Autism Spectrum Disorders

1. Autism Spectrum Disorders Jess P. Shatkin, MD, MPH Vice Chair for Education NYU Child Study Center New York University School of Medicine

2. Pervasive Developmental Disorders • PDDs are characterized by severe and pervasive impairment in several areas of development: • Reciprocal social interaction skills • Communication & language skills • The presence of stereotyped behavior, interests and activities • Generally evident within the first few years of life • Often associated with MR and/or a diverse group of medical conditions (e.g., chromosomal abnormalities, congenital infections, structural abnormalities of the CNS, etc.)

3. Learning Objectives Participants will be able to: • Name the 3 diagnostic domains of Pervasive Developmental Disorders • Identify 2 major distinguishing factors between Autistic Disorder and Asperger’s Disorder • Name 3 commonly comorbid psychiatric conditions and 3 commonly comorbid general medical conditions • Identify the key prognostic indicator for Autism • Describe 3 effective treatments for Autism • Describe the primary learning difficulties found in children with pervasive developmental delays

4. The History of Autism • Autistic children were historically believed to be schizophrenic • In 1943 Leo Kanner (Hopkins) described 11 cases of what he termed “early infantile autism,” noting ways in which it was distinctive from psychosis/schizophrenia • Kanner’s (unfortunate) choice of the word “autism” was meant to convey the unusual self-centered quality of these children (following Bleuler) • Although many of Kanner’s observations have lasted, his speculations about certain aspects of the illness (e.g., normal IQ, lack of association with other medical conditions, poor parenting/education) have been proven incorrect

5. The History of Asperger’s Syndrome • In 1944 Hans Asperger (in Austria) proposed a novel concept, autistic psychopathy (coincidentally using the same word as Kanner) based upon his observations of 4 children, which resembled Kanner’s concept in some ways • Now known as Asperger’s (a term coined by Lorna Wing in England) to avoid the use of the word psychopathy and to separate it from general autism • Asperger’s Syndrome has been better described in the European literature; these children in the U.S. have generally been diagnosed with high functioning autism

6. Historical Myths about Autism • Children with autism never make eye contact, show affection, or smile • Inside a child with autism is a normal child (or genius) waiting to emerge • Children with autism don’t speak, but they could if they wanted to • Children with autism don’t relate to peers & adults and don’t want friends • Children with autism are manipulative & selfish • Autism is an emotional disorder • Autism can be outgrown; or progress means a child is not autistic

7. Autistic Disorder • The best studied of the PDDs (DSM III in 1980) • Better definitions have been hindered by continuity w/other disorders, the broad range of syndrome expression, changes in syndrome expression w/age, high frequency of autistic-like symptoms in those w/MR, & the relative infrequency of this disorder • In most cases there is no period of unequivocally normal development (although 20% of parents report normal development for first 1-2 yrs of life)

8. What We Know About Autism • Autism is a biological disorder with multiple etiologies • No single cause, no single cure • No biological marker • No evidence of parenting defects or emotionally induced autism (e.g., the “refrigerator mother”) • Currently, the view is that some factor(s) act through one or more mechanism to produced a final common pathway of CNS insult that results in the behavioral syndrome of autism

9. Current Research into Etiology • Abnormalities in the genome • Chromosome 15q11-q13 is implicated based upon twin & family studies (re: PWS & Angelman) • Mechanisms underlying the expression of these abnormalities during brain development • Resulting structural and functional abnormalities in the brain • Behavioral expressions of autism

10. The Autism Gene • Numerous possible genes and chromosomal regions have been identified: • FXR1 (20 – 60% of affected kids are autistic) • 15q11-13 • 17q11-21 • SHANK3 (chromosome 22) • Copy Number Variations (CNVs)

11. Mirror Neurons • In monkeys, MNs are found in the inferior frontal gyrus and inferior parietal lobule. These neurons are active when monkeys perform a task or watch someone perform a similar task. A similar system is theorized to exist in the human brain. • These neurons are theorized to be important for understanding the actions of others and for learning new skills by imitation. • The most basic social brain system. • The mirror system may simulate observed actions and thus contribute to our Theory of Mind skills. • fMRI studies have now demonstrated decreasing activity (presumed MN activity) in the inferior frontal gyrus (pars opercularis) in humans with autism

12. Mirror Neurons

13. Monkey See, Monkey Do…Monkey Feel?

15. Amygdala • The amygdala (“almond”) is thought to have many important roles, including fear conditioning, memory consolidation, and in the generation of important emotional responses, which help the brain to process memories that are key to social learning • The amygdala has long been suspected as a source of some concern in autism • More recently, David Amaral at the UC Davis MIND Institute (Journal of Neuroscience, 2006) found that men and boys with autism have fewer neurons in the amygdala • One possibility is that there are always fewer neurons in the amygdala of people with autism. Another possibility is that autism is a degenerative process occurs later in life and leads to neuron loss.

16. However: Prior Amygdala Research • Prior research had demonstrated larger amygdala structures among children with autism; larger right amygdala volume has been associated with more severe social and communicative impairments in autistic 3 and 4 year olds. • This is predictive of a more severe clinical course and worse social/communicative outcome at the age of 6. (Munson et al., 2006). • Early studies of post-mortem evaluation among adults with autism found higher cell density in amygdala (Rapin & Katzman, 1998)

17. Implications of Amygdala Damage • Subjects are non-autistic individuals with unilateral or bilateral amygdala damage • Delivered questions about both basic emotions (‘‘Is it happy, sad, etc.?’’) and social emotions (‘‘Is it flirtatious,guilty, etc.’’). • Amygdala damage impairs recognition of complex mental states more than it does basic emotions, though both are affected • The impairment was evident when participants were presented with both full faces and only the eyes, an effect observed in autism (Adolphs et al., 2002).

18. Implications of Amygdala Damage (2)

19. “Judging the mind in the eyes” • Mentalizing task: participants had to decide for each stimulus which of two simultaneously presented words best described what the person in the photograph was feeling or thinking • Adults with HFA or AS with intelligence in a normal range show impairments in this task (Baron-Cohen, et al, 1997). • Cognitive Phenotype? Parents of children with AS were significantly less accurate at the task, indicating that certain cognitive qualities may be inherited (Baron-Cohen & Hammer, 1997).

20. Results: “Judging the mind in the eyes” • Adults with HFA or AS showed significantly less amygdala activation during the task • The autism group activated the frontal lobes less extensively than controls and did not activate the amygdala at all • Control group showed especially powerful response in left amygdala, which may be extensively involved in emotional processing • Autistic group had more processing activity in the temporal lobe, which is responsible for verbally labeling complex visual stimuli and processing faces and eyes • Compensation? (Baron-Cohen et al., 1999). • Control group only activation: yellow • Autistic group only activation: red • Coincidental activation: blue

21. Amygdala: Putting It All Together • Most recent theories suggest that social fear in autism may initially trigger a hyperactive, abnormally enlarged amygdala, which eventually gives way to a toxic adaptation that kills amygdala cells and shrinks the structure (Davidson, 2006) • In Davidson’s recent study, those in the autism group who had a small amygdala were significantly slower at identifying happy, angry, or sad facial expressions and spent the least time looking at eyes relative to other facial regions. Autistic subjects with the smallest amygdalae took 40 percent longer than those with the largest fear hubs to recognize such emotional facial expressions, and those with the largest amygdalae spent about four times longer looking at eyes than those with the smallest. Eye fixation did not correlate with amygdala volume among 24 control subjects. • In a related study, another research team led by Davidson found that well siblings of people with autism share some of the same differences in amygdala volume, and in the way they look at faces and activate social/emotional brain circuitry, particularly an area critical for face processing

22. Cerebellar Findings • Smaller number of Purkinje cells • The cerebellum is one of the brain's busiest computational centers, and the Purkinje cells are critical elements in its data-integration system. • At birth the brain of an autistic child is normal in size. But by the time these children reach 2 to 3 years of age, their brains are much larger than normal. This abnormal growth is not uniformly distributed. • Using MRI, Courchesne et al identified that both gray matter of the cerebral cortex and white matter account for this mushrooming in size. • One theory: The proliferation of connections projecting to and from the cerebral cortex and other areas of the brain, including the cerebellum, may cause signal overload that injures the Purkinje cells and ultimately kills them. 

23. The Basal Ganglia • “An obsessive desire for the maintenance of sameness.” (Kanner, 1943) • Stereotyped, ritualistic, repetitive motor behaviors and difficulties with environmental changes are phenomenologically similar to OCD and TS • Contrast “passion” or “desire” with feeling compelled • Functional and structural abnormalities of BG are present in these disorders, specifically the caudate (Hollander et al., 2005; Sears et al., 1999)

25. Right caudate volume 10% greater in autistic individuals. • Volume of the right caudate correlated with repetitive behaviors as measured by the Autism Diagnostic Interview Repetitive Behavior (ADI-C) domain total score (Hollander et al., 2005).

26. Oxytocin in Autism Oxytocin is synthesized in the hypothalamus and released via the posterior pituitary It is released peripherally (milk letdown & uterine contractions) and centrally (acts as a neuromodulator along with arginine vasopressin) There is some data to suggest that oxytocin has a role in social and repetitive behaviors (possibly involved in Tourette’s, OCD, and autism) Green & Hollander, 2010

27. Visual Research Data • It has long been know that autistic individuals have trouble with face recognition • As the following photos show (from the movie Who’s Afraid of Virginia Wolf?), autistic individuals demonstrate difficulties in following the salient facial features in others and the social context of situations (Klin et al, 2002).

28. Who’s Afraid of Virginia Woolf? • 1966 adaptation of Edward Albee’s play, staring Richard Burton and Elizabeth Taylor • They play a New England academic couple, whose marriage hangs by a thread • George Segal and Sandy Dennis play a young, new to campus unsuspecting couple, who come over for drinks after a faculty party • This movie was selected by Fred Volkmar and Ami Klin at the Yale CSC to study visual tracking in autistic individuals vs. non-autistic

33. The Fusiform Gyrus (1)

34. The Fusiform Gyrus (2) • The fusiform gyrus lies under the temporal lobe • There has long been a debate: Is the fusiform gyrus only a facial recognition area, or is it a general recognition area? It turns out that the FG is a general recognition area for things that people enjoy or like • For me, it lights up for guitars • For an autistic kid it might light up for whatever they’re passionate about • In the clips you’ve just seen of “Virginia Woolf,” effectively 90% of information comes from the eyes (not the mouth where autistics tend to look) • Groups of autistic individuals viewing “Virginia Woolf” fall into three groups: (1) The most impaired individuals look at everything/anything and are highly disorganized; (2) the moderately impaired individuals look at objects in the room; and (3) the higher functioning individuals look at mouths • Autistics tend to lack the facial inversion effect (that is, most individuals by 6 months of age are better at recognizing faces when presented right-side up); but autistics never achieve it and thereby recognize faces equally well right-side up or upside down

36. Visual Research Data (2) • In non-autistic children the fusiform gyrus is activated in response to a human face • In autistic children this activation is normal when shown pictures of their mothers but diminished when shown pictures of strangers • This may suggest that autistic individuals can be trained to learn better face recognition, thereby improving social skills

37. Brain Size and Growth • The brains of autistic individuals have long been suspected to be larger than non-autistic • More recent work (Courchesne, 2003) has demonstrated that at birth children with autism had smaller heads than non-autistics but then showed sudden and excessive growth from 1-2 months and 6-14 months • By adolescence the brain size had normalized • There appears to be an increase in the quantity of white matter in the brains of autistic children along with growth in the cerebellum (purkinje cells)

38. Vaccines • Measles, Mumps, Rubella vaccine (MMR) is given at 1 year (12-15 months) and booster at 4/5 years before school • Wakefield in the UK suggested in 1998 that MMR might cause autism b/c of a small number of cases (8 of 12) who had severe GI problems along with autistic/behavioural symptoms • Subsequent time trend analyses in the UK and California have shown that while the number and percent of MMR vaccinations have not changed, the number of cases of PDD/autism has grown by 7+ fold. • Numerous studies out of Japan have documented that even though the MMR vaccine was used only between 1989 and 1993, there has been no change in the number of cases of PDD/autism. • A very large retrospective cohort study of all children born in Denmark between 1991-98 (over ½ million) found no correlation between autism/PDD and MMR • A 2001 U.S. Institute of Medicine study confirmed no connection between MMR and PDD.

39. Diet • The theory is that some kids with PDD will show symptom improvement when gluten (found in wheat products) and casein (found in dairy products) are removed from their diet. The hypothesis states that G and C may be difficult for these kids to digest and that metabolites of this problematic digestion may include opioid like substances (far in excess of what you would expect to find due to CNS opioid production alone). • Opioids can be tested for in the urine, and some PDD children with self-injurious behavior have been found to have higher levels of opioids in their urine. • One problem with this theory is that naltrexone (an opioid blocker) is not generally helpful for these kids • 8 studies available for review, 6 of which were open, and 1 of which used a single blind approach and 1 of which used a double blind (but no placebo) approach (and only included 15 kids); all open and single blind studies reported improvement; DB study demonstrated no group effect, although some parents noted improvement. Need larger randomized DBPC trials to determine real effect.

40. Autism is a spectrum disorder • No good measure of “how autistic” someone is • Usually related to cognitive skills (roughly ½ – ¾ are MR; the relationship between cognitive and adaptive function [as determined by a Vineland/AAMR inventory] is vital & is often a useful starting point for interventions) • Autism is usually a retrospective diagnosis • Developmental history is vital to diagnosis • Because the natural course of autism is toward improvement, we may misdiagnose autistic adolescents and adults b/c we don’t obtain an adequate retrospective history (and they’ve shown some improvement)

41. Autism is a Developmental Diagnosis • Autism must be viewed developmentally: • The greatest hallmark is “inconsistency in development” (e.g., regressions, spurts, delays, greater variation in transition from one stage of development to the next) • A common referral notes: “he began to speak and then stopped”

42. Normal Developmental Oddities • Spinning • Toe Walking • Strobe Lighting • Odd/rigid food preferences • Dislike of labels and seams • Take Home Point: Many autistic symptoms are developmentally “normal”

43. Autism is a Developmental Diagnosis (2) • Signs and symptoms are related to chronological and mental age • Two Types of Onset: • Symptoms present in the first year of life (most cases) *Many of these children will fail to initiate baby games with parents at 4-6 months (e.g., peek-a-boo, giggling interactions, etc.) *These children may also not communicate common emotions well (e.g., pain, hunger) • Apparent normal development for the first 12 – 24 months of life prior to the onset of symptoms

44. Epidemiology • Autism is ubiquitous, occurring all over the world • Current CDC estimates 1:100 (2009) • Delays in diagnosis result in an average of at least 1.5 years from the time parents first reported odd speech problems or other social deficits, typically around the age of 3. • Kogan et al reported 1:91 with a gender ratio of 4:1 male to female • Nearly 40% of those ever diagnosed did not currently have the condition • Parent survey of 78K, US children aged 3 – 17 years, a child was considered to have ASD if parent reported that a doctor or other health care provider had said the child had ASD and that the child currently had the condition • Are increasing numbers real or just the result of “switching” diagnoses (e.g., reduced numbers of LD and MR)?

45. Epidemiology (2) • Male to female ratio varies but is generally somewhere between more than 1:1 and up to 4+:1 • Familial patterns are well established • One study reports that each subsequent child born into a family with an autistic child has a 8-9% chance of having autism (100 – 200x greater risk than the general population) • Twin studies show 60 –85% concordance for identical twins vs. 10% concordance for fraternal twins

46. Epidemiology (3) • Population based study of all 7- to 12-year-old children (N=55,266) in a South Korean community; the study used a high-probability group from special education schools and a disability registry and a low-probability, general-population sample from regular schools. • Autism Spectrum Screening Questionnaire for systematic, multi-informant screening; parents of children who screened positive were offered comprehensive assessments using standardized diagnostic procedures. • Prevalence of ASDs was estimated to be 2.64% (95% CI=1.91–3.37) or 1 in 38, with 1.89% (95% CI=1.43–2.36) in the general-population sample and 0.75% (95% CI=0.58–0.93) in the high-probability group; M:F ratios were 2.5:1 (gen pop) and 5.1:1(high-prob); ratio of autistic disorders to other ASD subtypes were 1:2.6 (gen pop) and 2.6:1 (high-prob) • 12% in the general-population sample had superior IQs, compared with 7% in the high-probability group; and 16% in the general-population sample had intellectual disability, compared with 59% in the high-probability group. • Two-thirds of ASD cases in the overall sample were in the mainstream school population, undiagnosed and untreated. • Kim et al, 2011

47. Associated Illnesses • Autism frequently occurs in association with other illnesses: • MR (most common coexisting disorder; Fragile X is MCC [5 – 15%]; Downs not uncommon) • Epilepsy • Developmental Syndromes • Turners, Tuberous Sclerosis • Metabolic Disorders (e.g., PKU) • ADHD • Obsessive/Compulsive Disorder • Depression & Anxiety (esp in higher functioning) • Other psychiatric disorders (e.g., psychosis)

48. Phenotype: Social Interaction • Younger children may have little or no interest in establishing friendships • Older individuals may have an interest in friendship but lack an understanding of social conventions and how to interact • Often an individual’s awareness of others is markedly impaired, demonstrating no concept of the needs & interests of others (e.g., happiness, distress, etc.), appearing oblivious to other children (including siblings)

49. Phenotype: Communication • When speech does develop, pitch, intonation, rate, rhythm, or stress may be abnormal (e.g., monotonous, inappropriate to context, or with question-like rises at the end of sentences) • Grammatical structure is often immature, stereotyped (e.g., repeating jingles), or idiosyncratic • Comprehension is often delayed • Disturbance in pragmatic/social use of language is evidenced by an inability to integrate words with gestures or understand humor and non-literal speech/irony/implied meanings • Imaginative play is often absent or markedly impaired

50. Phenotype: Stereotyped Behaviors and Activities • “Insistence on sameness” • Insistence on nonfunctional routines or rituals • demonstrating resistance and/or distress over trivial changes (e.g., a new driving route to school) • A markedly restricted range of interests • Stereotyped body movements & postural abnormalities • Preoccupation with parts of objects • Fascination with movement • Highly attached to inanimate objects