1. Autism Spectrum Disorder

2. DSM-V Criteria
Criterion A: Persistent deficits in social communication and interaction
Can include social-emotional reciprocity, nonverbal communicative behaviors, developing/maintaining relationships
Criterion B: Restricted, repetitive patterns of behavior
Repetitive motor movements (rocking), ecolalia, insistence on sameness and a routine, highly restricted, fixated interests, unusual interest in sensory aspects of the environment
Symptoms must be present in early developmental period and cannot be better explained by intellectual disability or global developmental disability
3 levels of severity
Viewed as a dimensional disorder
Specifiers for each criterion
Behaviors fitting criterion A: problems w/back and forth conversation, sharing emotion, responding to social interaction, poor nonverbal communication, problems maintaining or understanding eye contact and other body language, difficulty in imaginary play, making friends, absence of interest in peers
Specify with or without intellectual disability (often with, not always)
Needing support, substantial support, or very substantial support (high/medium/low functioning)
There’s been some work to subtype kids, but anything meaningful is explained by IQ
Dimensionality helps linking with biology
Relationship b/t IQ and symptom severity,

3. Secondary Features Intellectual disability Motor disabilities
Often large discrepancies in abilities in high functioning kids
Motor disabilities
Odd gait, clumsiness, walking on tiptoes
Self-injury
Inattention
Disruptive behavior
Catatonia
Possible, not particularly common
Most likely during adolescent years

4. Controversy
DSM-IV included categories for Autism, Pervasive Development Disorder NOS, High Functioning Autism, and Asperger’s Syndrome
Sevin et al (1995) studied 34 kids with autism and PDD-NOS. Did not find discrete categories.
Categories were collapsed into Autism Spectrum – PDD-NOS, HFA, and AS now “on the spectrum”
Concern about retaining diagnoses, receiving services, stigma
PDD-NOS – like autism but don’t clearly fit into the old category. Atypical or subthreshold symptoms
HFA – not with intellectual disability or requiring substantial support. Just odd social behavior and repetitive behaviors, can function alone. No cognitive issues, really, but they do have delayed motor milestones
Asperger’s Syndrome – even higher than HFA kid, just “socially awkward.” Facial expression, prosody, social gestures deficient but nothing else

5. Controversy Intent was NOT to remove anyone’s diagnosis
Will actually help some higher functioning kids get services
Everyone should convert to Autism Spectrum with specifications if criteria used correctly
DSM-IV included category for communication difficulty
This is covered by DSM-V criteria A and B. Separate category was not needed

6. DSM-V Schematic Genetics Core Symptoms Biological Substrate
Unknown
Core Symptoms
Social Deficits
Restricted, repetitive behaviors
Biological Substrate
Unknown
Secondary Symptoms
Intellectual, motor disabilities
Self-injury
Inattention/Disruptive Behavior
Catatonia

7. Assessment – ADI-R
Gold Standards are Autism Diagnostic Interview – Revised (ADI-R) and Autism Diagnostic Observation Scale (ADOS)
ADI-R is semi-structured interview for caregivers
93 items, about 2 hours
Based on DSM-IV criteria (Communication difficulties, social reciprocity, restricted, repetitive behaviors)
Chakrabarti and Fombonne (2001) found that interrater reliability was excellent on those subscales

8. Assessment - ADOS Observational
Can be used in nonverbal 2-year-olds – verbal adults and all between
4 Modules:
Pre-Verbal-Single Words
Phrase speech
Fluent Speech
Activities for daily living, plans, hopes

9. Psychometric Issues in Diagnosis
Low test-retest reliability on many instruments
Little investigation of specificity or validity of screening measures
Lack sensitivity and specificity
Severity scores quantifying social deficits needed
Sometimes alternative thresholds are suggested for research vs clinical diagnoses
Children of color or of less-educated parents less likely to receive ASD diagnosis than Caucasian kids or kids with well-educated parents (Mandell et al 2009)

10. Psychometric Issues in Diagnosis
In a study of children with language disorder, both the ADOS and ADI-R were administered to children
Studied 21 children ages 6-9
Correlation between instruments low (Bishop 2011)
Χ^2 (4) = 1.86, p= .762
----- Meeting Notes (10/28/14 20:06) -----
Chi squared - distributions of categorical data sig different or not? (ASD diagnosis or not)

11. Social Problems Most universal, specific characteristic of ASD
Consistent and replicated across studies
Lack joint attention, theory of mind
Cannot correctly assign motives, understand someone’s goals, difficulty participating in spontaneous symbolic play
Other groups show problems with theory of mind but may not show same deficits in joint attention
Down Syndrome, severe hearing impairment
Pay proportionately less attention to people than objects
Spend less time than TD kids doing something that shows intent
Children are attached to mothers as much as age- and IQ-matched TD kids (Rogers et al., 1991)
Tend not to point, show objects – attention-sharing behaviors (Sigman et al., 1986)
Do not seem to recognize emotions (facial expression, gesture, nonverbal vocalizations of emotion)
Range from aloofness, active and odd behavior, passivity, just not at all interested
*Toddler who doesn’t want to play with other kids
*Adult who’s never had a significant other
*Trouble understanding workplace roles, back and forth conversation, etc.
Will likely develop language but are never good at back-and-forth communication
Hobson 1986
Some people think they don’t form attachments, but they do
Joint Attention = person w/autism, another person, and object/event.
TOM = people have minds which differ from one’s own, one can learn from others by reading social signals and listening
(Lord & MaGill-Evans, 1995)
There is a DSM category for people with JUST these, no RRB’s – social communication disorder

12. Restricted, Repetitive Behaviors
Verbal and nonverbal repetitive, stereotyped behaviors
More heterogeneous and context-dependent than social deficits
Including them on diagnostic instruments increases specificity with little change in sensitivity
One study showed only 9 of 2700 children with ASD diagnosis did not show any RRB’s (Lord et al., 2012)
Interests – Heidi’s Charlie Brown kid. Symptoms must be present in childhood
Same thing to eat every day, certain activity only certain day a week,
Number and intensity at age 2 predictor of ASD diagnosis at age 9 (Lord et al 2006)
Predictive of parental stress, academic achievement
Longitudinal studies show that neither social deficits nor RRB’s account for each other, but they are correlated (about .5) - There may be something higher-level that accounts for both

13. Restricted, Repetitive Behaviors
Four subdomains:
Motor stereotypies – lining things up, flipping things, step counting, unusual responses to sensory input, rocking
Some of these may be common in young children – clinicians must look at the number and intensity of behaviors to discriminate TD from ASD
Tend to emerge early in life but are somewhat malleable
Most common subdomain
Rituals and sameness – like Rain Man’s pancake Tuesday
Prevalent in about 25% of ASD population
Develop later than motor type, stable throughout life
Circumscribed interests – highly fixated or unusual interests
A particular movie, cartoon character, topic, the phone book, shoe size
Self-injurious behavior – hand flapping, hitting
Present in other disorders
More common in ASD than general population
Subdomains show different trajectories
*found the trajectories noted but I don’t know much about them

14. Language Delay Language delay is not specific to ASD
Delays in receptive language may be specific to ASD as opposed to other communication disorders (Philofsky, Hepburn, Hayes, Hageran, & Rogers 2004)
Not yet connected to specific neurobiological problem
Language (particularly receptive language) scores correlate with IQ (specifically verbal) (Luyster et al., 2008)

15. Prevalence
In 1990’s it was 1 per 2,000, including Asperger’s Syndrome 1 per 1,000 (Tanguay 2000)
Current prevalence rates around 1/150 to 1/100 for ASDs (Croen et al., 2002, Rice, 2009)
True increase in milder cases
True increase of all case types
More awareness
Problems with diagnostic instruments
Incorrect diagnoses
Studies differ in screening methods, diagnostic instruments, diagnostic criteria
Diagnosed 4x as often in males than females
We don’t know why – probably combination of listed reasons for increase in prevalence

16. Diagnostic Criteria
Projects using ICD-10 criteria show prevalence around 1/2,000 (Autism) and 1/600 (Autism plus other pervasive developmental disorders)
Studies using less strict criteria show much higher prevalence rates
Bryson et al., 1988, 1/1,000 Used ABC (checklist)
Sugiyama and Abe (1989) used DSM-III and noted 1/760
Ehlers and Gillberg (1993) set of criteria specifically designed to diagnose ASD found 1/143
ASD = autism spectrum disorder

17. Onset and Course
Symptoms are usually noted first in months of a child’s life
Delayed language, odd play patterns, lack of social interaction
Pay attention to type, frequency, intensity of symptoms
Can experience developmental plateaus or regression
Rarely a severe regression after 2 years of normal development
Onset must occur by age 3
Individuals generally improve throughout lives
Robust diagnosis
Sensitivity of .82 and specificity of .87 (Volkmar et al 1994)
Earlier if severe, later if subtle
Lack of interest in social interaction may come about in first year
Sensitivity = true positive (82% of autistic group diagnosed). Not many false negatives. Not missing many.
Specificity = true negative (don’t diagnose 87% of healthy group) Not many false positives

18. Common Comorbidities
70% of ASD individuals have one comorbid disorder, up to 40% may have 2 or more (DSM-V)
Medical conditions such as epilepsy and sleep problems somewhat common
Comorbid diagnoses of ADHD, anxiety and depressive disorders, and developmental coordination disorder seen
First degree relatives have higher incidence of major depression and social phobia than the rest of the population (Bolton et al., 1998)
Relatives have 20% frequency of social phobia (Smalley et al., 1995)
10 times higher than controls
Over half (64%) had first episode before the birth of autistic child

19. Common Comorbidities?
Posited that autism shared genetic cause and thus comorbidities with:
Fragile X (no more than 2-5% have FRA-X mutation, Bailey et al., 1993)
Tuberous sclerosis (mostly seen in autistic people with severe deficits, Guiterrez et al., 1998)
Celiac disease (Pavone et al., 1997 study of 120 people with celiac disease showed none with diagnosis of autism based on DSM-III, nor celiac disease in the 11 patients with autism)

20. Biological Contributions?

21. Genetics
Concordance rates in monozygotic versus dizygotic twins range from 60-91% (MZ), 0-10% (DZ) (Folstein and Rutter, 1977, Steffenburg et al., 1989, Bailey et al., 1995.)
Variation in behavioral and cognitive deficits as great within MZ pairs as between pairs
These findings suggest that autism is highly heritable (broad cognitive and social impairment)
Different sets of genes do not act to produce different symptoms
Tuberous sclerosis – root-shaped growth in the brain, number correlated w/degree of intellectual disability
If so, MZ pairs would be almost identical (identical genes)

22. Genetics
Gender disparity led some researchers to wonder if ASD linked to X chromosome
Hallmayer et al (1996) found no major gene effect on X chromosome causing autism
International Molecular Genetic Study of Autism Consortium (1998) found possible connections for regions on chromosomes 7 and 16
Significance is not yet known
Found most often in those with severe language delays
Normal on the right, abnormal on left (inverted)

23. Neuroligins and Neurexins
Neuroligins and neurexins are the “building blocks” of synapses
Small percentage of those with ASD have mutations which can cause neurexin deletions
This affects synaptic formation and function
May increase risk for developing ASD
Neurexins and neuroligins “shake hands” and form the synapse, crucial for function and connectivity. Presynaptic, generally. Building blocks for synapse
Neurexin – presynaptic protein, helps “glue together” neuron at synapse
Variability of genetic profiles in ASD kids tells us maybe there are distinct genetic disorders with overlapping phenotypes

24. Neuropharmacological Studies
Cook and Leventhan (1996) noted that serotonin may be involved in many of the symptoms of autism
This is neither surprising nor particularly helpful
One study found people with ASD have autoantibodies to brain serotonin receptors (Todd and Ciaranello, 1985)
Two studies failed to confirm findings
People with ASD may have increased 5-HT on blood platelets
Found increased serotonin levels on blood platelets

25. Electroencephalography
ASD people unlikely to show more EEG abnormalities than the normal population
This is nonspecific and not particularly helpful

26. Neuroimaging and Neuropathological Studies
General difficulty confirming neuroimaging findings
Different measures used to correlate with brain function, generally weak measures
Future studies will probably add comparisons of ADHD or language impairments to ASD
Increased volume in amygdala, hippocampus, and limbic system, decreased Purkinje cells
We don’t know how high functioning these individuals were
Harris et al. (2006) claimed to find abnormal patterns of activity in the brains of those with ASD and claimed near-perfect identification
This has not been replicated
Ongoing NIMH effort to form neurobiologically based dimensions to help diagnose ASD, but no published data yet
I could not access the Harris 2006 study.
Been super difficult to link any biological findings with symptoms due to only a small percentage of ASD pop with any given abnormality
One solution is to turn behavior (like criteria A and B) into dimensions and connect those with biological findings
Purkinje cells – GABA-ergic neurons

27. Macroencephaly
14-30% of ASD people have increase in head circumference (Fombonne et al., 1999)
Developed in early/middle childhood (Lainhart et al), but this finding relies on retrospective data
Increase is in temporal, parietal, and occipital lobes (not frontal)
Cause and effects of increase unknown
Not correlated with IQ, verbal ability, seizure, other mental illness
----- Meeting Notes (10/28/14 20:06) -----
Lack of appropriate pruning?

28. Yellow – white matter, enlarged in ASD

29. Red – smaller in ASD, Grey matter

30. Neuropsychological Patterns
Compared to normal controls, ASD people have intact or superior performance in attention, simple memory, simple language, and visual-spatial domains
Impaired in skilled motor tasks, complex memory, complex language, and reasoning
While interesting, not helpful in understanding much more about autism than is already known
Minshew et al 1997
33 participants – autistic w/normal intelligence and normal controls

31. Neuropsychological patterns
Executive functioning deficits
Impairments in cognitive flexibility and set-shifting
Nonspecific to autism
May underlie theory of mind deficits
Price et al., (1990) study of 2 individuals with widespread frontal damage (early in developmental process)
Both showed severe impairment in role-taking, also seen in ASD and is part of theory of mind
Flexibility =
Cog set shift =

32. Neuropsychological Patterns
20 ASD, 19 Down’s Syndrome kids, 20 TD kids
Two tasks:
Delayed Non-Matching to Sample
Rule-learning ability, visual recognition memory
Amygdala and hippocampus
Delayed Response
Working memory and response inhibition
Dorsolateral PFC
Social and nonsocial stimuli task
Actually Autistic and PDD-NOS, back w/DSM-III criteria, now would be ASD
Diagnosed w/CARS –
Non_Matching to Sample:
Shown a sample object, rewarded when they reached for it (reward underneath)
Waited 5 seconds. Did again but w/second object there too. Rewarded when they reached for that one Established criterion performance (5 in a row right, 15 max)
DV’s - # of errors made, # of trial required until reached criterion performance
Delayed Response
Experimenter hid a toy in a container at midline, then moved right or left
5 second delay, screen lowered, identical container put on opposite side (now 2 containers)
Side hidden reversed after 2 correct. Continued until 3 reversals or 14 trials
DV – % correct in reverse trials
No diff in average # of reversal trials
Social – calling name or clapping hands Nonsocial – rattle, jack in the box

33. This shows 1st task
Autistic kids sig worse than other groups – took more trials
Less time attending to social things than other groups
Suggests the structures tested implicated in autism (amygdala, hippocampus, dorsolateral PFC)

35. Vaccines

36. Vaccines
One study published in a medical journal concluded a link between vaccines (MMR) and autism
Article was fully retracted in 2010
Lead author Andrew Wakefield had many undeclared conflicts of interest and manipulated some of his data
Found guilty of serious medical misconduct and no longer allowed to practice medicine
Study has been disproved many times since its original publication in 1998

37. Vaccines
DeStefano et al (2013) evaluated 256 ASD kids and 752 TD kids matched on birth year and sex, ages 6-13
Confirmed diagnoses via ADI-R and ADOS
Study inclusion criteria required elevated scores on both assessments and onset before 36 months
Obtained vaccination histories,
Looked at total antigen exposure, amount per day
No significant differences
Birth-3 months, 7-months, 2-years
Latest published study disproving connection b/t vaccines and autism

38. Bimodal because of different vaccines

40. Environmental Factors
Mouridsen et al. studied 328 children with autism, “autism-like conditions,” or “borderline child psychosis”
Children with autism had greater incidence of births in March or August
Children with autistic-like conditions most often born in May and November
Essentially, this means nothing.
DSM-III criteria

41. Environmental Factors
Rutter 1998 study looked at institutionalized children in Romania sent to the UK
Experienced horrible living conditions
7/165 met criteria for autism based on a screening questionnaire
Severe social deprivation may lead to autistic-like social and emotional difficulties
Could less severe social deprivation interact with genes to cause autism in some kids or worsen symptoms?

42. Treatment

43. Medication
Tricyclics and SSRI’s seem to decrease hyperactivity, anger, and compulsive behaviors (Gordon et al., 1993, Brodkin et al., 1997)
Neuroleptics may be effective in reducing hyperactivity, impulsivity, aggressiveness (Potenza et al., 1999)
(Obviously)
Pharmacological interventions have a limited role

44. Medication Double-blind study of 40 kids, given placebo or haloperidol
Given semistructured interviews, rated by teachers on Connors Parent-Teach Questionnaire
While on haloperidol, kids showed significant decreases in withdrawl, hyperacitvity, abnormal object relationships, fidgetiness, negativeism, angry affect, and lability of affect as compared to baseline or placebo
Ages years
2 weeks placebo for baseline
Then either haloperidol/placebo/H or Placebo/H/P for four weeks each
Rating scale
Doses ranged from mg/day, started low and stopped when started seeing either positive or negative effects
----- Meeting Notes (10/24/14 21:25) -----
Again, talking about kids 2-6 getting neuroleptic!

45. Therapy The key is early intervention! Two types
This means developing specific measures is crucially important
Two types
Traditional behavior learning (ABA)
Focus is on adult control and child compliance, uses positive reinforcement
Social-pragmatic teaching (child-centered therapy, incidental teaching)
Focuses mainly on social skills
Focus of therapy is on increasing independence and quality of life
----- Meeting Notes (10/24/14 21:25) -----
Measures not sensitive nor specific, nor do they correlate with each other, and they can have different thresholds for research vs clinical
When kids are 18 months, key predictors of diagnosis of autism in later life are two or more:
Lack of pretend play
Lack of protodeclarative pointing
Lack of social interest/play
Lack of joint attention

46. Applied Behavior Analysis
Gold standard
Based on behaviorism
Uses positive reinforcement to decrease maladaptive and unwanted behaviors, increase adaptive behaviors
Uses negative reinforcement/negative punishment when necessary (rarely)
Treatment can begin when children are as young as 3
In severe cases, focus is on compliance
Intensive (20-40 hours/week), one-on-one format
Targets a wide range of skills
Includes parents (and important others when possible – siblings, teachers, etc.)

47. ABA Effect Size Metrics
Meta-Analysis of 22 studies (Virués-Ortega 2010)
Different outcome reported: full-scale IQ (18 studies), nonverbal IQ (9), receptive language (10), expressive language (9), language composite (5), adaptive behavior-communication (10), adaptive behavior – daily living skills (10), adaptive behavior – socialization (10), adaptive behavior – motor skills (3), overall composite adaptive behavior (14)
Mean age ranged from months
Some studies included PDD-NOS
Because:
Participants, actual therapy highly variable, studies use different metrics when reporting outcomes
Often single-subject design
Because so many outcome instruments were used they “Used effect sizes to obtain standardized measurements of the effect of the intervention on the outcome variable”
Effect sizes were corrected for sample size
Pooled correlational coefficient was estimated from studies in which data available to calculate pre-post correlation coefficients for a given outcome
Those were then applied to all studies reporting the outcome
For each outcome, pooled estimates and 95% confidence intervals of effect sizes calculated
2 or more studies available, sensitivity analysis done by restricting the analysis to control group designs
Separate for intervention model (general ABA vs UCLA, don’t know diff), and format (clinic based or parent managed)
Only effect sizes over .5 reported for brevity”
Rank ordered by length of intervention (hours), dose-response meta then done

48. ABA ABA positively impacted:
IQ – 1.19 no evidence of effect from intensity/duration
Nonverbal IQ – 0.67
Receptive language – 1.48
Expressive language – 1.47
General language skills – 1.07
Communication – 1.45
Daily living skills – 0.62
Socialization
Motor skills – 0.71
Adaptive behavior (composite score) – 1.09
ABA leads to long-term medium to high positive effect sizes for adaptive behaviors
Social support (siblings) moderate response (Hastings, 2003)
95% CI’s
IQ – , p<.001
Nonverbal IQ – p = .008
Receptive language – , p<0.001
Expressive language p<0.001 General language – , p = 0.004
Communication p<0.001
Daily living skills – , p < 0.001
Socialization – p<0.001
Motor skills p =0.008
Adaptive behavior composite – p<0.001

49. CBT CBT has been modified for ASD kids presenting with anxiety
Goal is to remediate social skills in the hopes that this will translate to decreased anxiety
Random assignment to 16 sessions of CBT or 3-month waitlist
CBT model emphasized adaptive behavior, parental training, school consultation
78% of CBT group had reductions in anxiety on Clinical Global Impressions-Improvement scale compared to 8.7% of waitlist
CBT did not reduce self-reports of anxiety
----- Meeting Notes (10/28/14 20:06) -----
Where we might come in as they'll go to ABA therapist probably, but we might do this and it's possible.

50. Virtual Interactive Environments
Used for teaching social skills, theory of mind
Practical situations, such as taking the bus, going to the grocery store
Some studies use robots (can play games with kids)
Interactions (eye gaze, tough, contact time) increase
Not yet known if this generalizes to real life
Opposite effect – more complacent/happy to stay with computer?
Allows children to role-play, practice skills in a safe environment, may promote greater insight into minds of others
Designed as part of larger problem – with an instructor working on skills

51. AIT – 10 hours of music to decrease irritability/hyperactivity
Complimentary and Alternative Medicine Therapies (Mostly pseudoscience)
Auditory integration Training
Facilitated communication
Nonverbal/severely handicapped people are suddenly writing emotional, grammatically correct messages
This is due to the facilitator (Bomba et al 1996)
Viamin B6 and Magnesium
30% of children showed improvement in Martineau (1998) study.
Other studies show no improvement
Changes in nutrition
All are ineffective
AIT – 10 hours of music to decrease irritability/hyperactivity
Facilitated communication – therapist guides hand to keyboard to type messages
(removing food additives, sugar, increasing certain fats, yoga and massage, herbal remedies) all disproven
Of course can be useful for certain problems (yoga for sleep or anxiety, diet for GI problems) but not ASD itself
Fenfluramine
Decreases blood serotonin levels
May decrease hyperactivity but nothing else (Campbell 1988)
Naltrexone
Clonidine
Doesn’t work for social behaviors
Secretin
Endogenous gastroinestinal polypeptide, ineffective
Corticosteroids

52. Therapy Core Features Genetics Biological Substrate Genetics
ABA
Genetics
Some combination of:
Neurexin and neuroligin abnormality
Chromosome 16 abnormality
Chromosome 7 inversion
Core Features
Social difficulties
Restricted, repetitive behaviors
Biological Substrate
Some combination of:
Enlarged amygdala, hippocampus
Abnormal fusiform gyrus
Macroencephaly
Decreased Purkinje cells
Increased 5-HT
Genetics
Some combination of:
Neurexin and neuroligin abnormality
Chromosome 16 abnormality
Chromosome 7 inversion
Biological Substrate
Some combination of:
Enlarged amygdala, hippocampus
Abnormal fusiform gyrus
Macroencephaly
Decreased Purkinje cells
Increased 5-HT
Secondary Features
Intellectual disability
Inattention
Motor problems
Environment
Abuse
Social support
Genetics:
Combinations of 7, 16, possible X-chromosomal abnormalities, neurexin and neuroligin abnormalities
Biological substrate:
Increased levels of serotonin, macroencephaly, larger amygdala and hippocampus
Core and Secondary features the same as DSM specifies, no catatonia
Genetics
Some combination of:
Neurexin and neuroligin abnormality
Chromosome 16 abnormality
Chromosome 7 inversion
Medication
SSRI’s
Antipsychotics

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