Autism spectrum disorder (ASD) is still frequently characterized by the co-existence of a number of behavioral and perceptual abnormalities, such as delayed language development, an impaired ability to read other people’s minds, repetitive behavior and an obsession with detail. A recent study published in the journal Child Development shows that while autistic individuals do seem to exemplify these traits at the group level, individual autists often exemplify only one or two of these characteristics. This suggests that at the underlying neurological level ASD is not one disorder but a number of different conditions that have similar effects when measured in groups of individuals.
One common factor among many autistic individuals, however, is an abnormality in the serotonin system. Serotonin is commonly known as the feel-good chemical. When serotonin is reduced in the amygdala, a small almond-shaped region in the subcortical brain that processes fear, the activity of the amygdala increases. This leads to more fear processing, which can result in anxiety and depression. Reduced serotonin increases amygdala activity in this region by being coupled to another neurotransmitter known as GABA, which is the brain’s main inhibitory chemical. When the serotonin levels are high enough, the GABA system is activated, and that inhibits fear. When the serotonin levels are reduced, the activity in the amygdala is not being suppressed and fear processing goes rampant. Although serotonin is best known through its actions relating to fear and depression in this region of the brain, the chemical has many other functions in other brain areas. In other neural regions an increase in serotonin levels can increase brain activity. In the visual cortex, for example, increased serotonin can lead to increased neural activity by a coupling to glutamate, the brain’s main excitatory chemical.
The evidence that serotonin plays a crucial role in autism is overwhelming. About 30 percent of autistic individuals have a 25 to 70 percent increase in blood levels of serotonin, also known as hyperserotonemia. Increased blood levels have also been found to a similar degree in first-degree healthy relatives, such as parents and children. As serotonin cannot normally cross over from the blood to the brain in adults, high blood levels of serotonin are not necessarily a good indicator of high levels of extracellular serotonin in the brain. High blood levels of serotonin, however, may indicate brain levels of serotonin in young children, as the blood-brain barrier is not fully developed until the age of two. Higher rates of autism have also been found in children exposed to drugs that increase serotonin levels, such as cocaine, during pregnancy.
The high levels of serotonin in young children can negatively affect the development of serotonin neurons through negative feedback. As serotonin neurons develop and the extracellular levels of the neurotransmitter increase, growth of serotonin neurons is normally curtailed through a negative feedback mechanism, leading to a loss of serotonin terminals. This decrease in serotonin terminal development has also been found in animal studies administering serotonin-increasing antidepressant drugs, such as monoamine oxidase A and B inhibitors and serotonin reuptake inhibitors, during pregnancy.
Several studies have suggested that autism may be a syndrome of one of the brain’s two hemispheres, with decreased synthesis of serotonin in the left (or sometimes the right) hemisphere. A positron emission tomography (PET) neuroimaging study published in the journal Annals of Neurology found decreased serotonin synthesis in the left cortex and thalamus in five of seven autistic boys studied and in the right frontal cortex and thalamus in the two remaining male subjects.
In another PET imaging study of nine autistic girls conducted by the same authors, it was found that four of the subjects had decreased serotonin synthesis in one hemisphere, whereas the others had defects in both hemispheres. The subjects with a serotonin deficiency in the left hemisphere scored higher on nonverbal IQ tests than the girls with defects in both hemispheres, despite other symptoms of autism being similar in the two groups.
More recent PET studies of serotonin synthesis have confirmed the abnormal asymmetry of cortical serotonin synthesis in children with autism. The studies found cortical asymmetries of serotonin synthesis affecting the left or right cortex. In one study serotonin synthesis was decreased in the frontal lobe in 90 percent of cases. The researchers found significantly increased language impairment in subjects with decreased serotonin synthesis in the left hemisphere compared to individuals with right-hemisphere abnormalities and those with defects in both hemispheres. One possible explanation of the asymmetry is that the early serotonin depletion in the dominant left hemisphere leads to overcompensation in the right hemisphere, though sometimes it’s the other way around.
The different patterns of left-versus-right-sidedness in different individuals with autism line up with the old distinction between autism and asperger syndrome. On the old classification, autism required marked language deficits, whereas asperger syndrome did not. Many children diagnosed with asperger syndrome exhibit the same social difficulties, adhere to a rigid routine, and so on. but perform normally or above normal in left-brain activities like complex language, reasoning, mathematics and sensory integration.
Further evidence for the left-hemisphere hypothesis for autism comes from studies indicating functional improvement with selective serotonin reuptake inhibitors (SSRIs), such as Prozac. SSRIs block serotonin transporters, preventing extracellular serotonin from being transported back into the cell. When children with autism are treated with SSRIs, the symptoms they share in common with people with major depressive disorder and anxiety disorders drastically improve. Depleting the brain of its serotonin in a tryptophan depletion paradigm, on the other hand, results in a worsening of some symptoms. Deficiency of tryptophan can also be a contributing factor to a wide range of mood disorders in normal individuals. There is indeed evidence to suggest that autism is symptomatically and genetically related to mood disorders, such as major depressive disorder and bipolar disorder.
The left-hemisphere hypothesis for autism can explain many of the symptoms of autism, most notably the language deficits and delays in language development, as language is a left-brain skill. But it also explains regimented behavior, unusual attention to or avoidance of sensory input, social impairment and enhanced low-level perceptual memory processing. Studies show enhanced activation in the amygdala, the main fear processing center, in autistic subjects during attended face processing and other types of sensory processing. This suggests that autistic individuals may be processing too much emotionally relevant information owing to depressed serotonin levels. Increased amygdala activity would explain enhanced fear processing and social impairments, such as deviant eye gaze, withdrawal behavior and a seemingly impaired theory of mind. Increased amygdala activity might also explain why autistic individuals often engage in avoidance behavior with respect to certain types of sensory stimuli and why repetitive moment and regimented behavior seems to have a calming and stabilizing effect. Avoidance behavior naturally decreases fear processing, whereas repetitive movement and regimented behavior can naturally increase serotonin release from the serotonin neurons in the brain stem.
Importantly, unlike commonly accepted hypotheses that suggest that people with autism have less brain connectivity than normal individuals, the left-hemisphere hypothesis explains the fact that savant syndrome occurs in ten percent of individuals with autism. The leading hypothesis is that savant syndrome is caused by a lesion or birth defect in the left hemisphere that results in overcompensation by the right hemisphere. A related hypothesis is that we all have the skills of savants but that they are dormant because of the dominance of the left hemisphere in most individuals. If the left-hemisphere hypothesis is true for autism, that would explain the high incidence of savant skills in autistic individuals. It would also explain why savant skills often are right hemisphere skills.