Autism pathophysiology On the Web
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Despite extensive investigation, how autism occurs is not well understood. Its mechanism can be divided into two areas: the pathophysiology of brain structures and processes associated with autism, and the neuropsychological linkages between brain structures and behaviors. The behaviors appear to have multiple pathophysiologies.
- Autism appears to result from developmental factors that affect many or all functional brain systems, and leads to disruption in the development of the brain.
- Neuroanatomical studies and study in the area on genetic inheritance have suggested that autism occurs after conception.
- Enviromental factors play an important role in the development of autism after an anomaly in the brain leads to activation of pathological pathways.
Structural changes in the brain
- Although many major structures of the human brain have been implicated, almost all postmortem studies have been of individuals who also had mental retardation, making it difficult to draw conclusions.
- Brain weight and volume and head circumference tend to be greater in autistic children.
- The cellular and molecular bases f pathological early overgrowth are not known, nor is it known whether the overgrown neural systems cause autism's characteristic signs.
- Current hypotheses include:
Heterochrony (disturbed neural migration)
- The sensory and motor deficits associated with autism seem to be secondary to developmental change in the rate of events during division of germinal cells leading to abnormal migration of daughter cells to their target regions
Immune system disruption
- GI abnormalities and immune imbalance have been known to be involved in the parthenogenesis of autism. Repeated GI infections may also lead to an immune imbalance.
- Neuroinflammation consist of activation of microglial cells and innate neuroimmune system. The effectors of neuroimmune system have been found in the brain and cerebrospinal fluid (CSF) of ASD patient
- Interactions between the immune system and the nervous system begin early during embryogenesis, and successful neurodevelopment depends on a balanced immune response.
- Several symptoms consistent with a poorly regulated immune response have been reported in autistic children.
- It is possible that aberrant immune activity during critical periods of neurodevelopment is part of the mechanism of some forms of ASD.
- As autoantibodies have not been associated with pathology, are found in diseases other than ASD, and are not always present in ASD, the relationship between immune disturbances and autism remains unclear and controversial.
- Several neurotransmitter abnormalities have been detected in autism, notably increased blood levels of serotonin. Whether these lead to structural or behavioral abnormalities is unclear.
- Also, some inborn errors of metabolism are associated with autism but probably account for less than 5% of cases.
Mirror neuron system theory
- The mirror neuron system (MNS) theory of autism hypothesizes that distortion in the development of the MNS plays a major role in the development of impairment in social and communication skills.
- The MNS operates when an animal performs an action or observes another animal of the same species perform the same action.
- The MNS may contribute to an individual's understanding of other people by mimicing their behavior via embodied simulation of their actions, intentions, and emotions.
- Several studies have tested this hypothesis by demonstrating structural abnormalities in MNS regions of individuals with ASD, delay in the activation in the core circuit for imitation in individuals with Asperger's. The level of reduced functionality of the mirror neuron system directly correlates with the severity of autism.
- However, individuals with autism also have abnormal brain activation in many circuits outside the MNS Despite the mirror neuron theory, children suffering from autism are able to imitate goal-directed behaviors.
Task negative network
- A 2008 study of autistic adults found evidence for altered functional organization of the task-negative network, a large-scale brain network involved in social and emotional processing, with intact organization of the task-positive network, used in sustained attention and goal-directed thinking.
- A 2008 brain-imaging study found a specific pattern of signals in the cingulate cortex which differs in individuals with ASD.
Disruptions in high level neural connections and synchronization
- The underconnectivity theory of autism hypothesizes that autism is marked by underfunctioning high-level neural connections and synchronization, along with an excess of low-level processes.
- Evidence for this theory has been found in functional neuroimaging studies on autistic individuals and by a brain wave study that suggested that adults with ASD have local overconnectivity in the cortex and weak functional connections between the frontal lobe and the rest of the cortex.
- Other evidence suggests the underconnectivity is mainly within each hemisphere of the cortex and that autism is a disorder of the association cortex.
Two major categories of cognitive theories have been proposed about the links between autistic brains and behavior.
- The first category focuses on deficits in social cognition.
- Hyper-systemizing hypothesizes that autistic individuals can systematize—that is, they can develop internal rules of operation to handle internal events—but are less effective at empathizing by handling events generated by other agents.
- It extends the extreme male brain theory, which hypothesizes that autism is an extreme case of the male brain, defined psychometrically as individuals in whom systemizing is better than empathizing.
- This in turn is related to the earlier theory of mind, which hypothesizes that autistic behavior arises from an inability to ascribe mental states to oneself and others.
- The theory of mind is supported by autistic children's atypical responses to the Sally-Anne test for reasoning about others' motivations, and is mapped well from the mirror neuron system theory of autism.
- The second category focuses on nonsocial or general processing. Executive dysfunction hypothesizes that autistic behavior results in part from deficits in flexibility, planning, and other forms of executive function.
- A strength of the theory is predicting stereotyped behavior and narrow interests; a weakness is that executive function deficits are not found in young autistic children.
- Weak central coherence theory hypothesizes that a limited ability to see the big picture underlies the central disturbance in autism.
- One strength of this theory is predicting special talents and peaks in performance in autistic people.
- A related theory—enhanced perceptual functioning—focuses more on the superiority of locally oriented and perceptual operations in autistic individuals.
- These theories map well from the underconnectivity theory of autism.
- Neither category is satisfactory on its own; social cognition theories poorly address autism's rigid and repetitive behaviors, while the nonsocial theories have difficulty explaining social impairment and communication difficulties.
- A combined theory based on multiple deficits may prove to be more useful.
- There are many conditions comorbid to autism spectrum disorders, ranging from concurrent psychiatric conditions and neuroinflammation to a variety of colon and digestive disorders.
- In medicine and in psychiatry, comorbidity describes the effect of other diseases an individual patient might have other than the primary disease of interest.
- About 10–15% of autism cases have an identifiable Mendelian (single-gene) condition, chromosome abnormality, or other genetic syndrome, and ASD is associated with several genetic disorders.
- However, autism and other autism spectrum diagnoses, including Asperger syndrome, are diagnosed strictly as a cognitive disability, as a brain disorder that begins in early childhood, persisting throughout adulthood, and affecting three crucial areas of development: communication, social interaction and creative or imaginative play.
Some children with autism also have gastrointestinal (GI) symptoms, but there is a lack of published rigorous data to support the theory that autistic children have more or different GI symptoms than usual. It has been claimed that up to fifty percent of children with autism experience persistent gastrointestinal tract problems, ranging from mild to moderate degrees of inflammation in both the upper and lower intestinal tract. This has been described as a syndrome, autistic enterocolitis, by Dr. Andrew Wakefield; this diagnostic terminology, however, has been questioned by medical experts. Constipation, often with overflow, or encopresis, is often associated with developmental disorders in children, and is often difficult to resolve, especially among those with behavioral and communication problems.
Depression and Anxiety Disorders
Fragile X Syndrome
Fragile X syndrome is the most common inherited form of mental retardation. It was so named because one part of the X chromosome has a defective piece that appears pinched and fragile when under a microscope. Fragile X syndrome affects about two to five percent of people with ASD. It is important to have an autistic checked for Fragile X, especially if the parents are considering having another child. If one child has Fragile X, there is a one-in-two chance that boys born to the same parents will have Fragile X (see Mendelian genetics). Other members of the family who may be contemplating having a child may also wish to be checked for the syndrome.
Hyperactivity and Attention Abnormalities
Attention-deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and controversial neuropsychiatric disorders among children, and is increasingly recognized as afflicting adults as well. Its symptoms include inattention, hyperactivity, and impulsivity. According to sources such as the CDC, the causes are currently unknown, and it is thought that the term covers a variety of related disorders. There is no single medical test that can accurately diagnose ADHD, though there are assessment tools.
Autism is associated with mental retardation: a 2001 British study of 26 autistic children found about 30% with intelligence in the normal range (IQ above 70), 50% with mild to moderate retardation, and about 20% with severe to profound retardation (IQ below 35). For ASD other than autism the association is much weaker: the same study reported about 94% of 65 children with PDD-NOS or Asperger's had normal intelligence. When tested, some areas of ability may be normal or superior, while others may be especially weak. For example, an autistic individual may do well on the parts of the test that measure visual skills but earn low scores on the language subtests.
A 2006 review questioned the common assumption that most children with autism are mentally retarded. It is possible that the association between mental retardation and autism is not because they usually have common causes, but because the presence of both makes it more likely that both will be diagnosed.
Neuroinflammation and Immune Disorders
The role of the immune system and neuroinflammation in the development of autism is controversial. Until recently, there was scant evidence supporting immune hypotheses, but research into the role of immune response and neuroinflammation may have important clinical and therapeutic implications. The exact role of heightened immune response in the central nervous system (CNS) of patients with autism is uncertain, but may be a primary factor in triggering and sustaining many of the comorbid conditions associated with autism. Recent studies indicate the presence of heightened neuroimmune activity in both the brain tissue and the cerebrospinal fluid of patients with autism, supporting the view that heightened immune response may be an essential factor in the onset of autistic symptoms.
Nonverbal Learning Disorder
In Nonverbal learning disorder (NLD) there are a number of over-lapping signs and symptoms of Savant Syndrome traits and behaviors in some youngsters. Of special interest, however, is the observation and debate about the overlap particularly between NLD and the clinical characteristics of Asperger's Disorder, such as high verbal abilities, compromised motor and coordination abilities, and unique social and relationship difficulties. Clinically, Asperger's is part of the autistic spectrum. It has also been postulated that Asperger's is in fact a part of the far end spectrum of Nonverbal Learning Disorders. Proponents of this analysis point out that as high as 80% of Asperger's Disorder persons have neuro-psychological profiles consistent with NLD. Fitzgerald and Corvin have argued that the diagnosis of Asperger's is more useful clinically, and that NLD is "an example of excessive diagnostic splitting.
The initial accounts of Asperger syndrome and other diagnostic schemes include descriptions of motor clumsiness. Children with ASD may be delayed in acquiring motor skills that require motor dexterity, such as bicycle riding or opening a jar, and may appear awkward or "uncomfortable in their own skin". They may be poorly coordinated, or have an odd or bouncy gait or posture, poor handwriting, or problems with visual-motor integration, visual-perceptual skills, and conceptual learning. They may show problems with proprioception (sensation of body position) on measures of apraxia (motor planning disorder), balance, tandem gait, and finger-thumb apposition.
Obsessive-compulsive disorder is characterized by recurrent obsessional thoughts or compulsive acts. Obsessional thoughts are ideas, images or impulses that enter the individual's mind again and again in a stereotyped form. They are almost invariably distressing (because they are violent or obscene, or simply because they are perceived as senseless) and the sufferer often tries, unsuccessfully, to resist them. They are, however, recognized as the individual's own thoughts, even though they are involuntary and often repugnant.
Compulsive acts or rituals are stereotyped behaviours that are repeated again and again. They are not inherently enjoyable, nor do they result in the completion of inherently useful tasks. It must be recognized that this is different from the obsessions that are a feature of autism spectrum disorders in that the obsessions are not enjoyable or in any way beneficial, which can sometimes be the case with autism, for instance an obsession to study an interest.
The prevalence of Tourette syndrome among individuals with autism is estimated to be 6.5%, higher than the 2% to 3% prevalence for the general population. Several hypotheses for this association have been advanced, including common genetic factors and dopamine or serotonin abnormalities.
ASD is also associated with epilepsy, with variations in risk of epilepsy due to age, cognitive level, and type of language disorder. One in four autistic children develops seizures, often starting either in early childhood or adolescence. Seizures, caused by abnormal electrical activity in the brain, can produce a temporary loss of consciousness (a "blackout"), a body convulsion, unusual movements, or staring spells. Sometimes a contributing factor is a lack of sleep or a high fever. An EEG can help confirm the seizure's presence.
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Unusual responses to sensory stimuli are more common and prominent in autistic children, although there is no good evidence that sensory symptoms differentiate autism from other developmental disorders. The responses may be more common in children: a pair of studies found that autistic children had impaired tactile perception while autistic adults did not. The same two studies also found that autistic individuals had more problems with complex memory and reasoning tasks such as Twenty Questions; these problems were somewhat more marked among adults. Several studies have reported associated motor problems that include poor muscle tone, poor motor planning, and toe walking; ASD is not associated with severe motor disturbances.
Tuberous sclerosis is a rare genetic disorder that causes benign tumors to grow in the brain as well as in other vital organs. It has a consistently strong association with the autism spectrum. One to four percent of autistic people also have tuberous sclerosis. Studies have reported that between 25% and 61% of individuals with tuberous sclerosis meet the diagnostic criteria for autism with an even higher proportion showing features of a broader pervasive developmental disorder.
The following genes have been implicated in the development of autism phenotype in the presence of intellectual and other abnormalities of the syndrome producing the autistic phenotype:
|Syndrome||Gene involved||Major abnormalities|
|Fragile X syndrome||FMR1||
|Tuberous sclerosis||TSC1, TSC2|
|Williams Beuren syndrome||7q11.23 deletion|
|Prader-Willi syndrome||15q11-q13 deletion (paternal)|
|Angelman syndrome||15q11-q13 deletion (maternal)|
- Frontal cortex
- Amygdaloid nucleus
- Cerebello-thalamo-cortical pathways
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