Research Issues Involving the Biology of Autism

This article provides an overview and discussion on many of the major topics currently discussed in the autism research community. These topics include: prevalence, male-to-female ratio, diagnosis, genetics, environmental factors, neurology, medical comorbidities, sensory processing, and behavior. The article concludes with a discussion of future research in the field of autism.

Introduction

The term ”autism” was first used in 1943 to describe a small group of children whose behaviors were noticeably different from the behaviors of those who were mentally retarded or schizophrenic [29]. A turning point in the field came in 1964, when Dr. Bernard Rimland argued convincingly that autism was not caused by emotionally neglectful parents—the prevailing theory at that time—but rather was a result of one or more underlying biological impairments involving genetics and neurology [43]. In this article, I will discuss numerous research issues involving the biology of autism.

Prevalence

The prevalence rate of autism began to increase in the late 1980s [39]. Prior to this time, the reported rate was approximately 1 in 2,000 children (or 4.5 in 10,000). More recently, the Centers for Disease Control and Prevention, a U.S. health agency, reported a rate of 1 in 59 children [2]. The prevalence rate varies throughout the United States, with a high of 1 in 34 in the state of New Jersey and a low of 1 in 77 in the state of Arkansas.

A question often posed is: “Is there really an increase in autism, or is there a better awareness, resulting in more children diagnosed with autism?” Research is mixed regarding this important issue [24; 51]; however, one can argue that autism today is prevalent worldwide.

Males and females

Another important issue is the relatively high number of males with autism spectrum disorder (ASD). Historically, males outnumbered females at a rate of 3 to 1. Starting in the 1990s, the reported ratio increased to 4 or 5 males to 1 female [18]. However, a recent meta analysis indicates a 3 to 1 male to female ratio [37].

The male-to-female ratio is now under scrutiny after a survey conducted by The National Autistic Society in the United Kingdom. Their findings indicated that females with autism are under-diagnosed. Frequently, females with ASD are more sociable than males with the disorder, and their characteristic autistic symptoms are subtler [45]. In addition, some of the females’ behaviors may be interpreted using more neurotypical labels, such as “anorexia” rather than “picky eater” and “obsessive-compulsive behavior” rather than “insistence on sameness.” Eventually, a diagnostic criterion for autism will need to be established for females with ASD.

Diagnosis

Researchers are focusing much of their effort on identifying biomarkers to objectively diagnose autism [1; 42], but to date, there are no agreed-upon valid biomarkers. Currently, autism is diagnosed based on observable behaviors, and several popular diagnostic tools include the Autism Diagnostic Observation Schedule (ADOS), the Autism Diagnostic Interview (ADI-R), and the Childhood Autism Rating Scale (CARS). However, recent research has questioned the validity of the ADI-R in diagnosing children and adults [21; 23].

Genetics

Numerous studies have investigated the genetics of autism. For many years, researchers have examined specific genes with the goal of uncovering the autism gene or set of genes. Currently, 18% to 20% of those individuals diagnosed with autism have syndromic autism, i.e., known inheritable disorders. These include Angelman syndrome, Cornelia de Lange syndrome, Fragile X syndrome, Prader-Willi syndrome, Rett syndrome, Smith-Lemli-Opitz syndrome, and tuberous sclerosis complex [14]. In a highly-publicized study, approximately 100 genes, all of which were thought to contribute to autism, were examined in 85 families with two or more children with ASD [56]. Interestingly, shared genetic mutations were found in only 31% of the siblings, whereas 69% carried different autism-associated mutations. This relatively low overlap in autism-associated genes indicates that the underlying genetics of autism are much more complex than initially believed.

More recent research has employed whole genome sequencing in order to identify specific genes associated with an increase in autism [47; 55]. Regarding implications for treatment, researchers using a nanoparticle technique were able to successfully disable a gene responsible for repetitive behaviors in a mouse model of Fragile X [36]. Such an approach to understanding and treating autism will likely lead to major breakthroughs in the field.

There has also been limited research on the therapeutic effects of stem cells. In an open clinical trial, Dawson and colleagues [12] evaluated the effects of giving infusions of umbilical cord blood to a group of 25 children with ASD between two and six years of age. They reported the therapy to be relatively safe. In addition, parent reports indicated improvements in social communication and common autistic symptoms.

Environmental Factors

Over the years, researchers have suggested a relationship between viral exposure during pregnancy and an increased risk of autism. This relationship has been documented for congenital rubella, herpes simplex virus, measles, mumps, varicella, and cytomegalovirus [33].

Some researchers have speculated that certain insults or toxins play a role in causing autism in a subset of individuals with the disorder [35; 52; 54]. For example, studies have documented proximity relationships between autism and major highways [49; 50] and open fields spread with pesticides [44].

Neurology

The neurology of autism has been of interest in the research community for over 50 years [4; 43].  In general, the results have been mixed regarding specific structural abnormalities and biochemical imbalances [8; 9; 11]. Such inconsistencies are thought to be due to the use of different measurement techniques and/or the heterogeneity of the autism population [8]. However, there are several reliable findings including relatively large brain size early in life [8; 48], fewer long-range neurons that connect different regions of the brain [10], and an abundance of short-range neurons in specific areas of the brain [10]. Furthermore, impairment in structure and function of column-shaped neural bundles located in the cerebral cortex, called minicolumns, have been well-established and may lead to excessive stimulation in specific regions of the brain [6; 26].

Medical Comorbidities

Widespread interest in medical comorbidities began in the mid-1990s, and over the past 20 years, studies have indicated that many if not most individuals on the autism spectrum suffer from one or more medical problems [41].

Maternal immune activation, or MIA, is a very interesting area of study, with research revealing associations between maternal anti-brain autoantibodies and autism [19]. The reason for MIA is not known at this time, but some researchers have suggested a genetic susceptibility to environmental factors [5]. Another immune-related issue involves allergies, such as airborne (pollen), skin (eczema), and food allergies [27; 31; 53]. In addition, Jyonouchi and colleagues have documented an inflammatory autism subtype and observed irritability, lethargy, and hyperactivity in the “flare” state [28].

Gastrointestinal (GI) problems are common among individuals with ASD and include constipation, diarrhea, gastroesophageal reflex (or GERD), bloating, and excessive gas [25]. Researchers studying the microbiome have reported a lack of diversity in bacteria strains [32]; an increase in harmful bacteria, such as Clostridium [17]; and a deficiency in certain digestive enzymes, such as lactase [34]. It is interesting to note that clinicians often suspect that GI problems are due to non-nutritious, self-restricted diets [46]. Insufficient water consumption has also been suggested as a reason for the high rate of constipation in individuals with ASD [3].

Other medical comorbidities often associated with autism include seizures [20], sleep problems [30] and severe headaches or migraines [7]. 

Sensory Processing

Many if not most individuals on the autism spectrum suffer from sensory processing problems. These may involve vision, audition, touch, taste, smell, vestibular input, and proprioception. Some individuals are very sensitive to sensory sensations, or hyper-responsive, whereas others are insensitive to sensations, or hypo-responsive [40]. Unfortunately, published research on sensory processing in autism has been sparse.

Recently, researchers have studied the role of interoception in autism [22; 38]. Interoception refers to the ability to attend to internal sensations, such as hunger, thirst, bladder fullness, discomfort, and pain. The anterior insula, which is responsible for interoception, has been shown to be dysfunctional in autism [13]. This finding is consistent with self-reports and controlled experiments on interoceptive processing in autism. This may account for the exaggerated reactions of many individuals with ASD to discomfort or pain due to medical problems, and the inability of others to detect such internal sensations [15]. In the case of the latter, we have often heard reports of individuals with autism showing no outward signs of pain from a ruptured appendix or a ruptured eardrum.

Behavioral

Research on behavior modification, often referred to as Applied Behavior Analysis, has received a great deal of empirical support since the early 1960s. Thousands of studies have supported its validity and effectiveness, and research over the past 20 years has focused primarily on optimizing this behavior-based intervention. More recently, researchers in other areas, especially those studying medical comorbidities, have been interested in understanding the relationship between specific medical problems and challenging behavior [16]. When medical issues underlie or contribute to behavior problems, the treatment of choice would involve a medical-behavioral intervention rather than treating only the behavior.

Future Research

The majority of studies in the field of autism have focused on one aspect of autism—for instance, genetics, metabolism, immunology, GI function, or sensory processing—and researchers typically do not examine how these systems interact with one another. Funding agencies are urged to support multidisciplinary studies in order to obtain a clear picture of autism rather than relying on an incomplete mosaic.

Research is also needed to categorize autism into specific subgroups. Once this is accomplished, researchers can focus on examining homogeneous population samples. This will undoubtedly expedite the discovery of the underlying cause(s) of each subtype as well as help determine the most effective interventions for each group.

Although progress has been made over the past 75 years, there is still much to be learned about the underlying biology of autism. The more we discover about the roots of this disorder, the better we will be able to address the needs of individuals with ASD and the families who care for them.

1. Anderson G.M. Autism biomarkers: challenges, pitfalls, and possibilities. Journal of Autism and Developmental Disorders, 2015, vol. 45, pp. 1103—1113.
2. Baio J., Wiggins L., Christensen D.L. et al. Center for Disease Control and Prevention. Prevalence of autism spectrum disorder among children aged 8 years — Autism and developmental disabilities monitoring network, 11 sites, United States, 2014. // Surveillance Summaries, 2018, vol. 67, pp. 1—23.
3. Barnhill K.M., Winter H.L. Autism, water, and constipation. Autism Research Review International, 2016, vol. 30, pp. 3—6.
4. Bauman M.L., Kemper T.L. Neuroanatomic observations of the brain in autism: a review and future direction. International Journal of Developmental Neuroscience, 2005, vol. 23, pp. 183—187.
5. Bilbo S.D., Block C.L., Bolton J.L. et al. Beyond infection — maternal immune activation by environmental factors, microglial development, and relevance for autism spectrum disorders. Experimental Neurology, 2018, vol. 229, pp. 241—251.
6. Casanova M.F. The neuropathology of autism. Brain Pathology, 2007, vol. 17, pp. 422—433.
7. Casanova M.F. The minicolunopathy of autism: a link between migraine and gastrointestinal symptoms.
8. Medical Hypotheses, 2008, vol. 701, pp. 73—80.
9. Casanova M.F. The neuropathology of autism. In F. Volkmar, K. Pelphrey, R. Paul, S. Rogers (eds.) Handbook of Autism and Pervasive Developmental Disorders, 4th edition. New York: Wiley, 2014. Pp. 497—531.
10. Casanova M.F. The neuropathology of autism. In S.H. Fatemi (ed.) The Molecular Basis of Autism. New York: Springer Science, 2015. Pp. 153—171.
11. Casanova M.F., El-Baz A.S., Kamat S.S. et al. Focal cortical dysplasias in autism spectrum disorder. Acta Neuropathologica Communications. 2003, vol. 1, no. 67. doi:10.1186/2051-5960-1-67
12. Casanova M.F., Pickett J. The Neuropathology of Autism. In M.F. Casanova, A. El-Baz, J.S. Suri (eds.) Imaging the Brain in Autism. New York: Springer Science, 2003. Pp. 27—44.
13. Dawson G., Sun J.M., Davlantis K.S. et al. Autologous cord blood infusions are safe and feasible in young children with autism spectrum disorder: results of a single-center phase I open-label trial. Stem Cells Translational Medicine, 2017, vol. 6, pp. 1332—1339.
14. DuBois D., Ameis S.H., Lai M.C., Casanova M.F., Desarkar P // International Journal of Neuroscience. 2016. Vol. 52. P. 104—111.
15. Dykens E.M., Lense M. Intellectual disabilities and autism spectrum disorder: a cautionary note. In D.G. Amaral, G. Dawson, D.H. Geschwind (eds.) Autism Spectrum Disorders. —Oxford: Oxford
16. University Press, 2011. Pp. 263—269.
17. Edelson S.M. Internal sensory stress and discomfort/pain. Autism Research Review International, 2016, vol. 30, pp. 3—7.
18. Edelson S.M., Johnson J.B. (eds.) Understanding and treating self-injurious behavior in autism. — London: Jessica Kingsley Press, 2016. 304 p.
19. Finegold S.M., Molitoris D., Song Y. et al. Gastrointestinal microflora studies in late-onset autism. Clinical Infectious Diseases, 2002, vol. 35 (Supplement 1), pp. S6—S16.
20. Fombonne E. Epidemiology of pervasive developmental disorders. Pediatric Research, 2009, vol. 65, pp. 591—598.
21. Fox-Edmiston E., Van de Water J. Maternal anti-fetal brain IgG autoantibodies and autism spectrum disorder: current knowledge and its implication for potential therapies. CNS Drugs, 2015, vol. 29,
22. pp. 715—724.
23. Frye R.E., Casanova M.F., Fatemi S.H. et al. Neuropathological mechanisms of seizures in autism spectrum disorder. Frontiers in Neuroscience, 2016, vol. 10. doi: 10.3389/fnins.2016.00192
24. Fusar-Poli L., Brondino N., Rocchetti M. et al. Diagnosing ASD in adults without ID: accuracy of the ADOS-2 and the ADI-R. Journal of Autism and Developmental Disorders, 2017, vol. 47, pp. 3370—3379.
25. Hatfield T.R., Brown R.F., Giummarra M.J., Lenggenhager B. Autism spectrum disorder and interoception: abnormalities in global integration? Autism: the international journal of research and practice, 2017, pp. 1—11. doi: 10.1177/1362361317738392
26. Havdahl K.A., Bishop S.L., Suren P. et al. The influence of parental concern on the utility of autism diagnostic instruments. Autism Research, 2017, vol. 10, pp. 1672—1686.
27. Hoffman K., Weisskopf M.G., Roberts A.L. et al. Geographic patterns of autism spectrum disorder among children of participants in Nurses’ Health Study II. American Journal of Epidemiology, 2017, vol. 186, pp. 834—842.
28. Holingue C., Newill C., Lee L.C. et al. Gastrointestinal symptoms in autism spectrum disorder: a review of the literature on ascertainment and prevalence. Autism Research, 2018, vol. 11, pp. 24—36.
29. Hutsler J.J., Casanova M.F. Cortical construction in autism spectrum disorder: columns, connectivity and the subplate. Neurology and Applied Neuropathology, 2016, vol. 42, pp. 115—134.
30. Jyonouchi H. Autism spectrum disorders and allergy: observation from a pediatric allergy/immunology clinic. Expert Review of Clinical Immunology, 2010, vol. 6, pp. 397—411.
31. Jyonouchi H., Geng L., Davidow A.L. Cytokine profiles by peripheral blood monocytes area associated with changes in behavioral symptoms following immune results in a subset of ASD subjects: an
32. inflammatory subtype? Journal of Neuroinflammation, 2014, vol. 11, issue 187. doi:10.1186/s12974-014-0187-2
33. Kanner L. Autistic disturbances of affective contact. Nervous Child, 1943, vol. 2, pp. 217—250.
34. Katz T., Shui A.M., Johnson C.R. et al. Modification of the children’s sleep habits questionnaire for children with autism spectrum disorder. Journal of Autism and Developmental Disorders, 2018, vol. 48, pp. 2629—641.
35. Khakzad M.R., Javanbakht M., Soltanifar A. et al. The evaluation of food allergy on behavior in autistic children. Reports on Biochemistry and Molecular Biology, 2012, vol. 1, pp. 37—2.
36. Krajmalnik-Brown R., Lozupone C., Kang D.W., Adams J.B. Gut bacteria in children with autism spectrum disorders: challenges and promise of studying how a complex community influences a complex disease. Microbial Ecology in Health and Disease, 2015, vol. 26. doi:10.3402/mehd.v26.26914
37. Kumar P., Malhotra S., Kaur N. et al. Correlation between viral infections and autism: an overview. Dehli Psychiatry Journal, 2014, vol. 17, pp. 401—12.
38. Kushak R.I., Lauwers G.Y., Winter H.S. et al. Intestinal disaccharidase activity in patients with autism: effect of age, gender, and intestinal inflammation. Autism: the international journal of research and practice, 2011, vol. 15, pp. 285—94.
39. Landrigan P.J., Fuller R., Hu H. et al. Pollution and global health —n agenda for prevention. Environmental Health Perspective, 2018, vol. 126, issue 8. doi:10.1289/EHP3141
40. Lee B., Lee K., Panda S. et al. Nanoparticle delivery of CRISPR into the brain rescues a mouse model of fragile X syndrome from exaggerated repetitive behaviours. Nature Biomedical Engineering, 2018, vol. 2, pp. 497—07.
41. Loomes R., Hull L., Locke W.P. et al. What is the male-to-female ratio in autism spectrum disorder? A systematic review and meta-analysis. Journal of American Academy of Child & Adolescent Psychiatry, 2017, vol. 56, pp. 466—74.
42. Mahler, K.J. Interoception: the eighth sensory system. —enexa: AAPC Publishing, 2017. 184 p.
43. McDonald M.E., Paul J.F. Timing of increased autistic disorder cumulative incidence. Environmental Science & Technology, 2010, vol. 15, pp. 2112—118.
44. Miller L.J., Misher K. Sensory processing disorder and self-injurious behavior. In S.M. Edelson, J.B. Johnson (eds.) Understanding and treating self-injurious behavior in autism. London: Jessica Kingsley Press, 2016. Pp. 138—50.
45. Muskens J.B., Velders F.P., Staal W.G. Medical comorbidities in children and adolescents with autism spectrum disorders and attention deficit hyperactivity disorders: a systematic review. European Child & Adolescent Psychiatry, 2017, vol. 26, pp. 1093—103.
46. Ratajczak H.V. Theoretical aspects of autism: biomarkers — review. Journal of Immunotoxicology, 2011, vol. 8, pp. 80—4.
47. Rimland, B. Infantile autism. New York: Appleton-Century-Crofts, 1964.
48. Shelton J.F., Geraghty E.M., Tancredi D.J. et al. Neurodevelopmental disorders and prenatal residential proximity to agricultural pesticides: the CHARGE study. Environmental Health Perspectives, 2014, vol. 122, issue 10, pp. 1103—109. doi:10.1289/ehp.1307044
49. Supekar K., Menon V. Sex differences in structural organization of motor systems and their dissociable links with repetitive/restricted behaviors in children with autism. Molecular Autism, 2015, vol. 6, no. 50. doi:/10.1186/s13229-015-0042-z
50. Tharner A., Jansen P.W., Kiefte-de Jong J.C. et al. Bidirectional associations between fussy eating and functional constipation in preschool children. The Journal of Pediatrics, 2014, vol. 166, pp. 91—96.
51. Tychele N., Turner B.P., Coe D.E. et al. Genomic Patterns of De Novo Mutation in Simplex Autism. Cell, 2017, vol. 171, issue 3, pp. 710—22. doi:10.1016/j.cell.2017.08.047
52. Vaccarino F.M., Smith K.M. Increased brain size in autism —what it will take to solve a mystery. Biological Psychiatry, 2009, vol. 66, pp. 313—15.
53. Volk H.E., Hertz-Picciotto I., Delwiche L. et al. Residential proximity to freeways and autism in the CHARGE study. Environmental Health Perspectives, 2011, vol. 119, pp. 873—77.
54. Von Ehrenstein O.S., Aralis H., Cockbum M. et al. In utero exposure to toxic air pollutants and risk of childhood autism. Epidemiology, 2014, vol. 25, pp. 851—58.
55. Weintraub K. The prevalence puzzle: autism counts. Nature, 2011, vol. 479, pp. 22—4.
56. Williams E.L., Casanova M.F. Potential teratogenic effects of ultrasound on corticogenesis: implications for autism. Medical Hypotheses, 2010, vol. 75, pp. 53—8.
57.