Advances in Understanding and Treating Autism Spectrum Disorders

Fred R. Volkmar, MDIrving B. Harris Professor of Child Psychiatry, Pediatrics, and PsychologyChild Study Center, Yale University School of MedicineNew Haven, Connecticut

Overview

• Changes in Understanding

• Understanding the Neurobiological Basis of Autism

• Advances in Diagnosis/Assessment

• Treatments and Evidence-Based Treatments

• Outcome and Changing Face of Autism

A (quick) Discussion of Terms

PDD = pervasive developmental disorder.

• Autism, Autism Spectrum Disorder(s), Asperger’s, PDD, etc. – need better term

• Keep in mind that there is a BROAD range of syndrome expression – If you meet one person with autism you have met one

person with autism• Disorder vs Differences is indeed a discussion

– One of the major findings of past decade• Normative = neurotypical = some hypothetical population

average

How to (simply) Describe Autism

• It is a Social Learning Disability/Different

Changes in Our Understanding of Autism

SES = socioeconomic status.

• Autism– Initially seen as a potential form of schizophrenia,

associated with ⇡ parental SES, parents blamed– 3 major findings in 1970s

• Strong neural basis – high rates epilepsy, unusual onset

• Strong genetic basis – much higher risk for monozygotic twins

• Structured teaching much better than unstructured psychotherapy

– Gradual increase in research until 1980– Explosion of research following official recognition of

autism in 1980 (DSM-III)

Onset of Seizures in Autism

Normative data: Cooper JE. Br Med J. 1965;1(5441):1020-1022. Large samples of children with autism: Volkmar FR, et al. J Am Acad Child Adolesc Psychiatry. 1990;29(1):127-129. Deykin EY, et al. Am J Psychiatry. 1979;136(10):1310-1312.

Brain Mechanisms

fMRI = functional magnetic resonance imaging; EEG = electroencephalogram.

• As children were followed – higher rates of epilepsy– Autism was strongly brain based– Subsequent work:

• Early changes in brain volume, morphology• Issues in processing social information

– eg, faces, biological motion, emotion– Various methods used: eg, fMRI, EEG

Genetics

• First twin study in late 1970s– Higher concordance for identical (over fraternal) twins– Shown in multiple studies since then– Various methods used

• Large scale studies, rare mutation approaches, population samples

• Conclusions– Autism very strongly genetic with many genes

potentially involved– Awareness of broader spectrum issues

Genetic “Forms” of Autism

Emory University School of Medicine. Department of Human Genetics. http://genetics.emory.edu/research/index.html.

Advances in Treatment• Educational/Behavioral Interventions

– Applied Behavioral Analysis (ABA) – first developed, structured treatment, positive behavioral changes, LARGE body of work BUT mostly single case studies

– Developmental Models• Greenspan (Floortime) – some but limited research• Early Start Denver Model (ESDM; Rogers) more

research– Pivotal Response Training (PRT)

• Developed by Koegels, combines behavioral and developmental, growing body of data, especially good –infants

– Eclectic models – Division TEACCH – North Carolina• Schopler, Mesibov, and others, some data

• Drug treatments– Significant benefit of atypical neuroleptics for “irritability”

Research Has Increased!

• Both in terms of sheer volume of papers AND in sophistication of studies

• Now several journals devoted to Autism• Quick overview of research productivity and selected

research findings• Various theories developed

– All with pros/cons– Theory of Mind, Executive Functioning, Central

Coherence, Extreme Male Brain, etc. – They do (often) foster research!

Research Papers: 1943–1999

PubMed.gov.

Research Papers: 2000–2015

NOTE: Keep up with everything, you’d have to read about 5.25 papers each day! PubMed.gov.

Understanding the Neurobiological Basis of Autism

The search for mechanisms of social disability

Understanding the Social Brain

• Major advances over the last 30 years• Focus on understanding

– What is unique (or not) about social interest in babies?

– Understanding aspects of the social brain• Face recognition/processing• Social information processing regions• Connections to other brain systems – eg,

Emotional recognition/expression• Perception of biological movement• Perception of sounds and orientation to (and

towards learning) human voice

An Evolution Perspective: Neoteny

• In birds and mammals– Prolonged period of dependence on parents (unlike

reptiles)– This can be prolonged as in humans and many

birds (months and years of dependency attachment)

– Or the young animal can locomote shortly after birth as in sheep, geese potential for imprinting

• Presumed evolutionary function to keep young near mother

– In humans the drive for social connection is usually very, very strong people (parents) are at the center of the world!

• Absence of strong bonds, eg, as in orphanages, trouble for the developing child

Humans are social creatures –What is different in autism? Typical Early Social Development

• Probably starts in utero– Babies listen to mother’s voice

• At time of birth babies are VERY social– Parents’ faces and voices are the most interesting

things in the world and babies will look more at face like things!

– They become interested in what people are doing, feeling, and communicating

– All this comes without formal training and sets stage for language development and further learning

Put Another Way!

• If you come into the world (like most of us) with a social “frame” to view it many things happen!– People are the center!

• Joint attention• Imitation• Affective responsivity• Desire to communicate• Incidental learning, multitasking

– People become THE most important things in the world (starting with parents)!

What is the situation in autism? – It is as if people are hidden! Can you find and count the Navy SEALS?

Social Brain Regions Face Recognition: Normal Development

• Birth: Preferential interest in face/voice, top ½ face

• 2 to 3 months: Face recognition (internal features)

• 6 months: Inversion effect, gender discrimination

• 9 months: Strong stranger response, species effects

• Subsequent changes in strategies with greater expertise as children become older

Face Recognition in Autism

• Large literature on different approaches used by individuals with autism– Do not do well on normed facial

recognition tasks– Do as well recognizing inverted

faces as correctly oriented ones– Rely less on salient features of

face for recognition (eg, may focus on other characteristics)

• Limitations: Use of still faces

Event-Related Potentials (ERPs)

• Electric neural activity (EEG) recorded at scalp, time-locked to perceptual events to reveal evoked brain response

• Appropriate for range of cognitive and developmental levels

• Millisecond temporal resolution– Efficiency– Stages of processing

• Economical• Scalable• Yields indices of social

perception across lifespan

Typical negative “dip” at 170 millisecondsBut delayed and less deep in autism

ERPs and Faces: Autism

McPartland J, et al. J Child Psychol Psychiatry. 2004;45(7):1235-1245.

MRI studies brain anatomy.Functional MRI (fMRI)studies brain function.

MRI vs fMRI

Face Discrimination

Schultz RT, et al. Arch Gen Psychiatry. 2000;57(4):331-340.

• fMRI study• Comparison to normal controls• Task: Same or Different

– People– Objects– Patterns

• Regions of interest:– Fusiform gyrus (face)– Inferior temporal gyrus (objects)

• Both groups equally accurate– (tasks set up that way!)

• Finding now replicated > 20 ×

SAME or DIFFERENT Person?

Schultz RT, et al. Arch Gen Psychiatry. 2000;57(4):331-340.

SAME or DIFFERENT Object?

Courtesy of Robert T. Schultz, PhD.

Typical Individuals Persons with Autism/AS

Face Recognition: Fusiform Gyrus Group Differences

Looking at Faces is Dynamic Faces in an Ongoing Social Context

Eye Tracking Research

• Ecological validity– Viewing the world with new eyes

• Choice of subject – concerns and choices– Intensely social (small number of people)– Minimize action/objects (AKA no Terminator 2)– Black and white initially– Show short segments (not entire film)– Chose movie about a pleasant dinner party at a small

New England college with 2 faculty members and their wives

ADI-R = Autism Diagnostic Interview-Revised; ADOS = Autism Diagnostic Observation Schedule; FSIQ = Full Scale Intelligence Quotient.Klin A, et al. Am J Psychiatry. 2002;159(6):895-908.

Viewer with autismAge: 38, FSIQ: 119,ADOS-4 / ADI-R +,Vineland Socialization: 69

Typical ViewerAge: 27, FSIQ: 110

36

37 38

Focus on mouths vs focus on eyes lose about 90% relevant information

Information Lost by focusing on Mouth:All the social (nonverbal) cues of the nonspeaker

Group Results

Effect size (eyes): d = 3.81

Klin A, et al. Arch Gen Psychiatry. 2002;59(9):809-816.

Advances in Diagnosis and Assessment

Changes (pro AND con) with DSM-5

What’s in a Name?

ASD = autism spectrum disorder; CARS = Childhood Autism Rating Scale; M-CHAT = Modified Checklist for Autism in Toddlers; RDoC = Research Domain Criteria.

• Evolution of names and concepts over time– Kanner, Asperger, Rutter (1978)– DSM-III DSM-IV DSM-5– Infantile autism autistic disorder ASD

• 20 years of stability with DSM-IV and ICD-10• Multiple systems now in use

– DSM-5, RDoC (US), ICD-10 ICD-11, DSM-IV (for “grandfathered” cases)

• Problems for – Longitudinal, epidemiological studies

• Advent of screening and assessment techniques– ADI, ADOS, CARS, M-CHAT

Autism Today – Advances and Issues

• DSM-5– Good thing: NAME CHANGE to ASD– BUT singular not plural

• No subtypes/subthreshold• For ASD severity dimensions• As a practical matter

– Many fewer ways to get ASD diagnosis– Problems especially with young and more cognitively

able– Many reviews (and one meta-analysis not available)– Higher functioning and younger children most at risk

What happens to cases?

From McPartland JC, et al. J Am Acad Child Adolesc Psychiatry. 2012;51(4):368-383.

From NY TimesCurrent Controversies

• After 20 years of stability, 3 approaches I use– DSM-5, DSM-IV (grandfathered/ICD), RDoC– Issues of a stricter concept just when genetics help us

understand the broader phenotype!• Special problems for

– Higher functioning– Younger children– Eligibility issues– Changes in longitudinal samples

• Problems with assessment issues– Problems in screening– For diamniotic instruments several studies suggest

problems with bias in minority samples

Treatments and Evidence-Based Treatments

A growing body of work –But with some important limitations

Autism Interventions• Intervention 1950–1980

– Psychodynamic models – AKA blame the parents (IN the United States few went to public school)

– Studies began to suggest importance of structured treatment

– Parent founded schools/support• In the United States – major change with Public Law 94–

142 (1975)• Importance of planned, intensive intervention to cope

with social difficulties gradual changes in overall outcome

• 30 years ago: > 50% mute, over 80% with Intellectual Disabilities

• NOW: < 25 mute, < 50% have Intellectual Disabilities

Model Programs

Lord C, et al (Eds). Division of Behavioral and Social Sciences and Education. Committee on Educational Interventions for Children with Autism. National Research Council. Educating Children with Autism. Washington, DC: National Academy Press; 2001.

• Background• National Research Council report

– Structured intensive intervention– Commonalities (and differences) in

programs – NOT every child gets better– As a group improved/improving outcomes– Early intervention

• Some interesting issues– University-based/affiliated– Intensive

• Average about 25 hours/week

Developmental Issues in Treatment

Autism

Development

Minimize the impact of autismMaximize developmental gains

Evidence-Based Interventions

EBT = evidence-based treatment.

• A long and interesting history• First practice guidelines in 1999

– A number now available– Complexities given

• The nature of autism interventions, diversity of disciplines; range of syndrome expression in autism

• Nature of EBT• NOTE: Differences in standards, methods, etc.

Sample selection issues• Evidence-based practices and treatments

Implications for Teaching

• Recognize child’s difficulties in responding to complex (social/nonsocial) environments

• Balance of “pull out”, small group, classroom-based, and unstructured environments

• Classroom environment• Continuity and consistency

– Across settings and across people• Monitoring and flexibility

– Team approach and collaboration• School – home communication

An intervention never proven in a double-blind study!

A Range of Programs and Techniques

*Note nature of evidence.

• Programs– ABA*– Early Start– Pivotal Response– TEACHH*

• All have important similarities and some differences

• Techniques with some evidence-base– A host of behavioral

techniques– Social skills

interventions– Speech-

Communication Interventions

– Social skills– Some other

• Alternative and non-established treatments

Autism Interventions

• Intervention 1950–1980– Psychodynamic models – AKA blame the parents (IN

the United States few went to public school)– Studies began to suggest importance of structured

treatment– Parent founded schools/support

• In the United States – major change with Public Law 94–142 (1975)

• Importance of planned, intensive intervention to cope with social difficulties –––

Drug Treatments

SSRI = selective serotonin reuptake inhibitor.

• Importance of double-blind, placebo-controlled studies– Major “placebo effect”

• Medications most frequently studied– Risperidone and newer second-generation

neuroleptics – work well and quickly– SSRIs – used anxiety/depression, rigidity but seem to

work less well in children, better in adolescents and adults

• Side effects and balance of risk and benefit

RUPP Autism Network: Irritability Scale

ABC = Aberrant Behavior Checklist; RUPP = Research Units on Pediatric Psychopharmacology.McCracken JT, et al. N Engl J Med. 2002;347(5):314-321.

Drug Treatments (cont’d)

• Importance of double-blind, placebo-controlled studies– Major “placebo effect”

• Medications most frequently studied– Risperidone and newer second-generation

neuroleptics – work well and quickly– SSRIs – used anxiety/depression, rigidity but seem to

work less well in children, better in adolescents and adults

• Side effects and balance of risk and benefit• Several new products in development

– Single gene disorder– Other neural systems

Changes in Outcome

The Changing Face of Autism

Outcome – Two Snapshots

Good = independent; Fair = semi-independent; Poor = 24/7 care.Data adapted from Howlin P. J Neural Transm Suppl. 2005;(69):101-119.

First studies Next wave!

Brain Changes with Treatment

Figure 1. PRT conducted by the PI in our Center.

Enhanced Efficiency after PRTEEG Data N170

• Pre- vs post-treatment comparison shows fasterresponse to:– Faces– Emotional expressions

Brain Activity Pre- vs Post-PRT

LDLPFC = left dorsolateral prefrontal cortex; LVLPFC = left ventrolateral prefrontal cortex; RFG = right fusiform gyrus; rpSTS = right posterior superior temporal sulcus; vmPFC = ventromedial prefrontal cortex.

• Whole brain analysis with 5 participants:– LVLPFC (state), vmPFC (state), rpSTS (state), RFG

(state/trait), LDLPFC (trait)

Z = 10X = 44

Changes in Outcome

CBT = cognitive behavioral therapy.

• Even for “optimal outcome” individuals – Problems in vocational/school settings– Increased risk for mental health problems

• Especially anxiety and depression• Increased risk for suicide • Response to modified CBT and drug treatments

– Need for special support as adults• Accommodations under ADA NOT IDEAL

– A growing number of students are going to college– VERY limited literature on adults with autism– VERY, VERY limited literature on autism and aging

Case Example

• Please take a guess as to what the next page of equations is about!

ReferencesLearning Objective: Discuss the brain mechanisms underlying autism and their implications for treatment

• Kennedy DP, et al. The social brain in psychiatric and neurological disorders. Trends Cogn Sci. 2012;16(11):559-572.

• McPartland JC, et al. The social neuroscience of autism spectrum disorder. In: Volkmar FR, et al (Eds). Handbook of Autism and Pervasive Developmental Disorders. Volume 1: Diagnosis, Development, and Brain Mechanisms. Fourth Edition. Hoboken, NJ: John Wiley & Sons Inc; 2014:482-496.

• Pelphrey KA, et al. Brain mechanisms for social perception dysfunction in autism. In: Just MA, et al (Eds). Development and Brain Systems in Autism. New York, NY: Psychology Press; 2013:151-178.

• Schultz RT, et al. Abnormal ventral temporal cortical activity during face discrimination among individuals with autism and Asperger syndrome. Arch Gen Psychiatry. 2000;57(4):331-340.

• Voos AC, et al. Neural mechanisms of improvements in social motivation after pivotal response treatment: two case studies. J Autism Dev Disord. 2013;43(1):1-10.

References (cont’d)

Learning Objective: List 3 common comorbid conditions associated with autism and their management

• Abdallah MW, et al. Psychiatric comorbidities in autism spectrum disorders: findings from a Danish Historic Birth Cohort. Eur Child Adolesc Psychiatry. 2011;20(11-12):599-601.

• Hammond RK, et al. Adolescents With High-Functioning Autism: An Investigation of Comorbid Anxiety and Depression. J Ment Health Res Intellect Disabil. 2014;7(3):246-263.

• Memari A, et al. Investigation of autism comorbidities and associations in a school-based community sample. J Child AdolescPsychiatr Nurs. 2012;25(2):84-90.

• Scahill L, et al. Psychopharmacology. In: Volkmar FR, et al (Eds). Handbook of Autism and Pervasive Developmental Disorders. Fourth Edition. Hoboken, NJ: John Wiley & Sons Inc; 2014.

• Vasa RA, et al. A systematic review of treatments for anxiety in youth with autism spectrum disorders. J Autism Dev Disord. 2014;44(12):3215-3229.

References (cont’d)

Learning Objective: Describe changes in outcome over time and the impact of the awareness of the genetic complexity of autism to increased in rates of diagnosis

• Fein D, et al. Optimal outcome in individuals with a history of autism. J Child Psychol Psychiatry. 2013;54(2):195-205.

• Howlin PA. Outcomes in Adults With Autism Spectrum Disorders. In: Volkmar FR, et al (Eds). Handbook of Autism and Pervasive Developmental Disorders. Fourth Edition. Hoboken, NJ: John Wiley & Sons Inc; 2014.

• van Schalkwyk GI, et al. College students with autism spectrum disorders: A growing role for adult psychiatrists. J Am Coll Health. 2016;64(7):575-579.

• Vanbergeijk E, et al. Supporting more able students on the autism spectrum: college and beyond. J Autism Dev Disord. 2008;38(7):1359-1370.

• Wolff LE, et al. Students with Asperger Syndrome: A Guide for College Personnel. Shawnee Mission, KS: APC Publishing; 2009.