Autism spectrum disorder (ASD) is a neurodevelopmental disorder that involves the reduced ability to emotionally interpret communication, idiosyncratic preoccupations, repetitive motor patterns, sensory sensitivity, and resistance to change. Typically signs such as failure to respond to one’s name, or make eye contact with parents lead to the earliest diagnosis around age two. As usually is the case, early diagnosis and intervention lead to better outcomes Generalized and recurring patterns of brain enlargement in early childhood of children who are eventually diagnosed with autism spectrum disorder have led to the development of the early overgrowth hypothesis, suggesting that an early acceleration of brain development may play an active role in autism (Dinstein, 2017). However, researchers have failed to reach a general consensus on the cause and location of the overgrowth. Research from Maier (2015) indicates that increased hippocampal volumes are to blame, while Turner (2016) points to pallidum and lateral ventricle volume enlargement and Courchesne (2011) to neuron number and size in the prefrontal cortex. Contrastly, research from Piven (1996) indicates that the overgrowth is largely generalized and not regionally specific. Data from Libero (2017) supports the generalized theory by reporting that head growth is disproportionate to body growth early on in the development of children with ASD. Despite the lack of unanimity, there is support for the early overgrowth hypothesis which begs the question; could head circumference, a good predictor of brain volume, be diagnostically used as a biomarker for infants who are at risk for developing autism spectrum disorder?
According to Dinstein (2017), the early brain overgrowth hypothesis states that autism spectrum disorder may be hallmarked by abnormally large brain size caused by the premature acceleration of cell proliferation, migration, and or differentiation early on in development. The period of overgrowth is thought to be a result of both genetic predispositions and environmental insults. Additionally, the overgrowth is generally only distinguishable in children with ASD for the first few years of their lives as it is followed by a period of arrested growth that realigns their brain size back to normal dimensions (Dinstein, 2017). While most researchers agree such is the case, they have failed to unanimously pinpoint one region of the brain that is most affected by overgrowth. Rather, the research generally points to sizable differences early on in head circumference that is not indicative of any specific brain region. For this reason, generalizable head circumference measurements may be a superior biomarker for early detection of autism spectrum disorder, even prior to the onset of behavioral abnormalities.
Research from Maier (2015) sought to bring consistency to previous studies that dealt with the amygdala and hippocampal volume among individuals with autism spectrum disorder, specifically those who are high functioning. In fact, this study was the first manual morphometric study that focused on ASD adults with an IQ greater than 100 (Maier 2015). Prior research cited had reported findings of larger, while others reported smaller, amygdala and hippocampal volumes; Yet some studies had reported no differences at all. The exclusion of individuals with an IQ below 100 increased the likelihood of examining non-syndromic forms of autism spectrum disorder, which lead the researchers to hypothesize that there would be minimal differences in brain volume observed (Maier 2015). This would support the early overgrowth hypothesis in that differences in brain size are not distinguishable in adults with autism spectrum disorder due to the period of arrested growth. 30 ASD individuals were matched by age, gender, and IQ to 30 healthy individuals, and all were subjected to anatomical MRI scans focusing on amygdala and hippocampal volume (Maier 2015). The results showed that the ASD group generally maintained bilaterally larger hippocampal volumes with a slight decrease in amygdala volume (Maier 2015). The researchers also indicate that the hippocampal enlargement may play an active role in a more intensive experience of the world and therefore hyperactivity and hypersensitivity are commonly associated with autism spectrum disorder (Maier 2015). While this data refutes the argument that the period of arrested growth realigns the brain size of individuals with ASD back to typical development, it supports the theory that there is a sizable and distinguishable difference in brain size, and therefore head circumference, of ASD individuals.
In the largest study of brain morphology of autism spectrum disorder individuals to date, Turner (2016) found regional differences of enlargement in pallidum and lateral ventricle volumes. Similarly to the previous study, Turner (2016) looked at anatomical images of the brains of 472 ASD and 538 healthy individuals. More specifically researchers from this study compared subcortical brain volume, total brain volume, and intracranial brain volume between autism spectrum disorder and control individuals. All of the images were made available through international data exchange, and both groups were matched by age and handedness (Turner 2016). However, the ASD group differed in the proportion of males, IQ, social skills, and use of medication (Turner 2016). Based on the data, Turner (2016) reported that ASD individuals were found to have larger intracranial volumes, as well as caudate and hippocampal volumes. More significantly, the ASD group had larger pallidum and lateral ventricle volumes (Turner 2016). The enlarged pallidum likely plays a role in the repetitive behaviors and social dysfunction associated with autism spectrum disorder, Again, this data supports the early overgrowth hypothesis by finding regional brain volume differences that exist among ASD individuals. Yet although the designs of the two studies were similar in nature, they both point to different regions of the brain as biomarkers, which further reinforces the notion that perhaps a more generalizable measure such as head circumference would be a more useful predictor of ASD.
Courchesne (2011) took a different approach to a similar ideology by examining the post-mortem brains of 7 ASD and 6 non-ASD males who ranged in age from 2-16 years. Trained anatomists blind to the purpose of the study examined the weight of the brains and estimated the number of neurons that existed in the dorsolateral prefrontal cortex, and the medial prefrontal cortex as well as the mean neuron volume. Specifically, they hypothesized that early overgrowth in the brains of ASD individuals is not localized to any particular region, but rather due to a broad excess of neurons in the prefrontal cortex. (Courchesne, 2011). To minimize confounding, all of the subjects studied had passed away from accidents such as electrocution, or drowning and not prior abnormalities to the brain which could cause an increase in the number of neurons (Courchesne, 2011). Though blind to the study, the anatomists determined that the ASD group had a mean of 67% more neurons in the prefrontal cortex than did the control group, with the dorsolateral prefrontal cortex seeing the largest increase of neurons (Courchesne, 2011). Furthermore, the overall brain weight of the ASD group was found to be larger (Courchesne, 2011). This research confirms not only that an increase in neurons is likely the cause of brain overgrowth, but also that the overgrowth occurs between 10-20 weeks of gestation as neurons are not generated postnatally (Courchesne, 2011). This, in combination with the studies mentioned above, establishes that cortical development of ASD individuals is abnormal, leading to a measurably larger brain size. Specifically, this study identifies that the diversion from typical growth occurs and may even be identifiable during gestation.
Piven (1996) also tested the generalized ASD brain overgrowth theory by specifically looking to determine if the overgrowth is regionally associated with certain lobes or rather a generalized pattern that can be observed across all areas of the brain. Brain volume measurements and anatomical images of the total brain, cerebrospinal fluid, and lateral ventricles were examined in 22 ASD males and 20 matched controls (Piven, 1996). Participants were matched in regards to gender, age, IQ, and ability to sit through a 20-minute imaging scan. The results proved that the differences in the brain between the ASD and control group were regional to the temporal, occipital, and parietal lobes, but generalizable in the sense that they were caused by neurogenesis, decreased neuronal death, or increased production of glial cells (Pivan, 1996). This adds to the growing literature that recognizes differential patterns of brain enlargement in ASD individuals but poses yet another pathway for which these patterns take place. Because researchers cannot reach a general consensus on where brain overgrowth occurs, it is therefore impossible to use brain imaging as a means of detecting ASD, especially in utero and infancy when no behavioral abnormalities can be observed.
Using head circumference as a proxy to measure brain size Libero (2017) tested whether brain growth is disproportionate to body growth at age three in ASD children and whether the brain continued to grow with an abnormal trajectory up until the age of five. To test brain size, researchers collected longitudinal MRI scans at ages three, four, and five, as well as medical records that included measured head circumference from the target age points (Libero, 2017). The sample included 65 ASD children and 31 control matches (Libero, 2017). Head circumference was found to be a good predictor of brain size at younger ages, and a subgroup of ASD children continued to have an abnormal trajectory of brain growth at least until age five (Libero 2017). This study combined previous research that all seems to prove ASD children have abnormal brain size, at least early on in development, and looked at it in a broader scope by measuring brain size using head circumference. Although they looked at children as young as three years old, perhaps the same logic could be applied to infants who are genetically at risk for developing ASD.
The early brain overgrowth hypothesis is supported by research from many areas, however, researchers have failed to locate one single region of the brain that is most affected by accelerated brain growth. Yet, it is clear that there is a sizeable difference between the brains of ASD and typically developing children. For this reason, brain size could be an accurate proxy for detecting ASD, even before behavioral symptoms such as repetitive motor patterns, idiosyncratic preoccupations, sensory sensitivity, and resistance to change emerge. As head circumference was found to be a good predictor of brain size (Libero, 2017), this may be the most efficient way to prematurely diagnose children with ASD who otherwise may not be diagnosed until the age of two.
The early brain overgrowth hypothesis, researched by Dinstein (2017), suggests that ASD is hallmarked by the abnormally large brain size in children, caused by the premature acceleration of cell proliferation, migration, and or differentiation early in development. Although data supports this theory, research has been difficult to replicate and often points to different regions of the brain as being responsible or affected by the overgrowth. Manual morphometric research from Maier (2015) found that ASD individuals maintain bilaterally larger hippocampal volumes with a slight decrease in amygdala volume. Yet the largest study of brain morphology by Turner (2016) found that ASD individuals have larger intracranial, caudate, and hippocampal volumes. Taking a different approach, Courchesne (2011) examined post-mortem brains and indicated that ASD individuals had 67% more neurons in the prefrontal cortex than the control group. On the other hand, Piven (1996) found that the enlargement was regional to the temporal, occipital, and parietal lobes but generalizable in the sense that it is caused by neurogenesis decreased neuronal death, or increased production of glial cells. Finally, in a longitudinal study Libero (2017) found that head circumference in children with ASD as young as three years of age is a good predictor of brain size and that abnormal head circumference continues until at least the age of five for a subgroup of children. As a result of the data supporting the early brain overgrowth hypothesis, but disagreeing on the location, a more broad approach may be useful in early detection. Measuring head circumference from birth on may be key for early detection and subsequent intervention for children who are genetically at risk for developing autism spectrum disorder.