Autism was first identified by Kanner in 1942 and Asperger in 1944 as a pervasive developmental disorder characterised by a range of sensorimotor, cognitive and socio-behavioural impairments that arise before age 3 and continue throughout life.
The Diagnostic and Statistical Manual of Mental Disorders 5th edition (American Psychiatric Association, 1994) has redefined autism which now includes, the DSM-IV diagnoses of autism, Asperger syndrome, pervasive developmental disorder not otherwise specified and childhood disintegrative disorder. Autistic Spectrum Disorder (ASD) is characterised by social, language, cognitive and behaviour abnormalities and has become increasingly prevalent in recent years due to earlier and easier diagnosis and public awareness; however no single cause has yet been identified.
ASD is present in as much as 0.6% of the global population (Elsabbagh et al, 2012) with males being affected four times more than females (Baron-Cohen, Lombardo, Auyeung, Ashwin, Chakrabarti, & Knickmeyer, 2011). The earliest signs of social and communicative impairments can be detected from as young as twelve months old, however diagnosis is usually made around 2-3 years old from behaviours such as lack of eye contact, repetitive behaviour and non-responsiveness to people. It is believed that frontal lobe dysfunction plays a crucial role in these social and cognitive deficits (Baron-Cohen et al, 1999).
This literature review will critical examine the evidence that there are frontal lobe abnormalities in ASD as there is strong evidence that children with ASD perform poorly on frontal lobe tasks. The assignment will focus on structural and functional differences found from neuroimaging studies which show macrocephaly and abnormal processing in the frontal lobe on Executive Functioning and ToM tasks and finally on chemical differences, specifically the role that serotonin and dopamine play in ASD brains. Concluding that ASD brains are structured and function differently compared to TD brains, which could be explained by serotonin and dopamine levels in the brain, however, results are not always consistent.
Using brain imaging techniques such as magnetic resonance imaging (MRI) or measures of head circumference (HC), abnormal increases in brain growth have been found to occur within the first year of life in infants with ASD. Children later diagnosed with autism were found to have similar brain volumes compared to TC at birth, however, a sudden increase in head size is seen during the first few years of life in ASD individuals (Courchesne, Carper & Akshoomoff, 2003) with Courchesne, et al, (2001) finding 90% of children who were later diagnosed with ASD having larger brain volumes compared to TD at ages 2-4 years old. This abnormal growth in early childhood is then followed by slowed growth as the individual enters adolescence, which results in overall brain growth plateauing in later adolescence and then persisting to decline into adulthood. (Courchesne et al, 2001).
It’s unclear when macrocephaly begins in autism and the cause of abnormal brain growth is currently unknown; however research has found high levels of serotonin in key regions of the brain and increased neurotic sprouting and decreased pruning to play a role (Sacco et al, 2007).
Courchesne, Yeung-Courchesne, Hesselink, & Jernigan, (1988) were one of the first to identify abnormalities in several brain regions of ASD individuals, specifically in the frontal lobe. Hazlett et al, (2005) supported this when they found the frontal lobes to show the largest percentage increase of white and grey matter, concluding that it is the frontal cortex that suffers the most from excessive brain overgrowth in early childhood.
Even within the first year of life, differences can be seen in the Dorsolateral Prefrontal Cortex (DLPFC), medial frontal cortex (MFC), the anterior cingulate cortex (ACC) and the orbitofrontal cortex’s (OFC) in individuals with ASD compared to TD. Frontal role dysfunctions in these areas may underlie behaviour abnormalities found in ASD individuals as the frontal lobe plays an important role in cognitive, language, social and emotional processes and executive functions which are impaired in ASD individuals (Stuss & Knight, 2013).
MRI is the best method when investigating brain anatomy, especially when working with children as it doesn’t have any radiation exposure, however, MRI studies are rarely conducted on children under 24 months old, which could mean that MRI studies conducted after 24 months old examine the end result of the pathology of ASD and may miss the changes that take place in the brain during the first few months of life. Shen et al (2013) is the only study which has used MRI to look at the structure of infant’s brains that were at risk of developing autism before 24 months old. This longitudinal study allowed developmental changes in brain size over time to be seen, with greater extra-axial fluid in frontal lobes being found in children who later developed autism at 6-9 months which continued and remained high until 24 months compared to TD, concluding that the more fluid in the brain, the larger the brain size and the more severe the autism. Further longitudinal studies are needed to look at the changes in the ASD brain’s over time, ideally following a large sample size, with a mix of gender, from birth into adulthood, imaging them at regular time intervals to provide the most reliable results.
HC studies are used to provide evidence for brain growth during the first years of life. Sacco et al (2007) found a link between HC and behaviour impairments associated with autism; finding the smaller the HC; the more similar to TD, the less stereotypical behaviours displayed by individuals with ASD, compared to individuals with mid-range HC who were found to be less impaired in social cognition but were found to have intellectual disabilities, linking overall brain size to behaviours associated with ASD. However, it is unclear whether HC is an accurate indicator of actual brain size. Aylward, Minshew, Field, Sparks & Singh, (2002) tested the accuracy of HC studies by comparing them to MRI scans measuring brain volume and found HC to be a good indicator of actual brain size in children, however, although adolescents and adults HC was larger than TD; their brain volume was not, suggesting that HC tests may not be accurate indicator of brain size for adolescence and adults. These inconsistencies may be because Cerebrospinal fluid begins to take up an increasing amount of space in the skull relative to brain size during adolescence.
Many studies have found cortical thickness is increased in ASD compared to controls especially the left inferior frontal lobe, which Mak-Fan, Taylor, Roberts & Lerch (2012) found to be more pronounced at younger ages (7.5 years old than 14.5 years old). This was supported by Wallace et al. (2013) and Zielinski (2014) who found thickness of the frontal cortex decreased with age. An increased number of cortical folds have also been found in the left frontal lobe of ASD individuals which is greater in children compared to adolescents which then decreases with age in autistic individuals but not in TD (Awate, Win, Yushkevich, Schultz, & Gee, 2008). This cortical development in ASD individuals is consistent with overall brain growth abnormalities found in ASD children which changes in three distinct phases; increased thickness and cortical folds in early childhood, thinning and a reduction of folds in later childhood and adolescence and slowed thinning as the individual enters adulthood. However, the studies noted here use cross sectional design studying only high-functioning male participants so results may not be representative of females or lower functioning ASD individuals. Further longitudinal studies are needed to assess age related changes, including both females and low IQ ASD individuals to better understand age related changes within the brain of ASD individuals.
Courchense & Pierce (2011) found an underdevelopment of neurons in the frontal cortex in ASD individuals, which are vulnerable to the increased brain growth seen during childhood in ASD individuals as these neurons normally takes several years to develop. This underdevelopment is critical as the neurons are involved in high-order social, emotional and cognitive functions which are impaired with autism. However, this study used post-mortems of a small male sample which will not be the same as a living brain and so results cannot be generalised.
Research has indicated that the frontal lobe is abnormal in ASD individuals, especially in early childhood, which could explain the behaviour abnormalities shown by ASD individuals. However, structural evidence only implies dysfunction within the brain and so it is important to look at actual brain processing during tasks.
Although MRI scans are useful in investigating the structure of the brain, neuro-imaging studies take this a step further by observing brain activity during tasks which provides a more robust and reliable measure of the role of the frontal lobe. Executive functions (EF) are a set of mental processes that control goal directed behaviour such as planning, working memory and problem solving, all of which are impaired in people with ASD.
FMRI studies have found ASD individuals perform poorly on cognitive EF tasks which are driven by the prefrontal cortex and also show abnormal activation in the frontal lobe during these tasks compared to controls. Gomot, Belmonte, Bullmore, Bernard & Baron-Cohen, (2008) found ASD individuals responded quicker and displayed stronger activation in the PFC and inferior parietal cortices than TD during an auditory novelty detection. However, the majority of studies using fMRI have found decreased activation in the frontal lobes in ASD individuals; these differences could be explained as Gomot et al, (2008) used 22 high functioning ASD individuals which may not be achieved with lower functioning ASD individuals. Reduced activation in the frontal lobe has been found during a variety of EF tasks such as working memory tasks (Koshino et al, 2008) target detection task (Shafritz, Dichter, Baranek & Belger, 2008), motor sequence learning (Muller, Cauich, Rubio, Mizuno & Courchesne, 2004) and inhibition tasks (Kana, Keller, Minshew & Just, 2007) which support EF deficits seen in ASD individuals which are linked to the frontal lobe.
These results were supported by Sawa et al (2013) and Luna et al, (2002) who found children and adolescence with ASD had significantly less activity in the frontal lobe, specifically in
the DLPFC and OFC compared to TD when completing EF tasks, which suggests these areas are impaired in high functioning ASD individuals. However, Luna et al (2002) found no difference in ASD individuals compared to controls in the ACC; a brain region that has been found by others to be impaired in ASD individuals.
ACC dysfunction is linked to social impairment with neuroimaging studies finding functional abnormalities in the ACC during EF tasks in individuals with ASD. Haznedar, Buchsbaum, Metzger, Solimando, Spiegel-Cohen & Hollander (1997) found the ACC to be metabolically less active in individuals with autism compared to TD; however, a meta-analysis by DiMartino, Ross, Uddin, Sklar, Castellanos & Milham (2009) found subjects with ASD showed a greater likelihood of hypo-activation in the ACC compared to TD. This finding of increased activation in the ACC is supported by Thakker et al, (2008) who found ASD participants have increased rACC activation when looking at correct and incorrect answers compared to TD which could explain the repetitive behaviours associated with ASD. However, when the results were re-analysed using only ASD participants who weren’t taking any medications, the main findings were supported significantly less. This raises the question whether it is the ACC that is impaired in ASD or whether it is the medication that causes these impairments. The medication taken by ASD individuals could explain the inconsistent results found when looking at ACC activity.
The inconsistent results could also be explained by age differences in ASD individuals. Ozonoff et al (2004) used a set of task which examined cognition, looking specifically at the prefrontal region of the brain in ASD individuals of varying ages. They found that although there was no significant differences in the youngest group, differences in activation were found in the adolescence group, before this significant difference levelled off again at adulthood compared to TD when compared for age and IQ. However, the results may be explained by age-related improvements in planning efficiency in the TD rather than worsening EF deficits in ASD. The results found suggest that frontal lobe functions mature after age 12, however further investigation using larger samples using low and high functioning individuals would create more reliable results.
The abnormal activation found in regions of the brain in ASD individuals can be explained by poor communication between the frontal lobe and other cortical regions. The under-connectivity between different brain regions can explain why ASD individuals perform poorly on EF tasks which involve synchronisation between different regions as ASD individuals are unable to put together different features of the task. Reduced functional activity has been found between frontal and parietal regions in ASD individuals when completing Theory of Mind tasks (Kana, Cherkassky, Minskew & Just, 2009) and Tower of Hanoi/London tasks (Just, Keller, Malave, Kana & Varma, 2012) which results in ASD individuals performing worse compared to TD where no connectivity problems are seen. This reduced co-ordination between the frontal and parietal regions has also been seen in ASD individuals during inhibition tasks (Kana et al, 2007), social task involving face perception and working memory (Koshino et al, 2008) and tasks where participants are required to construct a visual image of a sentence in order to work out in the sentence a true or false (Kana, Keller, Cherkassky & Minskew, 2006).
Although it is clear from the evidence that ASD individuals perform poorly on EF tasks with neuroimaging studies showing they have atypical brain activity; the evidence isn’t always consistent which could be explained by differences in EF tasks. Hill and Bird (2006) found newer EF tasks were more complex, involving multi-tasking with number of individual processes, compared to more constrained classical EF tasks. No significant difference in performance were found between ASD individuals and TD on standard EF tests (Stroop and verbal fluency) however, significant differences were found on newer EF tasks (Six Element Test) which involve a combination of cognitive behaviours such as planning, organisation and action monitoring. The difference in individual processes needed to complete tasks could explain the inconsistent results found from fMRI tests of the frontal lobe.
Poor performance and abnormal activity of the frontal lobe during EF tasks has been found in ASD individuals using fMRI suggesting these regions are critical for EF abilities. However, activation during EF tasks is not always consistent, which could be explained by the participants or the type of task used.
Neurochemical studies suggest that overall brain development, structure and function can be affected by changes in neurotransmitters in the brain such as elevated levels serotonin and dopamine levels during development. Chemical abnormalities in the brain of individuals with autism was first recognized by Schain and Freedman in 1961 who found consistently elevated levels of serotonin (5HT) in 6/23 children with autism and suggested that low IQ was linked to higher levels of 5HT. Although Schain and Freedman (1961) used a small sample which makes it hard to generalise from, many studies support hyperserotonemia in ASD using PET proving serotonin plays an important role in brain development. Arieff, Kaur, Gameeldien & Merwe (2010) found increased serotonin pathways in the frontal lobe in ASD individuals across all ages suggesting that there may be an over-activation of the serotonergic system in ASD individuals. However, abnormal levels of serotonin found in ASD individuals have been found to change over time.
Chandana et al (2005) found differences in serotonin levels in the whole brain in ASD individuals compared to TD brains with 90% of 117 participants having cortical asymmetry of serotonin synthesis, in either the right or left side of the brain which showed involvement of the frontal lobe. 50 % of participants who showed lower levels on the left side of the brain showed evidence of severe language impairment compared to lower levels of the right side of the brain. Chandana et al (2005) also looked at age related changes of serotonin levels and found TD children have extremely high levels of serotonin until age 5, which gradually declines towards normal adult levels suggesting TD individuals have high levels of serotonin during a critical period during childhood which is important for normal development. However, this developmental process is disrupted in ASD as serotonin levels gradually increase between 2-5 years of age to values 1.5 times more than a TD adult, suggesting ASD children have more serotonin than TD adults which could explain the growth spurt found in overall brain size of ASD individuals mentioned earlier in the assignment.
Further support comes from Makkonen et al (2008) who looked at the binding capacity of serotonin receptor transporter (SERT) in the brain of 15 ASD children. ASD children showed significantly reduced SERT binding capacity in the medical frontal cortex, compared to TD; which is an area of the brain that is associated with a number of ToM tasks which ASD individuals show deficits in, providing further evidence for the connection between levels of serotonin and ASD.
A number of studies have found serotonin reuptake inhibitors (SSRIs) to be effective in reducing some behaviours associated with ASD supporting the idea that serotonin is a neurobiological factor in ASD. King (2000) and Kolevzon et al (2010) found SSRIs to have a positive effect on reducing aggression and self-injury when administered to ASD patients, which is supported by McDougle (1996) who also found a reduction in aggression, self-injury and impaired social relatedness in adults using SSRIs, however, found SSRI’s had limited effects on children with ASD aged 5-18. However, a meta-analysis found that SSRIs did not significantly reduce symptoms of ASD which questions the effectiveness of SSRI’s as results are unclear and so further work is needed (Carrasco, Volkmar & Bloch, 2012). These differences could be explained by the wide differences in ASD and comorbidity within the disorder.
Abnormal levels of dopamine in the brain of ASD individuals, especially in the frontal lobe have also been found to be a basis for autistic behaviours using PET, with low dopamine causing impaired attention and high levels causing the mind to race affecting the brains ability to process things. Nakamura et al, (2010) and Hamilton et al, (2013) found dopamine to be significantly higher in the OFC in ASD individuals compared to TD. Dysfunctions found in the OFC may be linked to impulsive and aggressive behaviours in autism as the OFC is a key structure in underlying emotional regulation. However, the results may not be representative of the whole population of ASD individuals, as this study used drug naive high functioning individuals with an IQ greater than 70, where the majority of ASD individuals have an IQ less than 70 and take medication for their disorder which could affect the levels of dopamine and serotonin in the brain. However, Ernst, Zametkin, Matochik, Pascualvaca, Cohen (1997) found decreased dopamine activity in the medial frontal cortex in children with ASD and linked these deficits to the cognitive impairment characteristic of children with ASD.
Although much research has found serotonin and dopamine levels within an ASD brain are different to a TD brain which can impact the structure and function of the brain, research on the role of chemicals within the brain is inconsistent and contradictory and so further research is needed.
Research has shown how ASD brains are structured and function differently compared to TD brains and frontal lobe dysfunctions have been found to play a critical role in ASD. The structural differences found in ASD brains compared to TD may be explained by the differences in chemical, specifically serotonin and dopamine which have been found to have abnormal levels in the brains of people with ASD. Functional differences have been found in the frontal lobe during EF and ToM tasks; however there are some inconsistencies which could be explained by the wide spectrum of ASD and the difference in tasks used.
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