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By Berit Brogaard and Kristian Marlow
Autism Spectrum Disorder (ASD) is a condition characterized by deficiencies in social interaction and communication that become apparent in the first three years of life. Symptoms of ASD gradually appear at the age of six months and continue to progress until age two or three, at which point symptoms remain stable through the individual’s adulthood. The exact number of children afflicted with autism is unknown, however recent reviews estimate a prevalence of up to 6 per 1,000 births. But this number may be low. There simply isn’t adequate data to tell.
Symptoms of ASD highly vary, but most individuals have trouble operating in social environments. Autists are often thought to lack the ability to empathize with others, an ability that neurotypical individuals may take for granted. This lack of intuition typically results in the inability for individuals with ASD to follow social norms and to respond appropriately in situations that involve judging the emotions of others. This may futher result in an inability to communicate at all.
The exact cause of ASD currently is unknown. For many years it was presumed that there exists a common genetic, cognitive and neural cause for the disorder, however recent research suggests that ASD may emerge from a combination of distinct co-occurrent causes. Although ASD has a strong genetic basis, the possibility for interactions among multiple genes and environmental and epigenetic factors make profiling the disorder extraordinarily complex.
Some research suggests that a dysfunction of nerve synapses plays a role in ASD. Synapses are the tiny junctions between nerve cells that facilitate communication throughout the brain. Mouse studies provide evidence for this hypothesis: in mice, autism-like symptoms emerge through developmental processes that depend on activity in synapses. Research also suggests developmental abnormalities that facilitate autism begin to occur during the first 8 weeks of gestation. This indicates that the foundation for ASD begins very early on in development
A few researchers have proposed links between environmental factors such as vaccines and prenatal stress, but evidence for such links has not been confirmed through replicable peer-reviewed academic studies.
But a relatively new theory of ASD may provide the insights necessary to tackle this debilitating mental disease. The Intense World Theory posits that pungent brain activity is the cause of autistic traits. According to the theory, excessive connectivity in local brain regions increases the ability to focus and pay attention to details, but this degree of intensity also frequently leads to a system overload, hypersensitivity and anxiety. This may lead to the intense focus and systematic decoupling from the world exhibited by individuals with autism.
The Intense World Theory emerged out of studies investigating the link between the known teratogen valproic acid (VPA) and ASD. Originally introduced as an anticonvulsant for the treatment of epilepsy, VPA has also been used in the treatment of bipolar disorder, migraine headaches and schizophrenia. Recent population studies have shown a strong link between prenatal VPA exposure and ASD. Prenatal VPA exposure causes similar neurological deficits in rats, including decreased social interactions, increased repetitive behaviors, enhanced anxiety, locomotor hyperactivity, lower sensitivity to pain, higher sensitivity to non-painful sensory stimulation, impaired pre-pulse inhibition, and enhanced eye-blink conditioning. All of these symptoms are thought to be related to autism in humans.
Prenatal VPA exposure has similar neurobiological effects for rats and humans. Exposure to VPA in rats leads to a reduction of the trigeminal and hypoglossal motor nuclei and loss of neurons in the abducens and oculomotor nuclei. These parallel losses found in the brainstem in human individuals with ASD. VPA exposure in rats also leads to a loss of cerebellar neurons, another feature of individuals with ASD. Researchers have also found abnormalities in the serotonergic system of both species. The similarity of the effects of VPA exposure in both rats and humans supports the use of a rat model in studying autism.
A series of experiments investigated the possible neurobiological basis of the Intense World Theory through the use of rat models. The study found that the neuronal network response in VPA-treated offspring is greatly amplified in comparison to the neuronal network response in non-treated offspring. This amplified response results in hyper-reactivity to network stimulation. However, the individual neurons in VPA-treated offspring were found to be hypo-excitable. This indicates that the individual neurons compensate for the strong hyperreactivity of the whole network.
The researchers also found that neuronal microcircuits in VPA-exposed rats exhibited significant hyperconnectivity that could lead to enhanced information flow, causing hyperreactivity across brain regions. This hyperreactivity may explain behavioral responses of VPA-treated rats. For example, VPA-treated rats were much better at discriminating between apertures of different sizes than normal control rats, which is consistent with hyper-functionality. Researchers also found enhanced neuroplasticity of the amygdala, leading to the amplification of conditioned cued and contextual fear memories when tested up to three months after conditioning.
The Intense World Theory differs from other theories for ASD in that it posits that the disorder is the result of hyper-reactivity to perceptual stimuli rather than the result of a deficit in perceptual processing. This difference may play a crucial role in treatment for the disorder. If autistic traits are the result of some perceptual deficit, then an effective treatment likely will involve enhancing the activity of the autistic brain to compensate for its deficits. However, if the autistic traits emerge as a response to overstimulation, the treatment may involve suppressing the activity in these overactive brain regions.
But why would it make sense to treat a neurological deficit by suppressing activity in the brain? Wouldn’t we want to enhance brain activity? The answer might turn out to be no. For example, consider how we treat attention deficit hyperactivity disorder (ADHD). Individuals with ADHD have difficulty maintaining staying focused and often exhibit poor impulse control. From the armchair, one would think the best way to treat ADHD is to prescribe a drug like Valium to calm the patient down, allowing them to slow down and think. But we actually prescribe the opposite type of drug: a stimulant. ADHD is thought to be the result of abnormally low cortical activity in the areas of the brain responsible for attention and impulse control. Amphetamine stimulants such as Adderall are believed to stimulate these areas, allowing the patient to better modulate their attention. ASD may call for the opposite sort of treatment. If the disorder results from perceptual hyperreactivity, the best drug may be one that would suppress excessive activity.
At this point there are a few caveats. First off, the Intense World Theory hasn’t been verified in humans. Although rats are believed to provide an excellent model in the lab, it could turn out that human autism develops through a completely different mechanism. The second caveat is that even if we show Intense World Theory to be correct, the theory may not provide us with answers on how to treat autism after it already has developed. According to Intense World Theory, perceptual overload present from birth causes very significant developmental changes that result in long-term structural differences between autists and neurotypical individuals. We still will have to figure out what to do with the brain once it’s formed.
But the Intense World Theory might provide us with preventative measures. If we can come up with a way to determine if a newborn is likely to develop autism later on, we might discover treatments that can prevent this development before it becomes serious.
My lab is taking the first step toward a rigorous investigation of this theory through a series of behavioral, epidemiological and neuroimaging studies. Over the next year, we hope to compile some serious data in support or against the Intense World Theory.
