Core Mechanisms of Attention and Emotion Regulation in Infants at High Risk for ASD

Susan E. Bryson, PhD Dalhousie University-IWK Health Centre

Acknowledgements

Lonnie Zwaigenbaum : University of Alberta Jessica Brian: Hospital for Sick Children (HSC)Wendy Roberts: HSC-University of TorontoIsabel Smith: Dalhousie University-IWK Health Centre Peter Szatmari: McMaster UniversityNancy Garon: IWK Health CentreNancy Garon: IWK Health Centre

Canadian Institutes of Health Research, Autism Speaks and National Institutes of Health

And, all the families who have contributed so much

Plan today

• Describe a Canadian study of infants at risk for ASD

• focus on core mechanisms of attention and emotion in ASDand emotion in ASD

• data on early signs of ASD• implications for early detection and

treatment

A Canadian Infant Sibling Study

• Multi-site prospective study of high-risk infants with an older sibling with ASD

Main Goals are to:

• identify early signs of ASD • identify early signs of ASD

• describe early ASD and non-ASD trajectories

• identify core mechanisms in ASD

• provide data on ASD co-occurrence rates

• evaluate efficacy of early intervention for ASD

Study Design

• 2 groups: high-risk infant siblings and low-risk controls with no family history of ASD

• assessed at regular (3- to 6-month) intervals from 6-24 months of agefrom 6-24 months of age

• independent “gold standard” assessment (ADI-R & ADOS) for ASD at 3 years

• children are being followed until 8 years

Autism Observation Scale For Infants (Bryson et al., 2007)

• measure designed to detect & monitor early signs of ASD

• 19-item direct observation scale

• items drawn from early markers suggested by:• items drawn from early markers suggested by:– parent’s retrospective reports

– early home videotape studies

– case reports

– our joint experience to date

• items rated 0-3 (markedly atypical)

Items from the Autism Observation Scale for Infants

• Visual tracking

• Disengagement of attention

• Response to name

• Social babbling

• Imitation

• Coordination of eye gaze and action

• Reactivity • Social babbling

• Eye contact

• Social smiling

• Social anticipation (peek-a-boo)

• Social interest and affect

• Response to change in facial emotion

• Reactivity

• Transitions between activities

• Motor behavior

• Atypical motor behaviours

• Atypical sensory behaviours

• 3 new items

12 –month old sib: Disengage visual attention and social interest

9–month old infant: Disengage visual attention

12 –month old sib: Response to name

12 –month old sib: Response to name

12 –month old sib: Anticipatory response (to peek-a-boo)

18 –month old sib: Atypical sensory behavior

Descriptive Overview

• recruited to date: 376 high-risk infants & 218 low-risk controls

• 225 and 92, respectively, followed until 36 months • 36-month ASD diagnosis: • 36-month ASD diagnosis:

– ~15-20% sibs (total of 32-52/225)– 1 female: 1.5-2 males

• an additional ~10% have related delays, typically in language development; also “stickiness” &/or social anxiety

__

AOSI Scores over Time in ASD Sibs,

Non-ASD Sibs and Controls

ASDNon-ASD sibNon-ASD

__Non-ASD Controls

__

AOSI Scores over Time in ASD Sibs,

Non-ASD Sibs and Controls

AutismASDNon-ASD sibNon-ASD ctrl

__

0.2

0.3

0.4

0.5

0.6

0.7

Fre

quen

cy sib-ASD

sib-N

control

1. Visual tracking2. Orient to name3. Imitation

7. Atypical reactivity8. Social interest9. Atypical sensory

behavior

4. Eye contact5. Social smile6. Social babbling

0

0.1

1 2 3 4 5 6 7 8 9

AOSI item

Predicting ASD from 12 -Month AOSI

• AOSI total score ≥ 9 at 12 months in:– Specificity for autism/ASD = 93%

– Sensitivity for autism/ASD = 47% (autism = 80%)

• wide variability in onset, nature & course of early • wide variability in onset, nature & course of early ASD behavioral/clinical signs (Bryson et al., 2007)

• 2 major subgroups, with earlier (6- to 12-month) and later (12- to 18-month) onset of symptoms

Longitudinal Head Circumference(e.g., Cody-Hazlett et al., 2005; Zwaigenbaum et al., 2008)

45

50

55

Hea

d C

ircum

fere

nce

Combined Controls

Autism

brain enlargement detected on MRI

onset of HC enlargement

30

35

40

45

0 3 6 9 12 15 18 21 24 27 30 33 36

Age (months)

Hea

d C

ircum

fere

nce

AOSI signs indicative of ASD

Early Cognitive & Communicative Development

• as a group, sibs diagnosed with ASD at 36 months are distinguished from non-ASD sibs & controls by lower scores on standardized controls by lower scores on standardized measures of cognition & communication at 12 months (e.g., Mitchell et al., 2006)

• but considerable variability within group diagnosed with ASD (Bryson et al., 2007)

IQ (Motor IQ) CASE

12 24 36 1 68 (61) <50 50

2 (F) 90 (69) 97 96

3 (F) NT <50 <50

Cognitive (Mullen) Data by Age(Bryson et al., 2007)

3 (F) NT <50 <50

4 93 (85) 52 <50

5 88 (77) 61 <50

6 (F) 107 (90) 79 85

7 82 (72) <50 <50

8 99 (81) 86 51

9 (F) 77 (89) 80 80

Cognitive Data

• at least 20% of ASD sibs show evidence of a plateau in cognitive development between 12-24/36 months

• no apparent relationship with sex; all had early onset of symptoms (6-12 months) onset of symptoms (6-12 months)

• of the 20%, less than half met standard criteria for “regression” (i.e., speech loss)

• many had not developed any speech• data argue for a re-conceptualization of

“regression” in ASD

24-month Temperament Data(Garon et al., 2008)

• assessed prospectively via Rothbart’s questionnaire completed by parents

3 main questions:1. Does temperament at 24 months distinguish

ASD sibs from non-ASD sibs & controls at ASD sibs from non-ASD sibs & controls at 36-months?

2. Does temperament predict 36-month diagnostic status beyond gender, symptom severity and IQ at 24 months?

3. Does temperament distinguish ASD subgroups?

Discriminant Function Analysis

• F 1: Behavioral/Social Approach (*26.4% variance)• Positive (largely social) Anticipation (.43)• Attention Shifting (.43)• Activity Level (-.41)

• F 2: Effortful Emotion Regulation (13.2% variance)• Inhibitory Control (.83), Attention Shifting (.57) & Focus (.47)• Inhibitory Control (.83), Attention Shifting (.57) & Focus (.47)• High Pleasure (.39)• Social Fear (-.38) • Anger (-.56) • Soothability (.48)

(*ps<.001 for combined effect of both functions & unique effect of F2 in accounting for between group variance)

Prediction of Diagnostic Group Status

ASD Non-ASD Controlssibs sibs

Beh. Approach* -1.04 < .55 ~ -.28 Beh. Approach* -1.04 < .55 ~ -.28 Effortful Emotion -.55 ~ -.17 < .50Regulation**

LRA: *Adds to prediction of ASD vs. non-ASD beyond symptom severity and IQ at 24 months (also found to moderate ASD symptom severity); both * & ** add to prediction of ASD vs. controls (ps<.001)

ASD Subgroups

• cluster analysis revealed 2 ASD subgroups distinguished by age of diagnosis, IQ, symptom severity and Behavior Approach (BA)

• group with lower BA, more severe symptoms, • group with lower BA, more severe symptoms, lower IQ & early diagnosis

• BA implicates ascending dopamine/motivational pathways (vs. descending cortical control of attention & emotion regulation; e.g., Panksepp, 2001)

12-Month Temperament Data

0.2

0.4

0.6

-0.6

-0.4

-0.2

0

0.2

Smiling Orienting Activity Soothability Fear Distress

12-month scales

z-sc

ores

ASD

non-ASD

control

Visual-Spatial Attention

• defined by engage, disengage and shift operations (Posner, 1989)

• mediated by posterior attention system that allows quick automatic shifts of attention

• forms part of a larger attentional network that includes anterior and sub-cortical systemsincludes anterior and sub-cortical systems

• disengage operation typically develops at 3-4 months of age (e.g., Johnson et al., 1994)

• prior to this attention is described as “obligatory” or “sticky”

Visual-Spatial Attention in ASD

• assessed on a simple visual orienting task• dependent measure = latency to begin an eye

movement/saccade to second stimulus• evidence that children with autism have:• evidence that children with autism have:

– difficulty disengaging attention from 2 competing visual stimuli, particularly to left side of space (Landry & Bryson, 2004; Rombough & Bryson, in prep.)

– problem is associated with distress behaviours, as predicted by claim that ability to disengage is central to emotion regulation (Rothbart et al., 1994)

Visual Orienting Task

attractor

shift

disengage

or

Mean Saccadic Latencies (msecs) by Group and Condition (Landry & Bryson,2004)

Shift Disengage

Autism 495 (147) 2164 (1358)Autism 495 (147) 2164 (1358)

Typical 541 (133) 1071 (443)

Downs 324 (82) 506 (126)

Mean Number of Self-regulatory Behaviours (SDs)

Approach Withdrawal

Autism 6.7 12.5(1.3) (1.8)(1.3) (1.8)

Down’s 14.1 6.1(1.7) (1.5)

Mean Saccadic Latencies (msecs) for Children with ASD

Lateral Shift Left 445 (272)Right 375 (161)

33

Right 375 (161)

Disengage Left 3144(2259)Right 2364 (2108)

Vertical Shift Up 624 (121)Down 350 (120)

Disengage Up 2756 (2185)Down 1400 (1397)

Disengagement in Infant SiblingsMain question : Does early disengage impairment

distinguish sibs later diagnosed with ASD from non-ASD sibs & controls?

Results:Results:• at 6 months, no Group effects; main effect of

Condition, p<.001, with shift > disengage RTs• at 12 months, Linear Group effect, p<.001, and

Group X Condition X Field, p<.05

6-Month Disengage Latencies by Group

800900

100011001200

mill

isec

onds ASD sibs

300400500600700800

left right

Disengage at 6 months

mill

isec

onds

non-ASD sibs

Controls

12-Month Disengage Latencies by Group

800

9001000

11001200

mill

isec

onds ASD sibs

300400

500600

700800

left right

Disengage at 12 months

mill

isec

onds ASD sibs

non-ASD sibs

Controls

Disengagement and Temperament

• Multiple regression analysis significant for left-(vs. right-) sided disengage RTs

• Longer disengage RTs to left side predicted by Group--ASD sibs--and by parent reports of: Group--ASD sibs--and by parent reports of: – increased irritability – less reactivity to environmental events – difficult to soothe

Conclusions: Visual Orienting• Atypical disengagement is an early ASD marker • Emergence at 12 (vs. 6) months implicates

dysfunctional development of frontal/voluntary control of attention (cf., Johnson, 1994)control of attention

• Support is provided for predicted relationship between impaired disengagement and poor regulation of emotions (cf., Rothbart et al., 1994)

• Both implicate non-dominant, usually right, hemisphere dysfunction (Schore, 1994) and reduced frontal input (Just, 2008)

Overall Summary

• 2 critical early periods of development in ASD: 6-12 and 12-24 months of age

• Preliminary findings implicate both ascending motivational/sub-cortical systems and descending cortical control of attention descending cortical control of attention

• Higher co-occurrence rates than estimated • Evidence for broad phenotype in non-ASD sibs• Opportunity to intervene even earlier and

influence trajectories of development (funded by Autism Speaks)

Implications for Early Diagnosis

Why diagnose early?– Optimize child outcomes via treatment – Address parental concerns / issues: uncertainty,

frustration, self-blame & provide information relevant to family planning to family planning

Current reality:– Average age of diagnosis = 3-4+ years – Average age at which parents express major

concerns = 17 months

Early Diagnosis

• Reliable and stable at 3 years (Lord et al., 2002)

• Reliable but less stable at 2 years, except for specialized and highly experienced clinicians (Stone et al., 1999; Turner & Stone, 2007)

• However, virtually all false positive at 2 years (17/18) had significant language or general developmental disorders

• Implications for early detection / diagnosis? • Data argue for early targeted intervention prior

to confirmation of diagnosis (e.g., Social ABCs)

Social ABC’s Training Manual

• The ABCs of Learning• Enhancing Communication• Sharing Positive Emotion• Motivation and Arousal• Motivation and Arousal

• Play and The Social ABCs• Daily Care-giving Activities

• Managing BehaviouralChallenges

• Taking Care of Yourself

March 2010 43Banff

Red Flags at 18 -24 Months

Social – less: • responsive to social overtures• back-and-forth interactions (e.g., in play)• imitation of actions of others • shared affect• shared affect• “showing off” for attention• interest in other children• social initiations

Red Flags at 18 -24 Months (cont’d)

Communication -- less:• use of eye gaze & gestures• communication to direct another’s attention• babbling & no single words (by 16 months) • inconsistent response to name/ sounds • loss of words &/ or communicative connectedness

Red Flags at 18 -24 Months (cont’d)

Play :• less functional play• more visual exploration / attention to detail • impoverished imaginative play

Repetitive behaviours/ behavioural inflexibility: • repetitive motor behaviours • difficulty with novelty or transitions • visual interests/ fixation• other sensory interests or sensitivities