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35.6B: Neurodevelopmental Disorders - Autism and ADHD - Biology

35.6B: Neurodevelopmental Disorders - Autism and ADHD - Biology


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LEARNING OBJECTIVES

  • Distinguish between the neurodevelopmental disorders of autism and ADHD

Neurodevelopmental disorders occur when the development of the nervous system is disturbed. There are several different classes of neurodevelopmental disorders. Some, like Down Syndrome, cause intellectual deficits, while others specifically affect communication, learning, or the motor system. Some disorders, such as autism spectrum disorder and attention deficit/hyperactivity disorder, have complex symptoms.

Autism

Autism spectrum disorder (ASD, sometimes just “autism”) is a neurodevelopmental disorder in which severity differs from person to person. Estimates for the prevalence of the disorder have changed rapidly in the past few decades. Current estimates suggest that one in 88 children will develop the disorder. ASD is four times more prevalent in males than females.

A characteristic symptom of ASD is impaired social skills. Children with autism may have difficulty making and maintaining eye contact and reading social cues. They also may have problems feeling empathy for others. Other symptoms of ASD include repetitive motor behaviors (such as rocking back and forth), preoccupation with specific subjects, strict adherence to certain rituals, and unusual language use. Up to 30 percent of patients with ASD develop epilepsy. Patients with some forms of the disorder (e.g., Fragile X syndrome) also have intellectual disability. Because it is a spectrum disorder, other ASD patients are very functional and have good-to-excellent language skills. Many of these patients do not feel that they suffer from a disorder and instead just believe that they process information differently.

Except for some well-characterized, clearly-genetic forms of autism (e.g., Fragile X and Rett Syndrome), the causes of ASD are largely unknown. Variants of several genes correlate with the presence of ASD, but for any given patient, many different mutations in different genes may be required for the disease to develop. At a general level, ASD is thought to be a disease of “incorrect” wiring. Accordingly, brains of some ASD patients lack the same level of synaptic pruning that occurs in non-affected people. There has been some unsubstantiated controversy linking vaccinations and autism. In the 1990s, a research paper linked autism to a common vaccine given to children. This paper was retracted when it was discovered that the author falsified data; follow-up studies showed no connection between vaccines and autism.

Treatment for autism usually combines behavioral therapies and interventions, along with medications to treat other disorders common to people with autism ( depression, anxiety, obsessive compulsive disorder). Although early interventions can help mitigate the effects of the disease, there is currently no cure for ASD.

Attention Deficit Hyperactivity Disorder (ADHD)

Approximately three to five percent of children and adults are affected by attention deficit/hyperactivity disorder (ADHD). Like ASD, ADHD is more prevalent in males than females. Symptoms of the disorder include inattention (lack of focus), executive functioning difficulties, impulsivity, and hyperactivity beyond what is characteristic of the normal developmental stage. Some patients do not have the hyperactive component of symptoms and are diagnosed with a subtype of ADHD: attention deficit disorder (ADD). Many people with ADHD also show comorbidity: they develop secondary disorders in addition to ADHD. Examples include depression or obsessive compulsive disorder (OCD).

The cause of ADHD is unknown, although research points to a delay and dysfunction in the development of the prefrontal cortex and disturbances in neurotransmission. According to some twin studies, the disorder has a strong genetic component. There are several candidate genes that may contribute to the disorder, but no definitive links have been discovered. Environmental factors, including exposure to certain pesticides, may also contribute to the development of ADHD in some patients. Treatment for ADHD often involves behavioral therapies and the prescription of stimulant medications, which, paradoxically, cause a calming effect in these patients.

Key Points

  • Disturbances in the development of the nervous system, genetic or environmental, may lead to neurodevelopmental diseases.
  • Individuals affected by autism are believed to have one of many different mutations in genes required for the disease to cause disruptions in the nervous system that are generally observed; however, studies on specifics are still inconclusive.
  • In ADHD, a strong genetic component may contribute to the disorder; however, no definitive links have been found.
  • Individuals with ADHD may experience other psychological or neurological disorders in addition to their ADHD symptoms; this experience of having more than one disorder is termed comorbidity.
  • The cause of both autism and ADHD are unknown and cures are unavailable; however, treatments to alleviate symptoms are accessible.

Key Terms

  • autism: disorder observed in early childhood with symptoms of abnormal self-absorption, characterised by lack of response to other humans and a limited ability or disinclination to communicate and socialize
  • attention deficit hyperactivity disorder: a developmental disorder in which a person has a persistent pattern of impulsiveness and inattention, with or without a component of hyperactivity
  • fragile X syndrome: a particular, genetic syndrome, caused by the excessive repetition of a particular trinucleotide
  • rett syndrome: a neurodevelopmental disorder of the grey matter of the brain that almost exclusively affects females, but has also been found in male patients
  • comorbidity: the presence of one or more disorders (or diseases) in addition to a primary disease or disorder
  • neurodevelopmental disorder: a disorder of brain function that affects emotion, learning ability and memoryand that unfolds as the individual grows

Autism spectrum disorder (ASD) is a neurodevelopmental disorder. Its severity differs from person to person. Estimates for the prevalence of the disorder have changed rapidly in the past few decades. Current estimates suggest that one in 88 children will develop the disorder. ASD is four times more prevalent in males than females.

This video discusses possible reasons why there was a steep increase in the number of people diagnosed with autism – rather than the vaccine conspiracy theory, which has no scientific basis.

A characteristic symptom of ASD is impaired social skills. Children with autism may have difficulty making and maintaining eye contact and reading social cues. They also may have problems feeling empathy for others. Other symptoms of ASD include repetitive motor behaviors (such as rocking back and forth), preoccupation with specific subjects, strict adherence to certain rituals, and unusual language use. Up to 30 percent of patients with ASD develop epilepsy, and patients with some forms of the disorder (like Fragile X) also have intellectual disability. Because it is a spectrum disorder, other ASD patients are very functional and have good-to-excellent language skills. Many of these patients do not feel that they suffer from a disorder and instead think that their brains just process information differently.

Except for some well-characterized, clearly genetic forms of autism (like Fragile X and Rett’s Syndrome), the causes of ASD are largely unknown. Variants of several genes correlate with the presence of ASD, but for any given patient, many different mutations in different genes may be required for the disease to develop. At a general level, ASD is thought to be a disease of “incorrect” wiring. Accordingly, brains of some ASD patients lack the same level of synaptic pruning that occurs in non-affected people. In the 1990s, a research paper linked autism to a common vaccine given to children. This paper was retracted when it was discovered that the author falsified data, and follow-up studies showed no connection between vaccines and autism.

Treatment for autism usually combines behavioral therapies and interventions, along with medications to treat other disorders common to people with autism (depression, anxiety, obsessive compulsive disorder). Although early interventions can help mitigate the effects of the disease, there is currently no cure for ASD.


Neurodevelopmental Disorders in Children

Autism, ADHD, learning disabilities, developmental delays and intellectual retardation are among the neurodevelopmental disorders that extract an enormous emotional, mental and financial toll in terms of compromised quality of life and lifelong disability. Additionally, these require special education, psychological and medical support services that drain resources and contribute to further stress on the families and communities. While it is generally accepted that the cause for these disabilities is likely to include genetic and environmental factors, for a vast majority of these disabilities, the cause remains unknown.

Many factors contribute in complex ways to brain development. These include gene expression, heredity, socioeconomic factors, stress, drugs, nutrition and chemical contaminants. Brain development is a long, complicated process involving cell proliferation, migration, differentiation and cell death (apoptosis). There are multiple ways by which chemicals can disrupt neurological development such as influencing gene expression, protein pathways (1) and hypothyroidism (2) . It is a well established fact that a child's nervous system is more sensitive to chemical exposures compared to an adult nervous system. This is evident from incidence of permanent brain damage in fetus of pregnant mothers who consumed alcohol during their pregnancy resulting in fetal alcohol spectrum disorder (3) . Similarly, pregnant women involved in methylmercury disasters showed minimal signs of toxicity compared to their children who displayed effects ranging from cerebral palsy to delayed development (4) .

In the 1950s, Thalidomide was introduced into the market to treat morning sickness and as a sedative. It created an epidemic of 15,000 babies worldwide with missing limbs and other developmental disabilities including mental retardation and autism (5) . Today, it is a widely accepted fact that chemicals in the environment can cause developmental disabilities in children. Even more intriguing is the fact that certain environmental agents can cause long-lasting damage to the developing brain at exposure levels that have no lasting effect in the adult.

A wide range of toxic chemicals in the environment have been associated with neurodevelopmental disabilities which affect an estimated 3-8% of the 4 million babies born each year in the Unites States. In a recent study published in The Lancet, researchers from Harvard School of Public Health and the Mount Sinai School of Medicine examined publicly available data on chemical toxicity to identify the industrial chemicals likely to damage the developing brain. The researchers compiled a list of 202 industrial chemicals that are known to be toxic to the human brain using the Hazardous Substance Data Bank of the National Library of Medicine and other data sources (6) . The exposure to these chemicals came from industrial accidents, occupational exposure, suicide attempts and accidental poisonings. The authors noted that the list was not comprehensive since the number of chemicals that can cause neurotoxicity in laboratory animal test exceeds 1000. A key point highlighted in the study was the fact that even though moderate amounts of chemicals, such as lead and mercury, were needed to cause neurological damage in most adults, only small amounts might be needed to damage the developing brains in babies, infants and young children.

It is a well known fact that certain chemicals, such as lead, mercury, PCBs, dioxins, arsenic and toluene can cause clinical and sub-clinical deficits in neurobehavioral development through injury to the fetal brain. The developing brain is extremely vulnerable to these environmental agents at doses much lower than those that affect adult brain function. Studies have shown that prenatal exposure to even relatively low levels of lead result in lifelong reductions of intellectual functions and disorders of behavior (7) . Polychlorinated biphenyls (PCBs) cross the placental barrier and can cause injury to the developing brain (8) . Organic mercury compounds such as methyl mercury are among the most potent neurotoxins causing severe developmental problems (9) . In view of this fact, it seems disconcerting that there is little information available on possible toxic potential for the 80,000 chemicals registered with the Environmental Protection Agency (EPA). Of the 3000 chemicals produced or imported at over 1 million pounds a year, a mere 23% have been tested for their potential to cause developmental damage (10) .

Autism is a neurodevelopmental disorder characterized by impaired social interaction as well as verbal and non-verbal communication. There are various degrees of severity involved in this disorder. Therefore, this condition is commonly referred to as "autism spectrum disorders" or ASD which include autism, Asperger's syndrome, pervasive developmental disorders not otherwise specified (PDD-NOS) and high-functioning autism. Statistics based on data gathered in 2002 indicates that more than 550,000 children are affected by varying degrees of autism spectrum disorders (ASD). In fact, it has been reported that autism is the fastest growing developmental disability, increasing at a rate of 10 to 17 percent annually according to the Autism Society of America. While improved diagnostic measures may contribute to the perceived increase in the number of cases, it is becoming increasingly apparent that environmental neurotoxins in combination with genetic predispositions could also create adverse gene-environment interactions.

Surveys conducted in California indicate an almost 210% increase in the number of cases of autism in children over the past 10 years. There is increasing concern that certain chemicals (such as mercury, halogenated aromatics and pesticides) and biotic factors (such as vaccine antigens) may act synergistically to alter certain susceptibility or genetic risk factors to result in ASD. The UC Davis Center for Children's Environmental Health has established the first large scale epidemiological study to investigate the underlying causes of autism. The UC Davis researchers at the Children's center have suggested an association between thimerosal (ethyl mercury) and immune system dysfunction in mice. In a recent study, Windham et. al. (2006) explored the possible association between ASD and environmental exposures to hazardous air pollutants in the San Francisco Bay area (11) . Based on the data from the study, the authors suggested that living in areas with higher ambient levels of HAPs, especially metals and chlorinated solvents, during pregnancy or early childhood could be associated with a moderately increased risk of autism. This study highlighted the need for more complex etiologic studies combining exposure to multiple compounds by various pathways with genetic information to further understand the contribution of environmental exposures to the development of autism.

Another developmental disorder that affect the areas of social skills, behavior and communication is Attention Deficit Hyperactivity Disorder (ADHD). Presently, some researchers believe that there is a correlation between ASD and ADHD. It is estimated that ADHD affects approximately 4.5 million children in the US. The main characteristics that define ADHD include inattention, hyperactivity and impulsivity. Though almost everyone at some point in their life blurts out something inappropriate or has difficulty focusing on a task or could become forgetful, experts say that such behavior must be demonstrated to a degree that is inappropriate for that age, for a diagnosis to be made. There is insufficient evidence that suggests that ADHD could be a result of simply social factors or child-rearing factors. Other factors such as environmental agents like heavy metals and organohalides, traumatic brain injury, food additives and sugar, neurobiology and genetics have been implicated in the etiology of this condition.

Medications that seem to be most effective in treating ADHD are a class of drugs known as stimulants such as Ritalin (methylphenidate). However, there is mounting controversy over the widespread use of methylphenidate and possible life-threatening effects from its long-term use. This makes it imperative that alternative modalities be implemented for ADHD management. Nutrient deficiencies are common in ADHD supplementation with minerals, the B vitamins (added in singly), omega-3 and omega-6 essential fatty acids, flavonoids, and the essential phospholipid phosphatidylserine (PS) can improve ADHD symptoms (12) . In a first of its kind study, Dr. Sarina Grosswald, an educator and expert in cognitive learning and clinical neuropsychologist, William Stixrud investigated the effect of meditation in kids with ADHD in the school setting. For the study, kids with ADHD meditated 10 minutes, twice a day. This study revealed that kids who meditated showed a 45 to 50 percent reduction in stress, anxiety and depression. These kids also showed significant improvements in organizational skills, memory, strategizing, mental flexibility, attention and impulsivity. According to Stixrud, teaching a child to regulate his own body and mind in response to anxiety should be the first response rather than putting them on medication.

Neurodevelopmental disorders have increased over the past 30 years and are at least partly attributed to exposure to environmental contaminants. Therefore, it becomes imperative to mitigate environmental factors that may influence disease. The impact of environmental toxins on children's health has become a major focus in the federal government resulting in establishment of eight new research centers in children's environmental health with joint funding from EPA and the National Institute of Environmental Health Sciences (NIEHS). "The brains of our children are our most precious economic resource, and we haven't recognized how vulnerable they are," says Philippe Grandjean, adjunct professor at Harvard School of Public Health and the lead author of the study published in The Lancet . "We must make protection of the young brain a paramount goal of public health protection. You have only one chance to develop a brain."

Discuss This Article

Bibliography

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  2. Selva KA, Harper A, Downs A, Blasco PA, Lafranchi SH. Neurodevelopmental outcomes in congenital hypothyroidism: comparison of initial T4 dose and time to reach target T4 and TSH. J Pediatr 2005147(6):775-80.
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  5. Lenz, W. A short history of the thalidomide embryopathy. Teratology. 1988. 38: 203-215.
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  8. Patandin S, Lanting CI, Mulder PG, Boersma ER, Sauer PJ, Weisglas-Kuperus N. Effects of environmental exposure to polychlorinated biphenyls and dioxins on cognitive abilities in Dutch children at 42 months of age. 1999. J Pediatr. Jan134(1):33-41
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  12. Kidd, PM. Attention deficit/hyperactivity disorder (ADHD) in children: rationale for its integrative management. Altern Med Rev. 2000 Oct5(5):402-28.

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Methods

Conditions included in the analysis

The conditions included in this review are shown in Table 1. These were identified from Rutter's Textbook of Child and Adolescent Psychiatry, 5th edition [4] and a review of behavioural phenotypes [5]. Those from the latter source were included only if an estimate of prevalence was available. The category of ‘intellectual disability’ (ID) posed problems, because this can be both a symptom of a known disorder, and a nonsyndromal condition of unknown etiology. Furthermore, in the UK, the term ‘learning disability’ is used to refer to intellectual disability, whereas elsewhere ‘learning disability’ is used for specific difficulties in a child of normal IQ. Despite these problems, it was decided to attempt an estimate of publications focusing on ID, but data on this condition need to be treated with particular caution.

Number of people affected

Estimates of prevalence per 100 were computed from Rutter et al. [4] or Udwin and Dennis [5], with the mean being used if a range was given.

Severity of condition

Measures of disease burden used in mainstream medicine focus mainly on mortality and morbidity and are not in general appropriate for neurodevelopmental disorders. It was therefore necessary to derive an ad hoc measure for this study. This was a 4-point scale representing the extent to which an affected individual could be expected to obtain educational qualifications and live independently in adulthood (see Table 2). Nine expert clinicians who saw children with neurodevelopmental disorders were asked to estimate severity for conditions shown in Table 1 on this scale. For some conditions, this scale was difficult to apply because of the wide variation in severity. For instance, a person with autistic disorder is unlikely to fall in category 1, but could fall into category 2, 3 or 4. In such a case, raters were asked to give their best estimate of the average level of severity. The data in Table 3 shows the average across all raters. For rare conditions, few clinicians had sufficient experience of cases to be able to make a judgement, and in those cases, the author provided a rating based on the description of the phenotype in Udwin and Dennis [5].

Estimates of number of publications

Web of Knowledge was the basis for research counts the search terms used are shown in Table 1 for a paper to be counted, the search term had to appear in the title. This exercise revealed that some disorders lacked consistent terminology and were correspondingly hard to search. Total number of articles for each condition was obtained for 5-year bands from 1985 to 2009. Note that coding of articles was not mutually exclusive, so that if search terms for two conditions were included in the title, the same article would be counted towards toward the total for both conditions. The word ‘Down’ is not a valid search term in Web of Knowledge, so it was necessary to estimate the number of articles on Down syndrome. From a Google scholar search it was established that 9.9% of articles on Down syndrome include ‘trisomy 21’ in the title. Thus the number of articles on Down syndrome in Web of Knowledge was estimated by multiplying the number of articles with ‘trisomy 21’ in the title by 10.1.

Publication index

This was derived in a method similar to that used by Al-Shahi et al [1] by dividing the total number of articles by prevalence. This was scaled so that it could be readily interpreted as a count of the N papers in 25 years per 100 affected cases in a population of 11.56 million, which is an estimate of number of children in the UK [6].

Rate of increase in publications

This measure was derived by computing the slope of the line linking the number of publications in 5-year time bins across the period 1985–2009.

Estimates of amount of genetic/animal research

Preliminary analyses suggested that the amount of research on a condition was partly determined by the disciplines involved for some conditions, a high proportion of studies involved genetics and/or mouse models. To gain an estimate of how much research on each condition was of this type, searches were re-run to find the proportion of papers on a condition that had the words ‘gene’, ‘genetic’, ‘mouse’, ‘mice’ or ‘chromosome’ in the topic field.

Amount of funding by the National Institutes of Health (NIH)

Data on NIH funding were obtained using the Research Portfolio Online Reporting Tools (RePORT) (http://projectreporter.nih.gov/reporter.cfm). For each disorder, the database was interrogated to identify funded projects for the period 2000–2010, and the total funding in thousands of dollars was computed, together with the NIH institute that provided the funds. It is important to note that the RePORT software identifies projects on the basis of keywords, and may include projects that do not have a central focus on the disorder in question. This means that, on the one hand, the amount of funding focused on a specific disorder is likely to be over-estimated, and on the other hand, that the same project is likely to be included in counts for more than one disorder. For this analysis, it proved impossible to obtain realistic estimates of funding for studies of intellectual disability, as the search terms from Table 1 identified numerous projects concerned with a wide range of disorders. This category was therefore omitted from this analysis. For the remaining conditions, a measure of rate of increase in funding between 2000–2010 was computed from the slope of the function for funding by year.


Neurodevelopmental Disorders

More than 300,000 children and youth in Ontario are living with autism, ADHD and other neurodevelopmental disorders.

The symptoms of these disorders – anxiety, depression, compulsive activity, social isolation, to name just a few – place a huge emotional cost on children and their families. The costs to society include lost productivity and potential, plus life-time bills to the medical system. There are few medications to treat these disorders, and those that exist are only partially effective.


What causes ASD?

Scientists believe that both genetics and environment likely play a role in ASD. There is great concern that rates of autism have been increasing in recent decades without full explanation as to why. Researchers have identified a number of genes associated with the disorder. Imaging studies of people with ASD have found differences in the development of several regions of the brain. Studies suggest that ASD could be a result of disruptions in normal brain growth very early in development. These disruptions may be the result of defects in genes that control brain development and regulate how brain cells communicate with each other. Autism is more common in children born prematurely. Environmental factors may also play a role in gene function and development, but no specific environmental causes have yet been identified. The theory that parental practices are responsible for ASD has long been disproved. Multiple studies have shown that vaccination to prevent childhood infectious diseases does not increase the risk of autism in the population.


Creating a genome-independent nosology from proteomes-interactomes

Human proteomes are hereditable molecular phenotypes 72 and as such constitute valuable, yet untapped, resources to create disorder classifications rooted in molecules and their pathways. The study of proteomes shares with the analysis of genomes its quantitative and unbiased character. However, proteomes and interactomes offer the distinctive advantage of being executors of phenotypic programs in cells and tissues. Therefore, proteomes and interactomes are causally closer to the identity of disease mechanisms than genomes. Proteomes are already beginning to shed light on complex neurological disorders such as schizophrenia. 81, 82 However, we should not limit ourselves to just exploring postmortem brains of subjects grouped solely by their clinical features. Instead, we advocate for the study of proteomes from cells isolated from individuals that are genetically related. Cell proteomes from affected probands compared with their unaffected first-degree relatives offer a great prospect for the identification of hereditable or de novo abnormalities in molecular phenotypes. Evidently, in the context of NDDs, human inducible pluripotent stem cells are a great resource, as they can be differentiated into neurons. 83 However, it is likely that the molecular mechanisms affected in NDDs are common to many, if not all cells. For example, Fragile X syndrome or velocardiofacial syndrome, where multiple tissues are affected 12 . Thus, fibroblasts or lymphoblasts from human pedigrees are likely to offer valuable insights into neuronal disorders. We predict that proteomes built from genetically related subjects’ cells will bridge two camps. On one hand, proteomes will help us to interpret results from genome-wide analyses. On the other hand, they will guide us to define NDD mechanisms at levels of complexity higher than the traditional single genes or proteins. These would include, for instance, subcellular compartments, such as synapses or mitochondria, and deficits in tissue organization, such as those in neural circuits. Genomes, proteomes and interactomes give us vantage points, the inevitable next step is to dive deep into the biology emerging from and converging to them.


Abstract

Neurodevelopmental disorders (NDDs), such as autism and ADHD, are behaviorally defined adaptive functioning difficulties arising from variations, alterations and atypical maturation of the brain. While it is widely agreed that NDDs are complex conditions with their presentation and functional impact underpinned by diverse genetic and environmental factors, contemporary and polarizing debate has focused on the appropriateness of the biomedical as opposed to the neurodiverse paradigm in framing conceptions of these conditions. Despite being largely overlooked by both research and practice, the International Classification of Functioning Disability and Health (ICF) endorsed by the World Health Organization in 2001 views functioning dynamically, offering a framework for investigating, assessing and treating NDDs holistically. Exemplified by autism and ADHD, we argue that the ICF provides not only a multitude of opportunities in accounting for the environmental determinants in researching and clinically managing NDDs, but opportunities for harmonizing the seemingly irreconcilable biomedical and neurodiverse paradigms.


Gene associations:

The researchers analyzed data from previous studies that involved a total of 93,294 people with at least one of the four conditions, along with 51,311 controls. They looked at common variants — single-letter changes to DNA that appear in more than 1 percent of the population — shared by any two of the four conditions.

Four of the six possible pairs have significant overlap autism and OCD do not, and ADHD and OCD appear to be negatively correlated, the researchers found. Autism, ADHD and Tourette syndrome also overlapped as a group.

The researchers also identified seven regions of the genome and 18 genes that harbor variants tied to autism, ADHD and Tourette syndrome, most of which were missed in the 2019 analysis. The newly identified variants tend to occur in genes that are highly expressed in the brain, the researchers found, including in the hypothalamus and the pituitary and adrenal glands. Together these regions form a system involved in the body’s response to stress that may function differently in people with autism, ADHD or Tourette syndrome.

“This is quite intriguing to us,” Paschou says. “These genes shed some further light into what causes these neurodevelopmental phenotypes.”

The work was published earlier this month in Biological Psychiatry.


35.5 Nervous System Disorders

By the end of this section, you will be able to do the following:

  • Describe the symptoms, potential causes, and treatment of several examples of nervous system disorders

A nervous system that functions correctly is a fantastically complex, well-oiled machine—synapses fire appropriately, muscles move when needed, memories are formed and stored, and emotions are well regulated. Unfortunately, each year millions of people in the United States deal with some sort of nervous system disorder. While scientists have discovered potential causes of many of these diseases, and viable treatments for some, ongoing research seeks to find ways to better prevent and treat all of these disorders.

Neurodegenerative Disorders

Neurodegenerative disorders are illnesses characterized by a loss of nervous system functioning that are usually caused by neuronal death. These diseases generally worsen over time as more and more neurons die. The symptoms of a particular neurodegenerative disease are related to where in the nervous system the death of neurons occurs. Spinocerebellar ataxia, for example, leads to neuronal death in the cerebellum. The death of these neurons causes problems in balance and walking. Neurodegenerative disorders include Huntington’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease and other types of dementia disorders, and Parkinson’s disease. Here, Alzheimer’s and Parkinson’s disease will be discussed in more depth.

Alzheimer’s Disease

Alzheimer’s disease is the most common cause of dementia in the elderly. In 2012, an estimated 5.4 million Americans suffered from Alzheimer’s disease, and payments for their care are estimated at $200 billion. Roughly one in every eight people age 65 or older has the disease. Due to the aging of the baby-boomer generation, there are projected to be as many as 13 million Alzheimer’s patients in the United States in the year 2050.

Symptoms of Alzheimer’s disease include disruptive memory loss, confusion about time or place, difficulty planning or executing tasks, poor judgment, and personality changes. Problems smelling certain scents can also be indicative of Alzheimer’s disease and may serve as an early warning sign. Many of these symptoms are also common in people who are aging normally, so it is the severity and longevity of the symptoms that determine whether a person is suffering from Alzheimer’s.

Alzheimer’s disease was named for Alois Alzheimer, a German psychiatrist who published a report in 1911 about a woman who showed severe dementia symptoms. Along with his colleagues, he examined the woman’s brain following her death and reported the presence of abnormal clumps, which are now called amyloid plaques, along with tangled brain fibers called neurofibrillary tangles. Amyloid plaques, neurofibrillary tangles, and an overall shrinking of brain volume are commonly seen in the brains of Alzheimer’s patients. Loss of neurons in the hippocampus is especially severe in advanced Alzheimer’s patients. Figure 35.30 compares a normal brain to the brain of an Alzheimer’s patient. Many research groups are examining the causes of these hallmarks of the disease.

One form of the disease is usually caused by mutations in one of three known genes. This rare form of early onset Alzheimer’s disease affects fewer than five percent of patients with the disease and causes dementia beginning between the ages of 30 and 60. The more prevalent, late-onset form of the disease likely also has a genetic component. One particular gene, apolipoprotein E (APOE) has a variant (E4) that increases a carrier’s likelihood of getting the disease. Many other genes have been identified that might be involved in the pathology.

Link to Learning

Visit this website for video links discussing genetics and Alzheimer’s disease.

Unfortunately, there is no cure for Alzheimer’s disease. Current treatments focus on managing the symptoms of the disease. Because decrease in the activity of cholinergic neurons (neurons that use the neurotransmitter acetylcholine) is common in Alzheimer’s disease, several drugs used to treat the disease work by increasing acetylcholine neurotransmission, often by inhibiting the enzyme that breaks down acetylcholine in the synaptic cleft. Other clinical interventions focus on behavioral therapies like psychotherapy, sensory therapy, and cognitive exercises. Since Alzheimer’s disease appears to hijack the normal aging process, research into prevention is prevalent. Smoking, obesity, and cardiovascular problems may be risk factors for the disease, so treatments for those may also help to prevent Alzheimer’s disease. Some studies have shown that people who remain intellectually active by playing games, reading, playing musical instruments, and being socially active in later life have a reduced risk of developing the disease.

Parkinson’s Disease

Like Alzheimer’s disease, Parkinson’s disease is a neurodegenerative disease. It was first characterized by James Parkinson in 1817. Each year, 50,000-60,000 people in the United States are diagnosed with the disease. Parkinson’s disease causes the loss of dopamine neurons in the substantia nigra, a midbrain structure that regulates movement. Loss of these neurons causes many symptoms including tremor (shaking of fingers or a limb), slowed movement, speech changes, balance and posture problems, and rigid muscles. The combination of these symptoms often causes a characteristic slow hunched shuffling walk, illustrated in Figure 35.31. Patients with Parkinson’s disease can also exhibit psychological symptoms, such as dementia or emotional problems.

Although some patients have a form of the disease known to be caused by a single mutation, for most patients the exact causes of Parkinson’s disease remain unknown: the disease likely results from a combination of genetic and environmental factors (similar to Alzheimer’s disease). Post-mortem analysis of brains from Parkinson’s patients shows the presence of Lewy bodies—abnormal protein clumps—in dopaminergic neurons. The prevalence of these Lewy bodies often correlates with the severity of the disease.

There is no cure for Parkinson’s disease, and treatment is focused on easing symptoms. One of the most commonly prescribed drugs for Parkinson’s is L-DOPA, which is a chemical that is converted into dopamine by neurons in the brain. This conversion increases the overall level of dopamine neurotransmission and can help compensate for the loss of dopaminergic neurons in the substantia nigra. Other drugs work by inhibiting the enzyme that breaks down dopamine.

Neurodevelopmental Disorders

Neurodevelopmental disorders occur when the development of the nervous system is disturbed. There are several different classes of neurodevelopmental disorders. Some, like Down Syndrome, cause intellectual deficits. Others specifically affect communication, learning, or the motor system. Some disorders like autism spectrum disorder and attention deficit/hyperactivity disorder have complex symptoms.

Autism

Autism spectrum disorder (ASD) is a neurodevelopmental disorder. Its severity differs from person to person. Estimates for the prevalence of the disorder have changed rapidly in the past few decades. Current estimates suggest that one in 88 children will develop the disorder. ASD is four times more prevalent in males than females.

Link to Learning

This video discusses possible reasons why there has been a recent increase in the number of people diagnosed with autism.

A characteristic symptom of ASD is impaired social skills. Children with autism may have difficulty making and maintaining eye contact and reading social cues. They also may have problems feeling empathy for others. Other symptoms of ASD include repetitive motor behaviors (such as rocking back and forth), preoccupation with specific subjects, strict adherence to certain rituals, and unusual language use. Up to 30 percent of patients with ASD develop epilepsy, and patients with some forms of the disorder (like Fragile X) also have intellectual disability. Because it is a spectrum disorder, other ASD patients are very functional and have good-to-excellent language skills. Many of these patients do not feel that they suffer from a disorder and instead think that their brains just process information differently.

Except for some well-characterized, clearly genetic forms of autism (like Fragile X and Rett’s Syndrome), the causes of ASD are largely unknown. Variants of several genes correlate with the presence of ASD, but for any given patient, many different mutations in different genes may be required for the disease to develop. At a general level, ASD is thought to be a disease of “incorrect” wiring. Accordingly, brains of some ASD patients lack the same level of synaptic pruning that occurs in non-affected people. In the 1990s, a research paper linked autism to a common vaccine given to children. This paper was retracted when it was discovered that the author falsified data, and follow-up studies showed no connection between vaccines and autism.

Treatment for autism usually combines behavioral therapies and interventions, along with medications to treat other disorders common to people with autism (depression, anxiety, obsessive compulsive disorder). Although early interventions can help mitigate the effects of the disease, there is currently no cure for ASD.

Attention Deficit Hyperactivity Disorder (ADHD)

Approximately three to five percent of children and adults are affected by attention deficit/hyperactivity disorder (ADHD) . Like ASD, ADHD is more prevalent in males than females. Symptoms of the disorder include inattention (lack of focus), executive functioning difficulties, impulsivity, and hyperactivity beyond what is characteristic of the normal developmental stage. Some patients do not have the hyperactive component of symptoms and are diagnosed with a subtype of ADHD: attention deficit disorder (ADD). Many people with ADHD also show comorbitity, in that they develop secondary disorders in addition to ADHD. Examples include depression or obsessive compulsive disorder (OCD). Figure 35.32 provides some statistics concerning comorbidity with ADHD.

The cause of ADHD is unknown, although research points to a delay and dysfunction in the development of the prefrontal cortex and disturbances in neurotransmission. According to studies of twins, the disorder has a strong genetic component. There are several candidate genes that may contribute to the disorder, but no definitive links have been discovered. Environmental factors, including exposure to certain pesticides, may also contribute to the development of ADHD in some patients. Treatment for ADHD often involves behavioral therapies and the prescription of stimulant medications, which paradoxically cause a calming effect in these patients.

Career Connection

Neurologist

Neurologists are physicians who specialize in disorders of the nervous system. They diagnose and treat disorders such as epilepsy, stroke, dementia, nervous system injuries, Parkinson’s disease, sleep disorders, and multiple sclerosis. Neurologists are medical doctors who have attended college, medical school, and completed three to four years of neurology residency.

When examining a new patient, a neurologist takes a full medical history and performs a complete physical exam. The physical exam contains specific tasks that are used to determine what areas of the brain, spinal cord, or peripheral nervous system may be damaged. For example, to check whether the hypoglossal nerve is functioning correctly, the neurologist will ask the patient to move his or her tongue in different ways. If the patient does not have full control over tongue movements, then the hypoglossal nerve may be damaged or there may be a lesion in the brainstem where the cell bodies of these neurons reside (or there could be damage to the tongue muscle itself).

Neurologists have other tools besides a physical exam they can use to diagnose particular problems in the nervous system. If the patient has had a seizure, for example, the neurologist can use electroencephalography (EEG), which involves taping electrodes to the scalp to record brain activity, to try to determine which brain regions are involved in the seizure. In suspected stroke patients, a neurologist can use a computerized tomography (CT) scan, which is a type of X-ray, to look for bleeding in the brain or a possible brain tumor. To treat patients with neurological problems, neurologists can prescribe medications or refer the patient to a neurosurgeon for surgery.

Link to Learning

This website allows you to see the different tests a neurologist might use to see what regions of the nervous system may be damaged in a patient.

Mental Illnesses

Mental illnesses are nervous system disorders that result in problems with thinking, mood, or relating with other people. These disorders are severe enough to affect a person’s quality of life and often make it difficult for people to perform the routine tasks of daily living. Debilitating mental disorders plague approximately 12.5 million Americans (about 1 in 17 people) at an annual cost of more than $300 billion. There are several types of mental disorders including schizophrenia, major depression, bipolar disorder, anxiety disorders and phobias, post-traumatic stress disorders, and obsessive-compulsive disorder (OCD), among others. The American Psychiatric Association publishes the Diagnostic and Statistical Manual of Mental Disorders (or DSM), which describes the symptoms required for a patient to be diagnosed with a particular mental disorder. Each newly released version of the DSM contains different symptoms and classifications as scientists learn more about these disorders, their causes, and how they relate to each other. A more detailed discussion of two mental illnesses—schizophrenia and major depression—is given below.

Schizophrenia

Schizophrenia is a serious and often debilitating mental illness affecting one percent of people in the United States. Symptoms of the disease include the inability to differentiate between reality and imagination, inappropriate and unregulated emotional responses, difficulty thinking, and problems with social situations. People with schizophrenia can suffer from hallucinations and hear voices they may also suffer from delusions. Patients also have so-called “negative” symptoms like a flattened emotional state, loss of pleasure, and loss of basic drives. Many schizophrenic patients are diagnosed in their late adolescence or early 20s. The development of schizophrenia is thought to involve malfunctioning dopaminergic neurons and may also involve problems with glutamate signaling. Treatment for the disease usually requires antipsychotic medications that work by blocking dopamine receptors and decreasing dopamine neurotransmission in the brain. This decrease in dopamine can cause Parkinson’s disease-like symptoms in some patients. While some classes of antipsychotics can be quite effective at treating the disease, they are not a cure, and most patients must remain medicated for the rest of their lives.

Depression

Major depression affects approximately 6.7 percent of the adults in the United States each year and is one of the most common mental disorders. To be diagnosed with major depressive disorder, a person must have experienced a severely depressed mood lasting longer than two weeks along with other symptoms including a loss of enjoyment in activities that were previously enjoyed, changes in appetite and sleep schedules, difficulty concentrating, feelings of worthlessness, and suicidal thoughts. The exact causes of major depression are unknown and likely include both genetic and environmental risk factors. Some research supports the “classic monoamine hypothesis,” which suggests that depression is caused by a decrease in norepinephrine and serotonin neurotransmission. One argument against this hypothesis is the fact that some antidepressant medications cause an increase in norepinephrine and serotonin release within a few hours of beginning treatment—but clinical results of these medications are not seen until weeks later. This has led to alternative hypotheses: for example, dopamine may also be decreased in depressed patients, or it may actually be an increase in norepinephrine and serotonin that causes the disease, and antidepressants force a feedback loop that decreases this release. Treatments for depression include psychotherapy, electroconvulsive therapy, deep-brain stimulation, and prescription medications. There are several classes of antidepressant medications that work through different mechanisms. For example, monoamine oxidase inhibitors (MAO inhibitors) block the enzyme that degrades many neurotransmitters (including dopamine, serotonin, norepinephrine), resulting in increased neurotransmitter in the synaptic cleft. Selective serotonin reuptake inhibitors (SSRIs) block the reuptake of serotonin into the presynaptic neuron. This blockage results in an increase in serotonin in the synaptic cleft. Other types of drugs such as norepinephrine-dopamine reuptake inhibitors and norepinephrine-serotonin reuptake inhibitors are also used to treat depression.

Other Neurological Disorders

There are several other neurological disorders that cannot be easily placed in the above categories. These include chronic pain conditions, cancers of the nervous system, epilepsy disorders, and stroke. Epilepsy and stroke are discussed below.

Epilepsy

Estimates suggest that up to three percent of people in the United States will be diagnosed with epilepsy in their lifetime. While there are several different types of epilepsy, all are characterized by recurrent seizures. Epilepsy itself can be a symptom of a brain injury, disease, or other illness. For example, people who have intellectual disability or ASD can experience seizures, presumably because the developmental wiring malfunctions that caused their disorders also put them at risk for epilepsy. For many patients, however, the cause of their epilepsy is never identified and is likely to be a combination of genetic and environmental factors. Often, seizures can be controlled with anticonvulsant medications. However, for very severe cases, patients may undergo brain surgery to remove the brain area where seizures originate.

Stroke

A stroke results when blood fails to reach a portion of the brain for a long enough time to cause damage. Without the oxygen supplied by blood flow, neurons in this brain region die. This neuronal death can cause many different symptoms—depending on the brain area affected— including headache, muscle weakness or paralysis, speech disturbances, sensory problems, memory loss, and confusion. Stroke is often caused by blood clots and can also be caused by the bursting of a weak blood vessel. Strokes are extremely common and are the third most common cause of death in the United States. On average one person experiences a stroke every 40 seconds in the United States. Approximately 75 percent of strokes occur in people older than 65. Risk factors for stroke include high blood pressure, diabetes, high cholesterol, and a family history of stroke. Smoking doubles the risk of stroke. Because a stroke is a medical emergency, patients with symptoms of a stroke should immediately go to the emergency room, where they can receive drugs that will dissolve any clot that may have formed. These drugs will not work if the stroke was caused by a burst blood vessel or if the stroke occurred more than three hours before arriving at the hospital. Treatment following a stroke can include blood pressure medication (to prevent future strokes) and (sometimes intense) physical therapy.