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Exploring the Manifestation of ADHD and ASD in Children



Introduction

According to the American Psychiatric Association, neurodevelopmental disorders are a “group of conditions with onsets in the early developmental period”. In other words, these are impairments in some regions of the brain or a system in the brain that are more likely to occur in children compared to adults. There is a wide range of impairments that can occur within this category of disorder, but the symptoms manifest themselves when a child is still in elementary school years and lead to future limitations in social skills, learning, and occupational functioning, to name a few. Another interesting aspect of this class of disorder is that most neurodevelopmental disorders, “co-occur” meaning that two of the disorders manifest themselves in the same individual. Some examples of neurodevelopmental disorders that are prevalent in children worldwide include autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and Down Syndrome.

The purpose of this literature review is to closely examine the similarities and differences between autism spectrum disorder and attention-deficit/hyperactivity disorder in children worldwide, but with a focus in the United States. More specifically, the review will discuss the mechanisms of the disorder and areas of the brain that are affected in the long-term. In addition, the review will explore the genetic and familial contributions to an individual with the prognosis of ASD or ADHD. External factors will also be discussed in their effects on the disorders including prenatal exposure and epigenetics. Finally, further research and potential treatments will be discussed briefly to understand how to move forward with the understanding of these disorders and preventing their manifestations in the future.

Overview and Neurological Mechanisms

Two of the most prevalent neurodevelopmental disorders across the world are Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD). These are considered developmental disorders because the symptoms present themselves within the patient’s first two years of life. The degree in which the symptoms are expressed varies from patient to patient and tend to last for their whole life, unfortunately.

ASD Neurological Mechanisms and Overview

Autism is a developmental and intellectual disorder that affects over “1 in 100 to even 1 in 150 children” across the world (Badescu et al., 2016). While one percent seems small, no children should have to face the complexities of any disorder for their entire lives. In disorders like autism, there is a wide range of symptoms that the patient may face, as well as the degree to which the symptoms manifest themselves throughout the lives of that patient. Some patients have mild symptoms and do not have a prognosis until much later, while other patients face more severe symptoms. Developmental disorders fall under an umbrella of psychiatric disorders and are classified in the Diagnostic and Statistical Manual of Mental Disorders, Edition 5 (DSM-5). According to the DSM-5 and the National Institute of Mental Health, there are some general patterns and symptoms that are indicative of a patient with autism. Some of these symptoms include, “ difficulty with communication and interaction with other people, restricted interested and repetitive behaviors, and symptoms that hurt the person’s ability to function properly in school, work and other areas of life” (National Institute of Mental Health). While there are so many possible symptoms a patient can have, it is usually possible to diagnose a patient with autism spectrum disorder by the age of two. In older individuals, parents and teachers tend to notice a pattern that corresponds to autism symptoms.

In the past decade, many studies have attempted to understand the complexities of autism, specifically the neurophysiology associated with autism as well as the mechanisms involved. Many studies have shown a link between, “structural chromosomal abnormalities and ASD phenotypes” which have led to the discovery of single-nucleotide polymorphisms in autism patients. (Badescu et al., 2016) With psychiatric disorders, it can be difficult to understand the genetics involved and the neurophysiology and for many autism patients, the link with structural chromosomal abnormalities is not evident. Therefore, a study by Badescu et al. proposed dysfunctional MicroRNAs in the neurons, which are RNA (ribonucleic acid) molecules that can alter gene expression following transcription, are part of different pathways that mediate primary genetic deficits in individuals with autism. In other words, the miRNAs normally perform modifications following transcription to make a gene active, but now that function is altered and is linked to the onset of autism. The authors found 5 miRNAs in patients with autism, 3 of which are associated with neurodevelopmental disorders and the other two with intellectual disability. (Badescu et al., 2016). Therefore, this could be a reason why autism patients tend to have developmental delays in processing as well as in social environments.

In addition to understanding some of the genetics involved in understanding autism, there have been mechanisms proposed to understand the disorder and why it is still prevalent among people. One of the most interesting of these mechanisms has been proposed by Gallese et al. in 2012. Autism is a disorder that is very controversial among the general population. Previously, people believed that parental neglect has contributed to children developing the social symptoms of autism; that theory has since been abandoned. In this study, Gallese et al. have approached understanding autism from a psychological and evolutionary perspective. Over twenty years ago, mirror neurons were discovered in the premotor cortex of macaque monkeys, a group of monkeys often used in understanding behavior and cognition. These neurons reflect the translation of pre-existing motor neurons and can help to ‘mimic’ actions. The mirror mechanism discovered shows that the motor cortex of human and non-human primate brains is constructed in an abstract manner. Multiple studies in infants confirmed the existence of such a mechanism and are responsible for infants understanding the purpose of any action they take.

In the case of ASD, muscle and reflex abnormalities are very common for infants that are 4-6 months old. Over time, many motor deficits endure in these individuals. The motor coordination issues are associated with dysfunctions in the cerebellum. Some studies showed that children with ASD are unable to understand the goal of an action when they observe and execute that action. This could suggest that there is a deficit with their mirror mechanism or abnormal neural organization. These issues translate to emotion, imitation, and other stereotypical symptoms of ASD individuals.

Another approach used to understand the complexities of ASD is predictive coding. Predictive coding has been proposed as a method to understand the underlying neural mechanisms of cognitive disorders such as ASD. In a 2015 study, the researchers used an auditory task to understand how top-down processing works in patients with ASD and ADHD in children. The researchers found that ASD patients have trouble adjusting the precision of their surrounding environments. In other words, the research suggests, “that ASD individuals fail to contextualize sensory evidence in relation to prior beliefs and that these difficulties mostly emerge in uncertain environments” (Gonzalez-Gadea et al., 2015). Further research could be needed to understand the underlying neural mechanisms of ASD and find a way to prevent the symptoms much earlier.

ADHD Neurological Mechanisms and Overview

In addition to ASD, another common developmental disorder that affects children throughout the world is Attention-Deficit/Hyperactivity Disorder (ADHD). ADHD is a developmental disorder with a 7.2% prevalence rate among children. This disorder affects more young boys than young girls in a ratio of 3:1. Similar to ASD, ADHD symptoms are variable and are often misdiagnosed as emotional symptoms or as other neurological disorders. However, there are some tell-tale ADHD symptoms, according to the National Institute of Mental Health. The most prevalent symptom among children is hyperactivity. Hyperactivity includes constant fidgeting, continuous talking, and the inability to stay in one spot for a long period of time. Other symptoms that emerge and persist through adulthood include inattention and emotional distancing. ADHD symptoms can appear in patients as early as 3 years old, but it is usually diagnosed in the patient’s elementary school years.

There are multiple neurological mechanisms and pathways that are affected in ADHD patients, the most prominent being impaired executive function. The brain’s executive functions encompass the working memory, planning, and execution of tasks. Higher-order processing in the brain occurs in the prefrontal cortex of the frontal-striatal complex of the brain. In a 2007 study by Mizuno et al., the researchers found that the cerebellum at the back of the brain is just as important in higher-order processing, specifically a subregion known as Crus I/II. The cerebellum and the prefrontal cortex have the same amounts of dopamine (DA) and DA-regulating proteins, which is essential for higher-order thinking. The researchers found that ADHD patients have reduced cerebellar volumes. This means that there is not enough dopamine circulating in the back of the brain, thereby disrupting the communication between Crus I/II and the prefrontal cortex. As a result, ADHD patients have a lower executive function (Mizuno et al., 2007).

Another deficit in ADHD patients is a polymorphism in the Catechol-Oxidase-Methyltransferase (COMT) enzyme. COMT is responsible for degrading catecholamines, which include norepinephrine, epinephrine, and dopamine, from synapses. These catecholamines are secreted by the adrenal cortex of the endocrine system in the brain. When a specific single-nucleotide polymorphism occurs in the sequence that produces COMT, it increases COMT activity (Mizuno et al., 2007). Increased COMT activity results in excess dopamine being removed from the synaptic cleft, which modulates lower connectivity between Crus I/II and the prefrontal cortex. The SNP that occurs with COMT also acts to lower executive processing in ADHD patients.

Finally, a significant neurological system that is impaired in children with ADHD is the circadian system. The circadian rhythm acts as an internal body clock to regulate the sleep-wake cycle and alertness. The circadian rhythm operates on a 24-hour schedule and is regulated by CLOCK genes that are synthesized in suprachiasmatic nuclei. CLOCK genes interact with the amount of light exposure, diet, and amount of physical exercise to regulate the body’s sleep-wake cycle. Many children with ADHD have chronic sleep-onset insomnia. In this case, the patients are naturally nocturnal (awake at night) rather than diurnal (awake during the day). These patients also have abnormal melatonin secretions whereby they are unable to fall asleep at night (Badescu et al., 2016). The alteration of the circadian rhythm is an essential feature of childhood ADHD.

External Factors and Risk of ASD/ADHD

In addition to understanding neurological impairments of ASD and ADHD patients, it is important to recognize the impact of external factors and the environment on the risk of prognosis. Environmental determinants alone are said to account for 10-40% of the risk of ADHD and ASD in children. In both ASD and ADHD, prenatal exposure is the root cause of many of the external factors that increase the likelihood of the fetus having either of those prognoses.

ADHD External Factors

One of the factors that increase the risk of ADHD is maternal smoking. Pregnancy is a crucial time and it is important for the mother to be extra careful with diet and substance use so as to not affect the fetus. However, a recent study showed that tobacco smoke exposure increases mental retardation in the fetus (Tran et al., 2017). Part of this is also due to a polymorphism that occurs in the nicotinic-cholinergic receptor gene such that heightened inattention and hyperactivity symptoms are likely to be present in the fetus (Lee et al., 2008). The study by Tran et al. also found that exposure to any nicotine product including vapes and e-cigarettes creates similar problems in the fetus.

In addition to maternal smoking, increased concentrations of BPA and phthalate (plastic-derived chemicals) in the mother’s urine increases the risk of ADHD in the fetus. BPA and phthalate, in high concentrations, affect the function of the endocrine system. The endocrine system is responsible for hormonal production and regulation, so endocrine dysfunction is harmful to the body. The BPA and phthalate can pass to the fetus through the mother’s placenta and breast milk post-pregnancy (Tran et al., 2017). These modes of transmission of BPA and phthalate will in turn affect the fetus’ endocrine system. Increased concentrations of BPA and phthalate in the body are associated with more aggressive behaviors and inattention symptoms that are associated with ADHD.

ASD External Factors

Prenatal exposure is also the root of some of the external factors that increase the risk of ASD prognosis, the first being maternal inflammation. Any maternal inflammation as a result of obesity or infection affects the risk of ASD of her fetus. Maternal infection from viruses or bacteria is common during hospitalization and is most harmful during the first trimester of the mother’s pregnancy. Any inflammation that results from these infections affects the autoimmunity of autism. With the Zika virus, for example, any infection that the mother has leads to induced brain damage and neurotoxicity by increasing programmed cell death of neuronal cells in the fetus. This can lead to developmental delays that are characteristic of most autism patients. Similarly, bacterial infections can affect the risk of ASD in the fetus. The most prominent example of this is Streptococcus, the most common pathogen of fetal environments (Madore et al., 2016). Streptococcus infections also increase neurotoxicity, which leads to similar symptoms in the child.

In addition to maternal inflammation, an environmental factor that increases the risk of ASD is air pollution exposure. Polluted air often has high concentrations of nitric oxide (NO) which is harmful to the body in acute and chronic amounts. Increased prenatal exposure to organic pollutants in the air leads to an increased risk of autism symptoms in the fetus. The organic pollutants increase neuroinflammation of the fetal cells in the brain, which is harmful (Oudin et al., 2019). Children themselves will develop heightened inflammation of neuronal cells if they are exposed to high concentrations of NO over a long period of time. As a result, the risk of ASD in these children will increase.

Epigenetics with ASD and ADHD

One factor that can increase the risk of any neurological, autoimmune disorder, including ASD and ADHD, is epigenetic inheritance. Epigenetics studies the changes in gene expression over time as a result of exposure to specific environmental factors through methods of DNA methylation, histone modification, and other mechanisms. Any environmental exposure, in addition to the person exposed, can affect future generations. This is known as a transgenerational inheritance (Tran et al., 2017). In a recent study, researchers found that alterations of microRNAs and DNA methylation, the process of adding a methyl group to cytosine, in the placenta are transmitted to later generations. Alteration of gene expression through these mechanisms increases the likelihood of ASD and ADHD in future children from the genetic level. Even if the direct fetus is not affected, the symptoms can present themselves in future grandchildren and great-grandchildren, for example.

Potential Treatments and Further Research

There is still a lot of research ahead to find the cure to autism and ADHD. After understanding the mechanisms and environmental impact on ASD and ADHD prognoses, there are a few non-invasive therapies and research techniques that can allow researchers to find a solution. With autism, the best way is to understand all SNPs that occur in every autism patient to understand why that is happening. For now, the best treatment options include brain mapping and living in environments of less pollution and toxicity. For ADHD, there are potential therapy options to alleviate symptoms. First, light treatment can help to re-regulate the circadian rhythm over time so that patients become diurnal and fall asleep during the night. Another option for ADHD treatment is to increase the intake of carbohydrates and Omega-3 in the child’s diet in order to allow for proper expression of CLOCK genes. In summary, there is still a long way to go for both disorders, but I hope that in the near future, we can finally find the cure for autism and ADHD.



References

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