue to find social situations difficult and are hampered in their ability to make friends or sustain lasting relationships.
A preference for routines and restricted behavior patterns remains throughout life, although the nature of obsessions and interests often undergo marked changes. In early childhood an individual may be drawn to shiny pieces of metal, in later childhood collect light bulbs, and in adulthood obsessively construct a novel dictionary. Hypersensitivity to touch, taste, sound, or vision is frequently mentioned in personal accounts and appears to play a role in restricting behavior by creating strong avoidances or preferences. Unfortunately, no neurobiological insight into these alterations in sensory function has yet emerged. People with autism are commonly susceptible to a variety of co-morbid psychiatric problems, particularly anxiety and depression. Nevertheless, reasonably good adaptation is possible when the environment is stable and highly structured.
There Is a Strong Genetic Component in Autism
Convincing data that autism has a strong genetic component come from studies of monozygotic twin pairs, who have identical genes. These studies show anywhere from 60% to 91% concordance of autism. The range is broad in part because some studies consider only the most serious forms of autism, whereas others consider the full spectrum of autism-like disorders. Dizygotic twins, in contrast, have been estimated to have 10–30% concordance when the full autism spectrum is considered. If a woman has one child with autism, the risk that a second child will have autism increases approximately 20-fold. Approximately 20% of siblings of a child with autism may also have autism. The risk increases if the second child is a male or if two prior children have disorders on the autism spectrum.
These family studies indicate that autism is not generally the result of mutations in a single gene but rather variation in many genes, giving rise to a complex pattern of inheritance. As in other polygenic disorders, it is likely that the genes responsible are not the same genes in all individuals but that different combinations are drawn from a larger pool of predisposing genes. This heterogeneity has made the identification of specific genes difficult.
Despite the difficulties, genomic regions have been implicated on several chromosomes. Of particular interest are mutations in two genes on the X chromosome in two sibling pairs with either autism or Asperger syndrome. These genes encode neuroligins, postsynaptic cell adhesion proteins important in synapse formation. These observations are intriguing because they are X-linked genes and may explain the male preponderance. The neuroligin discovery has recently been supported by a study of mice harboring mutations similar to the human mutations. These mice show impaired social interactions and, as a neural correlate, increased inhibitory synaptic transmission.
In addition to conventional mutations in specific genes, copy number variation has emerged as a potentially important genetic mechanism in autism. Copy number variation describes genomic deletions and duplications of pieces of a chromosome involving up to 100 consecutive genes on a chromosome. These deletions and duplications have recently been appreciated as a significant source of genetic variation in humans. Although copy number variants are almost always inherited, recent studies suggest that 10% of autistic patients carry a de novo gene copy number that neither parent carries. These are caused not by more common conventional mutations of discrete genes but by sporadic mutations of genomic structure in the germ-line in the cells that give rise to sperm and ova. Thus copy number variations may play an important role in autism (and other disorders) and perhaps explain the difficulties encountered in identifying autismsusceptibility genes.
Even though heritability, or the proportion of the phenotypic variance due to genetic factors, is very high for autism, environmental factors likely also play an important role, although no specific environmental factors have been conclusively identified. Infections by viruses (such as rubella, measles, influenza, herpes simplex, and cytomegalovirus) may contribute to the etiology of autism and perhaps represent environmental cues. The possibility that a genetic defect alters features of brain development by affecting the immune system is receiving greater attention. There is substantial evidence that mediators of immune functions such as cytokines and chemokines also play a role in brain development including synaptogenesis. Given the complexity of autism and its various forms, it is likely that a variety of etiologies will ultimately be discovered, some purely genetic, others that depend on genetic risk factors coupled with environmental factors, and some purely environmental causes.
Autism Has Characteristic Neurological Abnormalities
If autism is a developmental disorder of the brain, what parts of the nervous system are most severely affected? Research in this area is still in its infancy and no comprehensive picture of the neuropathology of autism is yet available. In fact, for a disorder with such a profound impact on the life of an individual, the brain, at least at a superficial level, looks relatively normal. However, more detailed quantitative analyses have begun to demonstrate consistent alterations in the size and time course of development of particular brain regions.
The first magnetic resonance imaging (MRI) studies of autism in the mid-1980s focused on the cerebellum and suggested that hypoplasia of the cerebellar vermis was characteristic of autism. These findings, however, have generally not been replicated. Other brain regions that have been found to be abnormal in autism include the cerebral cortex (although the salient portion of the cerebral cortex varies from study to study), medial temporal lobe structures such as the amygdala and hippocampus, and the corpus callosum (Figure 64–1).
Figure 64-1 Brain areas implicated in the three core deficits characteristic of autism: impaired social interaction, impaired language and communication, and severely restricted interests with repetitive and stereotyped behaviors. Areas implicated in social deficits include the orbitofrontal cortex (OFC), the anterior cingulate cortex (ACC), and the amygdala (A). Cortex bordering the superior temporal sulcus (STS) has been implicated in mediating the perception that a living thing is moving and gaze perception. Face processing involves a region of the inferior temporal cortex within the fusiform gyrus (FG). Comprehension and expression of language involve a number of regions including the inferior frontal region, the striatum, and subcortical areas such as the pontine nuclei (PN). The striatum has also been implicated in the mediation of repetitive behaviors. A number of imaging and postmortem studies have indicated that the cerebellum may also be pathological in autism.
The notion that cortical development may be altered in autism arose from clinical observations that before age 2 the head circumference of children with autism is often larger than typically developing controls. Approximately 20% of individuals with autism have unusually large heads (macrocephaly). These data would suggest that a large head and thus increased brain size might be a common, although by no means universal, feature of autism. There is, however, increasing evidence that an abnormal time course in development, not the outcome of brain development, is diagnostic of autism.
Several research groups have gathered provocative evidence for precocious growth of the brain, and particularly of the frontal lobe, during the first few years of life of autistic children. Most studies show that at birth the brains of children with autism are either of normal size or perhaps slightly smaller than typically developing children and this is true again in adulthood. Clearly, the development of the brain is a precisely orchestrated process; if one or more brain regions develop out of sequence, patterns of brain connectivity and thus brain function could be seriously disturbed.
Beyond the cerebral cortex, other brain regions also show abnormal development. Perhaps most striking is the amygdala, a region of the temporal lobe that is involved in the detection of dangers in the environment and in modulating some forms of social interaction (see Chapter 48). Interestingly, in typically developing boys the amygdala develops over an unusually long period, increasing in size by nearly 40% between the ages of 8 and 18 years. The rest of the brain actually decreases in size during this same time period by approximately 10% because of refinement of connectivity and function. For boys with autism the amygdala reaches adult size by eight years of age. Thus whatever refinement of connectivity takes place in typically developing preadolescent and adolescent children may not occur in boys with autism.
Many studies have gone beyond simply evaluating the volume of the brain or brain regions and have analytically broken down a region of the brain into compartments representing grey matter and white matter. Alterations in white matter volume may actually be a more sensitive indicator of pathology in autism than grey matter differences. In fact, some researchers have proposed that the enlarged brain volume that has been reported in young children with autism can be accounted for, in large part, by disproportionate increases in white matter volume. Thus some studies have found a larger volume of white matter in boys with autism aged 2 to 3 years compared to controls. Interestingly, this difference was not found in adolescence, further evidence of an abnormality of early development.
As these studies illustrate, autism is not a disorder that affects a single brain region. The amount and kind of brain pathology in a particular individual may depend on whether the etiology is more genetic or environmental. Finally, the pathology of autism may not be apparent in the mature size and shape of the brain but in the time course of development of both the structure and connections of the brain.
The picture of the neuropathology of autism at a microscopic level is also not clear. This is in part because of the paucity of brains available for analysis. To date fewer than 200 brains have been subjected to microscopic analysis, and only a small fraction of these have undergone quantitative analysis. Another problem is the co-morbid occurrence of epilepsy. Approximately 30% of individuals with autism also have seizure disorders, and seizures damage the amygdala and many of the other brain regions that have been implicated in autism.
One reasonably consistent finding in autism has been the lower number of Purkinje cells in the cerebellum. Gaps in the orderly arrays of Purkinje cells are noticeable when using neural stains that mark cell bodies. Whether this reduction in cell number is because of autism, epilepsy, or the co-occurrence of both disorders is not clear. It is also not clear whether reduced numbers of Purkinje cells are characteristic of autism or a more general finding in neurodevelopmental disorders. Cerebellar alterations have been found in cases of idiopathic intellectual disability, Williams syndrome, and many other childhood disorders. A few cases of alterations of brain stem nuclei that are connected to the cerebellum, such as the olivary complex, have also been reported.
Microscopic abnormalities have also been observed in the autistic cerebral cortex, including defects in the migration of cells into the cortex, such as ectopias, nests of cells in white matter that failed to enter the cortex. It has also been proposed that the columnar organization of the autistic cortex is abnormal. These provocative findings are awaiting confirmation in larger studies using quantitative strategies. Finally, one study found fewer neurons in the mature amygdala of people with autism. Because this study was carried out with individuals that did not have co-morbid epilepsy, the change in the amygdala looks to be a real component of autistic neuropathology. It raises the possibility that autism may have a neurodegenerative component to its pathology.
There Are Distinctive Cognitive Abnormalities in Autism
Social Communication Is Impaired: The Mind Blindness Hypothesis
One cognitive theory of social communication, termed theory of mind, postulates that humans have a particularly well-developed ability to attribute mental states to others in an intuitive and fully automatic fashion. Watching a young man surreptitiously trying to open a car door without a key, you instantly understand that he believes he can break in while being unobserved, and expect him to run away as soon as he realizes someone is watching. Thus you explain and predict his behavior by inferring his mental states (desires, intentions, beliefs, knowledge). This so-called mentalizing ability is thought to have an identifiable biological basis and to depend on a dedicated brain mechanism. Further, it is postulated that this mentalizing mechanism is faulty in autism, with profound effects on social development.
It is now generally agreed that certain social insights typical of humans depend on the capacity to mentalize spontaneously. Spontaneous mentalizing allows us to appreciate that different people have different thoughts and that thoughts represent internal functions of the mind that are different from external reality. From an evolutionary point of view, the capacity to mentalize is extremely advantageous. It enables us to predict what other people are going to do next by “reading” their minds. It helps us to deceive and outsmart others, but also to teach and persuade, thus facilitating social and cultural learning.
The inability to mentalize, or “mind blindness,” was first tested in autism with a simple puppet game, the Sally-Anne test. Young children with autism, unlike those with Down syndrome and unlike typically developing four-year-olds, cannot predict where a puppet will first look for an object that was moved while the puppet was out of the room. They are not able to imagine that the puppet will “think” that the object will be where the puppet had left it (Figure 64–2). Many autistic children eventually do learn to pass this task, but on average with a 5-year delay. Mentalizing acquired so slowly remains effortful and error-prone even in adulthood.
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