Neurodevelopmental Disorders
Monika A. Buerger
“A well-trained nervous system is the greatest friend a mind can have.”
Halleck, 1898
Neurodevelopmental disorder (ND) refers to disruption of the brain that results in gaps, delays, or variations in the way a child’s brain develops. NDs include pervasive developmental disorders (PDDs), attention deficit disorder (ADD), attention deficit hyperactive disorder (ADHD), learning disorders (LDs), sensory processing disorder (SPD), developmental delays, cerebral palsy (CP), mental retardation (MR), muscular dystrophy, epilepsy/seizure disorder, and various psychiatric disorders. Based on data gathered in the 1990s, it has been estimated that one in every six children in the United States has a developmental disorder, and in most cases these disabilities affect the nervous system (1). In 2000, U.S. News and World Report stated that one out of every six children suffers from problems such as autism, aggression, ADHD, and dyslexia (2). There has been ongoing debate regarding the cause of various NDs, especially when it comes to autism, with the oldest working theory being that of genetics. However, the current model of belief is that NDs may have a genetic component, but the greatest factor is how that genetic component may be triggered to result eventually in the ND that is the issue. Birth trauma, environmental factors, maternal stressors, and epigenetic factors are all likely contributors of NDs and subclinical brain dysfunction. In all probability, it is more likely that there are a number of factors that, when combined, result in the neurological disturbance.
EPIGENETICS
An area of recent study is that of the role of the “epigenetic factor” in NDs. Epigenetic factors are chemical substances both within as well as outside the genome that regulate the expression of the gene. Epigenetic insult does not change the actual sequence of the deoxyribonucleic acid (DNA) but it does alter gene expression. These expressive changes may last through cell division and can be passed on through generations. The primary epigenetic insult occurs prenatally because of maternal exposure to various environmental toxins, endogenous toxins, nutritional factors, maternal stressors, and drugs (recreational and/or prescription). Until recently, it has been believed that epigenetic modification is stable and that the pattern is faithfully preserved after DNA replication during cell division, leading to stable epigenomic patterns during one’s lifetime. However, more recent reports of environmental stress altering the epigenomic patterns within a short time frame after birth, followed by alterations in gene expression and phenotype, indicate that epigenetics not only is involved in congenital NDs but also in acquired diseases, including PDDs, through gene-environment interactions (3).
Birth Trauma
The role of birth trauma is another key area of research of children later developing NDs and is of growing concern. Less than 2% of neonatal deaths or stillbirths in United States are caused by birth trauma. However, there is an average of six to eight injuries per 1,000 live births in the United States; autistic children are 12 times more likely to suffer birth trauma or complication than their nonautistic siblings. In the United States, cesarean section is the most commonly performed surgery and has increased from 4% in 1965 to about 33% today. The World Health Organization recommends that a 5% to 10% Cesarean rate is optimal and that a rate >15% does more harm than good (4). A British study of one hospital whose policy was to schedule all mothers for elective Cesarean sections 1 week before their due date reported autism birth rates 21 times higher than that in neighboring hospitals (5). In the United States, Utah
has one of the highest autism rates: 1 out of every 133 children and 1 out of every 79 boys. They also have a higher ratio of breech births, cesarean sections, and newborns who required more than 30 minutes of assisted ventilation among children with autism (6). Glasson et al. (7), from the University of Western Australia School of Psychiatric and Clinical Neuroscience, compared the birth records of the 465 children diagnosed with autism between 1980 and 1995 with the records of 1,313 randomly selected nonautistic children. They found that, when compared to the non-autistic group, the autism patients experienced more difficulties during pregnancy, labor, delivery, and during the neonatal period. They stated that the autism group was characterized by increased maternal age, being first born, a threatened abortion before 20 weeks’ gestation, fetal distress, and an elective caesarean (7). In a study published in Pediatrics, Juul-Dam et al. (8) looked at perinatal factors of 74 participants, 61 of whom were autistic and 13 of whom had PDDs-not otherwise specified (PDD-NOS). The study showed that some of the perinatal factors that had significantly higher incidences in the autistic group were found with the induction of labor and prolonged and precipitous labor. The PDD-NOS group showed results similar to those of the autism group. The specific reason for the induction of labor was not specified; therefore, it is difficult to assess the relevance, if any, to the later diagnosis of autism or PDD-NOS (8). Prolonged labor may be caused by fetal malposition, fetopelvic disproportion, excess sedation, inadequate contractions, and rupture of the fetal membranes before the onset of active labor. Risks associated with this include increased rates of operative vaginal deliveries or emergent cesarean section, an increased risk of intrauterine infection, and an associated increased risk of fetal compromise. Fetal compromise may take the form of asphyxia, infection, or head trauma from prolonged pressure, all of which may have lasting neurologic consequences. Some researchers also hypothesize that in children with childhood disintegrative disorder (CDD) predisposing genetic factors combined with environmental stressors such as prenatal or postnatal virus exposure or birth trauma have resulting brain deposition of amyloid and disruption of synaptic transmissions (9).
has one of the highest autism rates: 1 out of every 133 children and 1 out of every 79 boys. They also have a higher ratio of breech births, cesarean sections, and newborns who required more than 30 minutes of assisted ventilation among children with autism (6). Glasson et al. (7), from the University of Western Australia School of Psychiatric and Clinical Neuroscience, compared the birth records of the 465 children diagnosed with autism between 1980 and 1995 with the records of 1,313 randomly selected nonautistic children. They found that, when compared to the non-autistic group, the autism patients experienced more difficulties during pregnancy, labor, delivery, and during the neonatal period. They stated that the autism group was characterized by increased maternal age, being first born, a threatened abortion before 20 weeks’ gestation, fetal distress, and an elective caesarean (7). In a study published in Pediatrics, Juul-Dam et al. (8) looked at perinatal factors of 74 participants, 61 of whom were autistic and 13 of whom had PDDs-not otherwise specified (PDD-NOS). The study showed that some of the perinatal factors that had significantly higher incidences in the autistic group were found with the induction of labor and prolonged and precipitous labor. The PDD-NOS group showed results similar to those of the autism group. The specific reason for the induction of labor was not specified; therefore, it is difficult to assess the relevance, if any, to the later diagnosis of autism or PDD-NOS (8). Prolonged labor may be caused by fetal malposition, fetopelvic disproportion, excess sedation, inadequate contractions, and rupture of the fetal membranes before the onset of active labor. Risks associated with this include increased rates of operative vaginal deliveries or emergent cesarean section, an increased risk of intrauterine infection, and an associated increased risk of fetal compromise. Fetal compromise may take the form of asphyxia, infection, or head trauma from prolonged pressure, all of which may have lasting neurologic consequences. Some researchers also hypothesize that in children with childhood disintegrative disorder (CDD) predisposing genetic factors combined with environmental stressors such as prenatal or postnatal virus exposure or birth trauma have resulting brain deposition of amyloid and disruption of synaptic transmissions (9).
The role of birth trauma among children with NDs is particularly important for the doctor of chiropractic. Given the research regarding the implications of birth trauma as one of the contributors leading to NDs, it is imperative that the doctor of chiropractic treating children be well versed in NDs and be one of the cornerstones of treatment for these children. A careful prenatal and birth history should be obtained whenever treating children with NDs. If possible, the precise mechanism of injury should be determined so that specificity in correction of the vertebral subluxation can be achieved. When looking at cranial nerve injury resulting from birth trauma, it was found that unilateral branches of the facial nerve and vagus nerve, in the form of the recurrent laryngeal nerve, are most commonly involved. Cranial nerve and spinal cord injuries result from hyperextension, traction, and overstretching with simultaneous rotation. Approximately 80% of lesions involve the right side and approximately 10% are bilateral (10). The high incidence of right-sided lesions may be indicative of the higher magnitude of force being placed on the baby’s right upper cervical spine by the right-handed obstetrician during the delivery process. This is the type of information that the doctor of chiropractic must take into consideration when treating pediatric patients, especially those with NDs.
Maternal Stress
In some women, the effects of psychological stress may play some role in the complications with fetal development. The theory is that this level of emotional or psychological stress may contribute to the abnormal development of the cerebellum, hypothalamus, pituitary, adrenal glands, and amygdala. Pathological changes in the cerebellum in autism are thought to correspond to an event before 30 to 32 weeks’ gestation. The purpose of one recent study was to determine whether there is an increased incidence of stressors in autism before this time period. Surveys regarding the incidence and timing of prenatal stressors were distributed to specialized schools and clinics for autism and Down syndrome, along with the mothers of children without neurodevelopmental diagnoses at walk-in clinics. Incidence of stressors during each 4-week block of pregnancy was recorded. Incidence of stressors in the blocks before and including the predicted time period (21-32 weeks’ gestation) in each group of surveys was compared to the other prenatal blocks. A higher incidence of prenatal stressors was found in autism at 21 to 32 weeks’ gestation, with a peak at 25 to 28 weeks. This study supports the possibility of prenatal stressors as a potential contributor to autism. The timing of stressors is consistent with the embryological age suggested by neuroanatomical findings seen in the cerebellum in autism (11).
Environmental
Dr. Irva Hertz-Picciotto, an epidemiologist at University of California Davis states, “You could estimate that 60% of autisms have a genetic component but that doesn’t mean the environment causes the other 40%. It could cause 90% because among those 60% of cases there had to be something environmental that dysregulated the gene at some point in development.” There is currently
a tremendous amount of research demonstrating the neurotoxic affects from many environmental chemicals. There is ongoing study of the exposure affects from chemicals in the environment such as lead, mercury, polychlorinated biphenyls (PCBs), and pesticides. In 2004, researchers analyzed umbilical cord blood samples from 10 neonates, all born in US hospitals in August and September of that year. The 10 samples were from blood donated to the American Red Cross and were chosen randomly and came with no identification. The researchers had no geographical information about where the infants were born and only knew that the samples came from around the country. Of the more than 400 chemicals for which the researchers tested, 287 were detected in umbilical cord blood. Of these, 180 are known to cause cancer in humans or animals, 217 are toxic to the brain or nervous system, and 208 cause birth defects or abnormal development among animals. Scientists now refer to the presence of such toxins in the newborn as “body burden.” According to the study’s authors, the scope of testing was limited because chemical companies are not required to divulge methods for detecting the presence of their chemicals in the human body. They believed that had they been able to test for a broader array of chemicals, they would almost certainly have detected far more than 287. Of the toxins, mercury was found in samples from all 10 newborns, with the average concentration being 0.947 parts per billion. Additional toxins found during this study are listed in Table 25.1. The findings of this study are extremely alarming when considering the developing fetus and the possible long-term developmental implications these toxins may bring. An immature and porous blood-brain barrier, which does not fully form until 6 months of age, allows for greater chemical exposures to the developing brain. Also, children have lower levels of some chemical-binding proteins, which allow for more of any particular chemical to reach “target organs,” and systems that detoxify and excrete industrial chemicals are not fully yet developed.
a tremendous amount of research demonstrating the neurotoxic affects from many environmental chemicals. There is ongoing study of the exposure affects from chemicals in the environment such as lead, mercury, polychlorinated biphenyls (PCBs), and pesticides. In 2004, researchers analyzed umbilical cord blood samples from 10 neonates, all born in US hospitals in August and September of that year. The 10 samples were from blood donated to the American Red Cross and were chosen randomly and came with no identification. The researchers had no geographical information about where the infants were born and only knew that the samples came from around the country. Of the more than 400 chemicals for which the researchers tested, 287 were detected in umbilical cord blood. Of these, 180 are known to cause cancer in humans or animals, 217 are toxic to the brain or nervous system, and 208 cause birth defects or abnormal development among animals. Scientists now refer to the presence of such toxins in the newborn as “body burden.” According to the study’s authors, the scope of testing was limited because chemical companies are not required to divulge methods for detecting the presence of their chemicals in the human body. They believed that had they been able to test for a broader array of chemicals, they would almost certainly have detected far more than 287. Of the toxins, mercury was found in samples from all 10 newborns, with the average concentration being 0.947 parts per billion. Additional toxins found during this study are listed in Table 25.1. The findings of this study are extremely alarming when considering the developing fetus and the possible long-term developmental implications these toxins may bring. An immature and porous blood-brain barrier, which does not fully form until 6 months of age, allows for greater chemical exposures to the developing brain. Also, children have lower levels of some chemical-binding proteins, which allow for more of any particular chemical to reach “target organs,” and systems that detoxify and excrete industrial chemicals are not fully yet developed.
Knowing the types of exposures to which a child with an ND may have been subjected is important when treating this population group. For the doctor of chiropractic, it may mean treating the child with detoxification methods and supplementation of various vitamins and minerals. Or, if this is not within the scope of their practice or expertise, they should consider cotreating with a naturopath, homeopath, or medical provider that specializes in these particular methods for the pediatric patient.
EARLY DETECTION
Other than cause, an equally important focus for children with NDs is that of early detection. There is an increasing push for pediatricians to perform various
developmental screening procedures to determine if a child may be at risk for developmental delay and/or NDs. Many within the medical community who are involved in the research and treatment of children with NDs suggest that screening for specific developmental milestones as well as for retained primitive reflexes should become a regular practice for the pediatrician. Many pediatricians screen for various developmental milestones only within the first year of life. Few test for retained primitive reflexes beyond the first year. It is important to understand that developmental milestones continue to be significant beyond the first year of life, and primitive reflexes, if retained beyond the first year, have a significant impact on proper neurological development. For the doctor of chiropractic caring for the pediatric patient, it is crucial that he or she knows and understands specific developmental milestones and their significance should the child be delayed in reaching them (refer to Chapter 6 for specific milestones). Doctors of chiropractic caring for the pediatric population should also know how to examine for retained primitive reflexes beyond the first year of life and understand their neurological implications. The testing for retained primitive reflexes, as well as their significance, is discussed in detail in Chapter 24. Some of the latest research for early detection of autism will be presented later in this chapter. This type of information is important for the doctor of chiropractic to be aware of because many children are treated by their chiropractor on a regular basis from birth. Consequently, it is important that the doctor of chiropractic be skilled in early detection of any developmental delay.
developmental screening procedures to determine if a child may be at risk for developmental delay and/or NDs. Many within the medical community who are involved in the research and treatment of children with NDs suggest that screening for specific developmental milestones as well as for retained primitive reflexes should become a regular practice for the pediatrician. Many pediatricians screen for various developmental milestones only within the first year of life. Few test for retained primitive reflexes beyond the first year. It is important to understand that developmental milestones continue to be significant beyond the first year of life, and primitive reflexes, if retained beyond the first year, have a significant impact on proper neurological development. For the doctor of chiropractic caring for the pediatric patient, it is crucial that he or she knows and understands specific developmental milestones and their significance should the child be delayed in reaching them (refer to Chapter 6 for specific milestones). Doctors of chiropractic caring for the pediatric population should also know how to examine for retained primitive reflexes beyond the first year of life and understand their neurological implications. The testing for retained primitive reflexes, as well as their significance, is discussed in detail in Chapter 24. Some of the latest research for early detection of autism will be presented later in this chapter. This type of information is important for the doctor of chiropractic to be aware of because many children are treated by their chiropractor on a regular basis from birth. Consequently, it is important that the doctor of chiropractic be skilled in early detection of any developmental delay.
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PERVASIVE DEVELOPMENTAL DISORDERS
PDD refers to a group of developmental conditions that affect children and involve delays or impairments in communication and social skills. Autistic disorder (AD) is the most well-known of the PDDs, which also include Asperger’s syndrome (AS), PDD-NOS, and two less common conditions called CDD and Rett syndrome. Typically, PDDs are first diagnosed during infancy, the toddler years, or early childhood. All PDDs affect communication and social skills as well as cognitive skills and behavior. They all have things in common, but each has specific characteristics that set it apart from the others. To date there are no specific diagnostic tests to confirm a diagnosis of PDD. Often, parents recognize that there is something “different” about their child; however, they are either fearful of a diagnosis or think that the child will grow out of his or her behavior. When presenting their concerns to a pediatrician, parents are often told that it is either a behavioral issue or that the parent is overly concerned and that the child will “grow out” of their behavior or will “catch up” developmentally. For an “official” diagnosis to be made, the child should be evaluated by a doctor with expertise in PDDs. Most often this will be either a neurodevelopmental psychiatrist or psychologist, a pediatric neurologist, or a developmental pediatrician. Because of subtle characteristics within the group of PDDs and other NDs, along with the subjectivity of the examiner, different physicians may pronounce a different diagnosis. Parent questionnaires, educational and cognitive assessments, language assessments, or play and behavior assessments might also be used to help diagnose a PDD. Each disorder within the diagnosis of PDD has specific diagnostic criteria outlined by the American Psychiatric Association in its Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) which is included in Table 25.2.
Characteristic Signs of a PDD
Signs of a PDD are usually recognizable before a child is 3 years old. However, symptoms can range from severe to so subtle that they seem to be normal aspects of a young child’s development. For that reason, it may take a few years for a PDD to be fully identified. Early signs of a PDD can include:
Avoiding eye contact; not looking people in the face
Not pointing to objects
Trouble interacting, playing with, or relating to others
Unusual movements such as hand flapping, spinning, or tapping
Not using or seeming not to understand language
Delays in developmental milestones or loss of milestones already achieved
Playing with the same toy in a way that seems odd or repetitive
Not exploring the environment with curiosity or interest
Classic Autism
The classic type of autism (Kanner autism) is characterized by little if any speech and a poor understanding of nonverbal communication, problems with social interaction, and various other behaviors such as hand flapping or body rocking, insistence on sameness, or resistance to change. The classic picture of autism is a child with a blank expression sitting on the floor, rocking back and forth and/or flapping his or her hands. They often display abnormal postures such as toe walking, arching of the back, and extreme extension of the neck. The prevalence of classic autism is said to be approximately
4 or 5 out of every 10,000 live births, and it is estimated that 90% are boys and 10% are girls. Classic autism is not noted to be sharply on the rise, but it is with autism spectrum disorder (ASD) and regressive autism in which the dramatic increase in numbers is being seen. Kanner’s original description of autism noted that many of the patients had unusually enlarged heads. However, this observation did not receive much attention until recently, when postmortem and magnetic resonance imaging (MRI) studies began to confirm that in children with autism the brain is enlarged, although it still has not been confirmed whether all the brain regions and/or systems are enlarged equally.
4 or 5 out of every 10,000 live births, and it is estimated that 90% are boys and 10% are girls. Classic autism is not noted to be sharply on the rise, but it is with autism spectrum disorder (ASD) and regressive autism in which the dramatic increase in numbers is being seen. Kanner’s original description of autism noted that many of the patients had unusually enlarged heads. However, this observation did not receive much attention until recently, when postmortem and magnetic resonance imaging (MRI) studies began to confirm that in children with autism the brain is enlarged, although it still has not been confirmed whether all the brain regions and/or systems are enlarged equally.
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Brain size has been defined using head circumference, which is said to be a reliable indicator of volume, especially during early childhood. At birth, head circumference is shown to approximate normal, but by age 3 or 4, brain size in autistic children exceeds the normal average by approximately 10%. However, these differences diminish somewhat by later childhood or adolescence. The few cross-sectional studies that examined age-related changes of the brain reveal a complex pattern of growth abnormalities in the cerebellum, cerebrum, amygdala, and possibly the hippocampus. Researchers Janet Kern and Anne Jones (12) state that increased brain volume can be contributed to environmental exposure to heavy metals. In one study they showed that brain volume was increased among rodents exposed to lead. It was also said that the cerebellum is preferentially susceptible to lead, possibly because of its delayed maturation compared to the cerebrum (12).
Autism Spectrum Disorder
At one time ASD was considered to be an emotional disturbance resulting from early attachment experiences. However, now it is recognized as a disorder of prenatal and postnatal brain development. In 2001, James J. Bradstreet, director of research for the International Autism Research Center, testified in front of the House of Representatives Committee on Government Reform; he stated that there had been a sevenfold increase in ASD during the previous decade. More children are diagnosed with autism in the United States than those diagnosed with cancer, AIDS, or diabetes combined. ASDs are brain-based developmental disabilities that affect a child’s ability to communicate, understand language, play, and relate to others. It is a neurodevelopmental syndrome with a markedly high hereditary rate. Siblings born to families with a child with ASD have a 50- to 100- fold greater chance of having ASD, with a recurrence rate of 5% to 8% (13).
At the commencement of writing this text, according to the Centers for Disease Control and Prevention, it was estimated that ASDs affect 1 in 150 births, or 1 in 68 families in the United States. In October 2009, the Maternal and Child Health Bureau of Health Resources and Services Administration, U.S. Department of Health and Human Services, released a study evaluating the number of children in the United States who currently have an ASD diagnosis. The study evaluated data from the National Survey of Children’s Health (NSCH) in which 78,000 US households were surveyed to estimate the prevalence of ASDs among children ranging from ages 3 to 17. The survey estimated the prevalence rate of ASD to currently be 1 in 91 children and 1 in 57 boys ages 3 and 17. A recent British study reports that, in Britain, an estimated 1 in 64 children between the ages of 5 and 9 have ASD (14).
It is known that boys are four times more likely to develop autism than girls. Professor Boyd Haley, mercury expert at the University of Kentucky, testified before congress in August 2002 regarding synergistic toxicity and the possible reason for a four to one ratio of boys to girls when it comes to autism. Dr. Boyd tested the effects of estrogen and testosterone on the neurotoxicity of thimerosal, a mercury compound found in some vaccines. He found that 50 nanomolar of thimerosal causes <5% neuron death within the first 3 hours of incubation and 1 micromolar of testosterone causes no significant neuronal death. However, mixed together there is 100% neuronal death. In addition, at 12 hours the neuron death effected by 50 nanomolar thimerosal alone could be reversed by 1 micromolar of estrogen. This suggests that estrogen acts as an insulation effect on the myelin sheath against the neurotoxicity of thimerosal, whereas testosterone seems to increase the neurotoxic uptake of thimerosal. Boyd also found that the aluminum in vaccines will also increase the neurotoxicity of thimerosal.
Diagnosis A diagnosis of autism is made when an individual displays at least 6 of 12 symptoms distributed across three areas: communication, social interaction, and repetitive/stereotyped patterns of behavior and interest. Core behavioral symptoms rather than definitive neuropathological markers are the diagnostic indicators for ASD. There may be several different phenotypic profiles in the autistic child. For example, social development and repetitive behaviors follow different timelines; social development often improves during preschool years, whereas repetitive behaviors become more obvious. Approximately 25% to 35% of autistic children develop a few spontaneous words and early social routines by 1 year of age. Then, they reach a plateau for several months and gradually begin to lose the skills altogether; this generally occurs between 12 and 24 months of age, which correlates with the recommended time frame of the measles-mumps-rubella (MMR) vaccine. This pattern is often referred to as regressive autism.
The correlation between vaccines and autism has been a long-standing debate, particularly with the MMR vaccine. The current US childhood immunization schedule calls for 28 injections with 11 different vaccines against 15 different diseases by 2 years of age. Of these vaccines, only the MMR has been studied in relation to autism and only the ingredient thimerosal has been studied. However, there are many other ingredients, such as copper and aluminum, that also could be contributing factors to autism and other NDs. A study by the Centers for Disease Control of the MMR plus chickenpox vaccine showed that the risk for febrile seizures in infants who had received the MMR plus chickenpox vaccine was doubled when compared with giving the MMR vaccine without the chickenpox vaccine (15). A study published in the September 2009 issue of the respected journal Annals of Epidemiology showed that giving the hepatitis B vaccine to newborn baby boys during the first month of life more than triples the associated risk of developing an autism spectrum disorder (16) (refer to Chapter 11).
It is estimated that 2% of those diagnosed with autism will attain normal function, whereas 40% will be considered high functioning. One interesting finding correlated with the NSCH study mentioned previously is that, when asked if the child who had been diagnosed with ASD currently has the disorder, it was reported that 38.2% did not. This suggests that, with the current trend in biomedical and behavioral treatments, children can recover from ASD. Biomedical approaches to the treatment of ASD and other NDs will be discussed later in this chapter.
The diagnosis of autism is not typically made until around age 3; however, research is now focusing on signs and symptoms for earlier detection. The primary focus is early detection via identification of abnormal developmental signs or developmental progress. One sign in particular is that normally developing children will pay attention to other people’s faces and engage in eye contact. However, children with autism will not focus on the eyes or will not look others directly in the face at all. Newborns should be able to fixate both eyes on an object for a few seconds and by age 5 to 6 months and they should be able to hold fixation for 10 seconds. Dr. Mel Rutherford (17), an associate professor of psychology at McMaster University, has been using eyetracking technology that measures eye direction while babies look at faces, eyes, and bouncing balls on a computer screen. With this technology Rutherford was able to diagnose autism in a high-risk group—babies who had a sibling with autism—from a control group as early as 9 months (17). At the MIND Institute at the University of California Davis, Sacramento, infants were assessed at 12 months of age for their ability to respond when their name was called. The researchers took 101 infants who were considered to be at high risk for autism because they had an older sibling with autism and compared them with 46 control infants. While each child sat at a table playing with a small toy, a researcher walked behind the child and called their name in a clear voice. If the child did not respond after 3 seconds, the name was called again. They found that 100% of the infants in the control group “passed” by responding on the first or second name call, whereas 86% of the children in the at-risk group did not. They then followed 46 of the at-risk infants and 25 of the control infants for 2 years. Threefourths of those who did not respond to their name at age 12 months were identified with developmental problems at age 2. Of the children who were later diagnosed with autism, half failed the test at 12 months, and of those who were identified as having any type of developmental delay, 39% failed the test at 12 months (18). At the University of Florida in the Departments of Psychology and Child Psychiatry, 17 autistic children, who were diagnosed around age 3, were studied using the Eshkol-Wachman Movement Analysis System combined with still-frame videodisc analysis to study video of when these children were infants. In all 17 cases they found movement disorders, which varied from child to child in the shape of the mouth and in some or all of the milestones of development, including lying, righting, sitting, crawling, and walking. One example of abnormal movement was that of rolling over from a supine position to prone, which should begin around 3 months of age and involves rotation around the longitudinal axis of the body. Normally, the pelvis turns first, then the trunk, and lastly the shoulders and head. By 6 months, the order should be reversed, with the head turning first, then the shoulders and torso, and lastly the pelvis (Fig. 25-1). Some autistic children do not turn over at all. Others may start from lying on their side, rather than on their back, then arch themselves sideways by raising the head and pelvis upward, and then move their upper leg forward to help topple them over (Fig. 25-2). Another example is that of crawling; instead of crawling on all fours (Fig. 25-3), the autistic child would not support himself with his hands and instead would lean on his upper arms and bring his knees off the floor, extending his legs and bringing his bottom up (19) (Fig. 25-4). Another autistic crawling posture may be that of “dragging” one leg or one arm while doing an “army” crawl (Fig. 25-5).
As stated earlier in this chapter, it is important that the doctor of chiropractic working in the pediatric arena be able to recognize any abnormal or delayed development in children and be able to participate in
the process of early diagnosis. Table 25.3 is referred to as the Checklist for Autism in Toddlers (CHAT) and is a standard recommendation to be performed during a child’s 18-month developmental checkup.
the process of early diagnosis. Table 25.3 is referred to as the Checklist for Autism in Toddlers (CHAT) and is a standard recommendation to be performed during a child’s 18-month developmental checkup.
 FIGURE 25-1 Stages of rolling in a normal ˜6-month-old infant from a supine position (phase I). At this age, the head should initiate the movement process (phase II), followed by the shoulders and torso in a “corkscrew” fashion (phase III). The pelvis will follow sequentially until the infant reaches the prone position. The infant should then be able to push himself or herself up on all fours and into a crawling position (phase IV). |
 FIGURE 25-2 “Autistic” roll. The infant does not roll in a “corkscrew” fashion. Instead, they roll onto their side and laterally bend (raise their head and pelvis upward) and move their superior leg forward to help them “topple” over. |
Neurobiology Neurobiology is the study of the structure and the function of the nervous system. The social, language, and behavioral problems that occur with autism suggest that the syndrome affects a functionally diverse and widely distributed set of neural systems. However, at the same time, it seems to spare many perceptual and cognitive systems. This may be why autistic children are not contradictory to those children with normal intelligence and why so many autistic children have even higher visual, perceptual, and other neuropsychological skills and talents.
Nearly every part of the brain and every neuronal circuit have been theorized as the cause of or as being a contributor to autism. With recent advancements in diagnostic availability, the use of functional MRI is now being widely used to investigate various areas of the brain in relation to autism and other NDs. There is a current body of research that suggests selected aspects of the temporal, parietal, and frontal lobes and portions of the amygdala as part of the pathobiology of autism. Recent genetic findings, coupled with emerging anatomical and functional imaging studies, suggest a potential unifying model in which higher-order association areas of the brain that normally connect to the frontal lobe are partially disconnected during development (20). The frontal lobe plays a large role in executive brain function and is divided into three areas: (a) dorsolateral, (b) orbitofrontal, and (c) anterior cingulate. The dorsolateral circuit has broad neuroanatomic connections from a large area of the lateral cortex and is the
most important for executive function. It is involved in regulation necessary for working memory, organization, planning, problem solving, environmental monitoring, self-awareness, attention, mental flexibility, and abstract reasoning. It specifically controls initiative and initiation, disinhibition, and shifting of cognitive ability. The orbitofrontal cortex has deep connections to the basal ganglia complex and is responsible for behavioral regulation. Lastly, the medial cortex via the anterior cingulate circuit, with links to the limbic system, is responsible for emotional regulation. It modulates emotional arousal, expression of mood, and self-soothing strategies. Behavior may be repetitive and obsessive because of an inability to modify ones behavior to fit various social contexts. Therefore, the concept of “developmental disconnect” fits cohesively with the neurobehavioral features that are observed among autistic children, their emergence during development, and the heterogeneity of autism etiology, behaviors, and cognition. Executive function deficit is also associated with other NDs such as obsessive-compulsive disorder, Tourette’s syndrome, depression, schizophrenia, LDs, and ADHD. Because of its complexity, the frontal lobe develops slower than other parts of the brain, so executive functions do not fully mature until adolescence.
most important for executive function. It is involved in regulation necessary for working memory, organization, planning, problem solving, environmental monitoring, self-awareness, attention, mental flexibility, and abstract reasoning. It specifically controls initiative and initiation, disinhibition, and shifting of cognitive ability. The orbitofrontal cortex has deep connections to the basal ganglia complex and is responsible for behavioral regulation. Lastly, the medial cortex via the anterior cingulate circuit, with links to the limbic system, is responsible for emotional regulation. It modulates emotional arousal, expression of mood, and self-soothing strategies. Behavior may be repetitive and obsessive because of an inability to modify ones behavior to fit various social contexts. Therefore, the concept of “developmental disconnect” fits cohesively with the neurobehavioral features that are observed among autistic children, their emergence during development, and the heterogeneity of autism etiology, behaviors, and cognition. Executive function deficit is also associated with other NDs such as obsessive-compulsive disorder, Tourette’s syndrome, depression, schizophrenia, LDs, and ADHD. Because of its complexity, the frontal lobe develops slower than other parts of the brain, so executive functions do not fully mature until adolescence.
 FIGURE 25-3 Normal infant crawling on all fours. |
 FIGURE 25-4 Abnormal crawling posture associated with the autistic child diagnosed later. The infant will lean on his or her upper arms and bring his or her knees off the floor, extend the legs and bringing the bottom up. |
 FIGURE 25-5 “Army” crawl posture in an infant diagnosed with autism later. The infant may “drag” one of their arms or legs as they attempt to crawl. |
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Another recent theory is that autism may stem from impaired regulation of the locus coeruleus (LC), a bundle of neurons in the brain stem that processes all sensory signals from all areas of the body (21). The LC is a dense cluster of neurons in the dorsorostral pons and is considered to be the major source of norepinephrine in the brain with projections throughout most central nervous system regions, including the cerebral cortex, hippocampus, thalamus, midbrain, brain stem, cerebellum, and spinal cord (22). Some refer to the LC system as the locus coeruleus noradrenergic system (LC-NA). Together with other nuclei located in the anterodorsal part of the brain stem, it belongs to what use to be
termed the “ascending reticular activating system,” which is a critical area involved in arousal and wakefulness (refer to Chapter 24 for more information on the role of the reticular activating system [RAS]). This particular system is thought to be critically involved in a number of functions, including stress, emotion, attention, motivation, decision making, learning, and memory. The connection between the LC and autism comes from decades of anecdotal observations that some autistic children seem to improve during times of fever and regress when the fever ends. The working theory is that the LC system is a neuronal network that is involved in mediating the cognitive and behavioral properties compromised in ASD; it also has regulatory control over fever. Fever-induced reversibility of autism suggests that there is temporary restoration of the neurological function of the networks subserving the LC-NA system (23). The role of epigenetics and NDs was discussed at the beginning of this chapter. Interestingly, the LC-NA system can undergo alterations of complex gene-environmental interactions, leading to dysregulation caused by epigenetic mechanisms during decisive developmentally critical periods (24). A prospective study of 30 children aged to 18 years with ASD during and after an episode of fever was published in 2007 in Pediatrics (25). The researchers found that fewer aberrant behaviors were recorded for febrile patients on the Aberrant Behavior Checklist subscales of irritability, hyperactivity, stereotypy, and inappropriate speech compared with control subjects, and all improvements were temporary. The researchers did suggest that more research is needed to prove conclusively fever-specific effects on ASD and to be able to explain the underlying neurological mechanisms, possibly involving immunological and neurobiological pathways, intracellular signaling, and synaptic plasticity. The LC is an area of the brain that is not irreversibly altered; therefore, if it is responsible for ASD, this gives hope that there are remedies for those with ASD. Because the LC is responsible for the processing of all sensory information from the body, the role of sensory processing therapy for children with ASD must be explored as one of the foundations of treatment.
termed the “ascending reticular activating system,” which is a critical area involved in arousal and wakefulness (refer to Chapter 24 for more information on the role of the reticular activating system [RAS]). This particular system is thought to be critically involved in a number of functions, including stress, emotion, attention, motivation, decision making, learning, and memory. The connection between the LC and autism comes from decades of anecdotal observations that some autistic children seem to improve during times of fever and regress when the fever ends. The working theory is that the LC system is a neuronal network that is involved in mediating the cognitive and behavioral properties compromised in ASD; it also has regulatory control over fever. Fever-induced reversibility of autism suggests that there is temporary restoration of the neurological function of the networks subserving the LC-NA system (23). The role of epigenetics and NDs was discussed at the beginning of this chapter. Interestingly, the LC-NA system can undergo alterations of complex gene-environmental interactions, leading to dysregulation caused by epigenetic mechanisms during decisive developmentally critical periods (24). A prospective study of 30 children aged to 18 years with ASD during and after an episode of fever was published in 2007 in Pediatrics (25). The researchers found that fewer aberrant behaviors were recorded for febrile patients on the Aberrant Behavior Checklist subscales of irritability, hyperactivity, stereotypy, and inappropriate speech compared with control subjects, and all improvements were temporary. The researchers did suggest that more research is needed to prove conclusively fever-specific effects on ASD and to be able to explain the underlying neurological mechanisms, possibly involving immunological and neurobiological pathways, intracellular signaling, and synaptic plasticity. The LC is an area of the brain that is not irreversibly altered; therefore, if it is responsible for ASD, this gives hope that there are remedies for those with ASD. Because the LC is responsible for the processing of all sensory information from the body, the role of sensory processing therapy for children with ASD must be explored as one of the foundations of treatment.
In one study that looked at specific sensory processing patterns in 54 children with AD and their association with adaptive behavior, the researchers found support for the continued use of sensory-based interventions in the remediation of communication and behavioral difficulties among autistic children (26). In yet another study, they examined 104 persons diagnosed with autism ranging from 3 to 56 years of age. They found that sensory disturbances correlated with severity of autism in children but not in adolescents or adults. Evidence from this study also suggested that all the main modalities and multisensory processing seem to be affected and that sensory processing dysfunction in autism is global in nature (27). A study of 40 children with high-functioning autism or AS were tested for physiological responsivity and given the Short Sensory Profile used to screen for SPD. Among these autistic children, 78% were found to have significant symptoms of SPD (28). As with children suffering from SPD, children with autism were found to have reduced cardiac parasympathetic activity. In one study researchers measured baseline cardiovascular autonomic function in children with autism using the NeuroScope, a device that can measure this brainstem function in real time. Resting cardiac vagal tone (CVT), cardiac sensitivity to baroreflex (CSB), mean arterial blood pressure, diastolic blood pressure, systolic blood pressure, and heart rate (HR) were recorded in three different groups of children. The symptomatic group consisted of 15 children with autism who exhibited symptoms or signs of autonomic dysfunction. The asymptomatic group consisted of 13 children with autism who did not have symptoms or signs of autonomic dysfunction, and 117 healthy children were in the control group. The CVT and CSB were significantly lower in association with a significant elevation in HR, mean arterial blood pressure, and DBP in all children with autism compared with the healthy controls. Furthermore, the levels of CVT and CSB were lower in the symptomatic than in the asymptomatic group. The levels of CVT and CSB were not related to age in all the three groups. These results suggest that there is low baseline cardiac parasympathetic activity with evidence of elevated sympathetic tone in children with autism, whether or not they have symptoms or signs of autonomic abnormalities (29). For further information about SPD, refer to Chapter 24.
Another main area of research focus in ASD, as well as other NDs, is that of hemispheric deficit and cortical connectivity. There are opinions and research supporting that left hemisphere deficit may be the key role in ASD, as well as opinions and research supporting that it is primarily right hemisphere deficit that is the area of involvement. As stated earlier, nearly every neuronal circuit or area of the brain has been studied and theorized to play a role in autism. Therefore, when analyzing the conflicting theories of right versus left hemisphere deficit, it is important to keep in mind that both may play a role in the manifestation of symptoms in autism. In fact, it may be that there is no one specific location in the brain that is solely responsible for the symptoms of autism; rather, it is a connection abnormality between neuronal networks that process information that is to blame. In addition, there may be multiple areas of brain deficit/dysfunction of varying degrees that can be responsible for the symptoms expressed in children with autism and other NDs. In one study, hemispheric activation was measured using electroencephalographic recordings of alpha rhythm in autistic and matched normal control
subjects during four motor imitation tasks. Autistic subjects showed significantly greater right hemisphere activation during the imitation tasks than the normal subjects. This pattern was particularly evident among younger autistic subjects and during oral rather than manual imitation tasks (30). In another study, brain functional imaging using single photon emission computed tomography was used to measure left/right asymmetry and absolute values of regional cerebral blood flow in 18 autistic children ages 4 to 17 years and 10 agematched controls. The results confirmed the existence of left-hemispheric dysfunction in childhood autism, especially in the cortical areas devoted to language and handedness, leading to anomalous hemispheric specialization (31). In yet another study that looked at regional cerebral blood flow in children with autism, a statistically significant global reduction of cerebral blood flow was found in the group of autistic children compared with their normal counterparts. There was existence of left-hemisphere dysfunction, especially in the temporoparietal areas devoted to language and the comprehension of music and sounds. The researchers suggested that these abnormal areas are related to the cognitive impairment observed in autistic children, such as language deficits, impairment of cognitive development and object representation, and abnormal perception and responses to sensory stimuli (32). A device for measuring signal transfer within and between hemispheres has been developed at the Center for Neuropsychological Research at the University of Trier in Germany. The device was used for measuring brain asymmetry in tactile processing of autistic children. Results indicated that brains were more asymmetrical in autistic children than in controls, with the right hemisphere functioning quicker than the left (33). Melillo and Leisman (34) propose that there is a functional disconnect with reduced activity and coherence in the right hemisphere that would explain all the symptoms of ASD. If this is the case, they suggest that the best way to address the symptoms of ASD is via multimodal therapies that would include somatosensory, cognitive, behavioral, and biochemical interventions, all directed at increasing right hemisphere activity to the level that it would become temporally coherent with the left hemisphere. In one particular study of 14 autistic boys ages 6 to 14 years with relatively intact verbal functions and without severe or moderate MR, the autistic boys showed significantly lower driving characteristics of electroencephalographic photic driving. The findings were only in the right hemisphere and were compared with those of 21 normally developing boys (35). In one other study, the researchers examined regional grey matter differences and similarities in children and adolescents with ASD and ADHD in comparison with healthy controls using structural MRI and voxelbased morphometry. With regard to clinical criteria, the clinical groups did not differ with respect to ADHD symptoms; however, only patients with ASD showed deficits in social communication and interaction according to parental ratings. Structural abnormalities across both clinical groups compared with controls became evident as grey matter reductions in the left medial temporal lobe and as higher grey matter volumes in the left inferior parietal cortex. In addition, autism-specific brain abnormalities were found as increased grey matter volume in the right supramarginal gyrus. The researchers concluded that, although the shared structural deviations in the medial temporal lobe might be attributed to an unspecific delay in brain development and might be associated with memory deficits, the structural abnormalities in the inferior parietal lobe may correspond to attentional deficits observed among children with ASD and ADHD. By contrast, the autism-specific grey matter abnormalities near the right temporoparietal junction may be associated with impaired “theory of mind” abilities. These findings shed some light on both similarities and differences in the neurocognitive profiles of patients with ADHD and ASD (36).
subjects during four motor imitation tasks. Autistic subjects showed significantly greater right hemisphere activation during the imitation tasks than the normal subjects. This pattern was particularly evident among younger autistic subjects and during oral rather than manual imitation tasks (30). In another study, brain functional imaging using single photon emission computed tomography was used to measure left/right asymmetry and absolute values of regional cerebral blood flow in 18 autistic children ages 4 to 17 years and 10 agematched controls. The results confirmed the existence of left-hemispheric dysfunction in childhood autism, especially in the cortical areas devoted to language and handedness, leading to anomalous hemispheric specialization (31). In yet another study that looked at regional cerebral blood flow in children with autism, a statistically significant global reduction of cerebral blood flow was found in the group of autistic children compared with their normal counterparts. There was existence of left-hemisphere dysfunction, especially in the temporoparietal areas devoted to language and the comprehension of music and sounds. The researchers suggested that these abnormal areas are related to the cognitive impairment observed in autistic children, such as language deficits, impairment of cognitive development and object representation, and abnormal perception and responses to sensory stimuli (32). A device for measuring signal transfer within and between hemispheres has been developed at the Center for Neuropsychological Research at the University of Trier in Germany. The device was used for measuring brain asymmetry in tactile processing of autistic children. Results indicated that brains were more asymmetrical in autistic children than in controls, with the right hemisphere functioning quicker than the left (33). Melillo and Leisman (34) propose that there is a functional disconnect with reduced activity and coherence in the right hemisphere that would explain all the symptoms of ASD. If this is the case, they suggest that the best way to address the symptoms of ASD is via multimodal therapies that would include somatosensory, cognitive, behavioral, and biochemical interventions, all directed at increasing right hemisphere activity to the level that it would become temporally coherent with the left hemisphere. In one particular study of 14 autistic boys ages 6 to 14 years with relatively intact verbal functions and without severe or moderate MR, the autistic boys showed significantly lower driving characteristics of electroencephalographic photic driving. The findings were only in the right hemisphere and were compared with those of 21 normally developing boys (35). In one other study, the researchers examined regional grey matter differences and similarities in children and adolescents with ASD and ADHD in comparison with healthy controls using structural MRI and voxelbased morphometry. With regard to clinical criteria, the clinical groups did not differ with respect to ADHD symptoms; however, only patients with ASD showed deficits in social communication and interaction according to parental ratings. Structural abnormalities across both clinical groups compared with controls became evident as grey matter reductions in the left medial temporal lobe and as higher grey matter volumes in the left inferior parietal cortex. In addition, autism-specific brain abnormalities were found as increased grey matter volume in the right supramarginal gyrus. The researchers concluded that, although the shared structural deviations in the medial temporal lobe might be attributed to an unspecific delay in brain development and might be associated with memory deficits, the structural abnormalities in the inferior parietal lobe may correspond to attentional deficits observed among children with ASD and ADHD. By contrast, the autism-specific grey matter abnormalities near the right temporoparietal junction may be associated with impaired “theory of mind” abilities. These findings shed some light on both similarities and differences in the neurocognitive profiles of patients with ADHD and ASD (36).
Two separate studies revealed significant bitemporal hypoperfusion among autistic children. In one study of 23 children with autism and 26 control children, Ohnishi et al. used single photon emission computed tomography imaging and found significant bitemporal hypoperfusion located bilaterally in the superior temporal gyrus (STG) and in the left frontal region. In another study by Boddaert and Zilbovicius (38) of 21 children with autism and 10 controls using positron emission tomography imaging, significant bitemporal hypoperfusion located bilaterally in the STG and in the right superior temporal sulcus was found among autistic children. The function of the corpus callosum is also thought to play a role in the population with autism and NDs. The corpus callosum is responsible for effective communication between the left and right cerebral hemispheres. It allows us to integrate information from specialized centers of the right and left hemisphere and to coordinate a planned response. The corpus callosum also must be able to inhibit the transmission of information from one hemisphere to the other. If this fails, too much interference may result and there will be a lack of hemispheric “specialization.” The corpus callosum is one of the last membranes to myelinate at the age of 12 years or older. Some studies have shown reduction in the size of the corpus callosum in children with autism, but the specific regions contributing to the deficit have differed among studies. In one study using MRI scans with 3 T, the total and regional areas of the corpus callosum were determined using traditional morphometric methods. Additionally, three-dimensional (3D) surface models of the corpus callosum were also created from the MRI scans. Traditional morphometric methods
detected a significant reduction in the total callosal areas and in the anterior one-third of the corpus callosum among patients with autism. However, 3D maps revealed significant reductions in both the splenium and genu of the corpus callosum. These abnormalities suggest aberrant connections between cortical regions, which is consistent with the hypothesis of abnormal cortical connectivity in autism (39).
detected a significant reduction in the total callosal areas and in the anterior one-third of the corpus callosum among patients with autism. However, 3D maps revealed significant reductions in both the splenium and genu of the corpus callosum. These abnormalities suggest aberrant connections between cortical regions, which is consistent with the hypothesis of abnormal cortical connectivity in autism (39).
The amygdala has long been an area of concentration and research in autism because this region of the brain is a center for neural processing involved in social function, emotional reactions, and memory. Several studies have shown the amygdala to be enlarged in children with autism. It seems that the amygdala undergoes an abnormal pattern of postnatal development that includes early enlargement and then ultimately a reduction in the number of neurons. In a recent study of 50 children diagnosed with autism before the age of 2, left and right amygdala volumes were 15% and 19% larger, respectively, than those of 33 nonautistic children at two time points up to age 4 (40). Kleinhans et al. (41) demonstrated that a normative long-lag fMRI adaptation effect in the amygdala caused by repeated exposure to faces is reduced in individuals with autism spectrum conditions. In addition, Kleinhans et al. (41) demonstrated that normative “face-adaptation” effects in the amygdala are important yet absent features of face processing in individuals with autism. This is yet another piece of evidence of atypical amygdala function in patients with ASD, which, together with structural abnormalities, is broadly consistent with the amygdala theory of autism. In a study using a technique called “unbiased stereological analysis,” researchers counted the neurons in representative samples of postmortem amygdale tissue from nine men who had autism, ranging in age from 10 to 44 years at the time of their death. They found significantly fewer neurons in the whole amygdala and in the lateral nucleus in the samples from the autistic individuals (42).
Recently, the role of the cerebellum has been explored as a possible contributor to the symptoms manifested in those with autism and other NDs. There is evidence of aberrant brain structure of the cerebellum that creates disruption of a multisensory feedback loop. As discussed in Chapter 24, there is a closed-loop circuit that makes up the interactions of the cerebrocerebellar connections. The cerebellum is primarily responsible for motor movements but may also play a role in speech, learning, emotions, and attention. Thus, cerebellar abnormalities may help to explain the aberrant motor activity, impaired cognitive abilities, and apparent lack of emotion that are characteristic of autism. Cerebellar input exerts a facilitatory drive upon the contralateral cerebral cortex; therefore, cerebellar lesions depress the excitability of the contralateral motor cortex. In the first neuroimaging study to examine motor execution in children with autism, researchers at the Kennedy Krieger Institute have uncovered important new insight into the neurological basis of autism (43
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