infant brain imaging study network - iacc · ibis (infant brain imaging study) network . nih autism...
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Infant Brain Imaging Study Network an NIH Autism Centers of Excellence (ACE) Network
University of North Carolina University of Washington
Washington University in St. Louis Children’s Hospital of Philadelphia Montreal Neurological Institute
University of Utah University of Alberta
Principal Investigator: Joe Piven Carolina Institute for Developmental Disabilities
University of North Carolina
IACC Meeting Washington, D.C. April 2011
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IBIS (Infant Brain Imaging Study) Network NIH Autism Center of Excellence (www.ibis-network.org )
“A Longitudinal MRI Study of Infants at Risk for Autism”
Infant Siblings
of
Older Autistic Children
6 months 12 months 24 months
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Rationale for the IBIS Network:
(1) onset of brain overgrowth
and
(2) onset of autistic behavior
both appear to occur in the latter part of the first year of life in autistic individuals
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MRI Studies Brain Volume Subject Age Piven et al. (1992) increased mid-sagittal area 18 - 53 yrs Piven et al (1995) increased total brain volume 14 – 29 yrs Hazlett et al (2005) increased total brain volume (N=51) 2 yrs Courchesne et al (2001) increased cerebral. gray and white 2 – 4 yrs only Sparks et al (2002) increased total cerebral 3-4 yrs
Aylward et al (2002) increased TBV (HFA) under 12 yrs Lotspeich et al (2004) increased cerebral gray (N=52) 7 – 18 yr
Herbert et al (2004) increased (radiate) white matter (N=13) ~ 9 yrs Palmen et al (2005) increased TBV, cerebral gray (N=21) 7 – 15 yrs
Schultz et al (unpub) increased TBV, GM, WM (N=117) 7-36 yrs Hyde et al, (2008) increased gray vol (VBM + cortical thick) young adults
Freitag et al, (2009) increased TBV, GM and WM (N=15) HFA adol/adult Hardan et al, (2006) increased TBV, gray/cortical thick 17 HFA children
Schuman et al (2010) increased cerebral gray and white 2-5 yrs
Studies Reporting Increased Brain Volume (5-10%) in Autism
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MRI Studies Brain Volume Subject Age Piven et al. (1992) increased mid-sagittal area 18 - 53 yrs
Piven et al (1995) increased total brain volume 14 – 29 yrs Hazlett et al (2005) increased total brain volume (N=51) 2 yrs
Courchesne et al (2001) increased cerebral. gray and white 2 – 4 yrs Sparks et al (2002) increased total cerebral 3-4 yrs
Aylward et al (2002) increased TBV (HFA) under 12 yrs Lotspeich et al (2004) increased cerebral gray (N=52) 7 – 18 yr
Herbert et al (2004) increased (radiate) white matter (N=13) ~ 9 yrs Palmen et al (2005) increased TBV, cerebral gray (N=21) 7 – 15 yrs
Schultz et al (unpub) increased TBV, GM, WM (N=117) 7-36 yrs Hyde et al, (2008) increased gray vol (VBM + cortical thick) young adults Freitag et al, (2009) increased TBV, GM and WM (N=15) HFA adol/adult Hardan et al, (2006) increased TBV, gray/cortical thick 17 HFA children Schuman et al (2010) increased cerebral gray and white 2-5 yrs
Increased Brain Volume Noted by Two Years of Age
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.0 6.5 7.0
Hazlett et al., in press
Parallel Growth Trajectories in Autism and Controls from Age 2 to 4
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The Timing of Brain Overgrowth: Clues from Head Circumference (Hazlett et al., 2005)
Head Circumference
55
50
45
40
35
30
Combined Controls
Autism
trajectories significantly different
N = 113 autistic subjects
N = 189 local, community controls
ave = 4 observations (birth – 3 yrs)
adj maternal educ, body size, ethnicity
0 3 6 9 12 15 18 21 24 27 30 33 36 Age (months)
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The Timing of Brain Overgrowth: Clues from Head Circumference (Hazlett et al., 2005)
Head Circumference
55
50
45
40
35
30
Combined Controls
Autism
brain enlargement detected on MRI at 2 years of age (N=51)
suggests onset of brain enlargement in the latter part of the first year
0 3 6 9 12 15 18 21 24 27 30 33 36 Age (months)
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Brain Overgrowth in Autism
there is direct evidence for an increased rate of brain growth in autism occuring before age 2 (MRI)
and
indirect evidence that the onset of this overgrowth is in the latter part of the first year of life. (head circumference)
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Rationale for the IBIS Network:
(1) onset of brain overgrowth
and
(2) onset of autistic behavior
both appear to occur in the latter part of the first year of life in autistic individuals
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‘Baby Sibs’ or ‘Infant Sibs’ Studies a New Autism Research Paradigm
• autism is a genetic disorder (twin, family, molecular).
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‘Baby Sibs’ or ‘Infant Sibs’ Studies a New Autism Research Paradigm
• autism is a genetic disorder (twin, family, molecular).
• risk of having a 2nd child with autism (or, recurrence risk) is 10-20 times higher than risk in the general population.
risk: general population risk ~ 1% recurrence risk ~ 10-20%
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Canadian ‘Infant Sib’ Study Zwaigenbaum, Bryson, Roberts, Brian, Szatmari (2005)
• 10 of 74 infant siblings (of older autistic children) met criteria for an Autism Spectrum Disorder at age 36-48 months (recurrence =13.5%)
• examined at 6, 12 and 18 months with
Autism Observation Scale for Infants (AOSI) Bryson et al. (2008)
• visual tracking • imitation • coordination of eye gaze and action • reactivity • transitions between activities • motor behavior • atypical motor behaviors • atypical sensory behaviors • engagement • social referencing
• disengagement of attention • response to name • social babbling • eye contact • social smiling • social anticipation (peek-a-boo) • social interest and affect • response to change in facial emotion
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Canadian ‘Infant Sib’ Study Zwaigenbaum, Bryson, Roberts, Brian, Szatmari (2005)
• 10 of 74 infant siblings (of older autistic children) met criteria for an Autism Spectrum Disorder at age 36-48 months (recurrence =13.5%)
• examined at 6, 12 and 18 months with
Autism Observation Scale for Infants (AOSI) Bryson et al. (2008)
• visual tracking • disengagement of attention • response to name • social babbling • eye contact • social smiling • social anticipation (peek-a-boo) • social interest and affect • response to change in facial emotion
• imitation • coordination of eye gaze and action • reactivity • transitions between activities • motor behavior • atypical motor behaviors • atypical sensory behaviors • engagement • social referencing
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control
(Zwaigenbaum et al., 2005)
__
3-year10 diagnosis Autism/ASD non-ASD sib
8
6
4
2
0
6-months 12-months 18-months
Autism Observation Scale for Infants: Scores ASD and Non ASD Siblings
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Children with Autism: Features at 6 months
• subtle differences – visual tracking1 – anticipatory responses1 – motor control1,2
• many typical social behaviors (defining features of autism) – eye contact (100%) – reciprocal social smiling (88%) – social interest and affect (88%)
1Sibs-ASD>controls; 2Sibs-ASD>Sibs-N; p<.01
Zwaigenbaum et al., 2005
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control
__
3-year 10 diagnosis Autism/ASD non-ASD sib
8
6
4
2
0
6-months 12-months 18-months
Autism Observation Scale for Infants: Scores ASD and Non ASD Siblings
(Zwaigenbaum et al., 2005)
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control
10
8
6
4
2
0
__
profound change in behavior during an early post-natal window
6-months 12-months 18-months
3-year diagnosis Autism/ASD non-ASD sib
Early Post-natal Onset of Autistic Behavior
(Zwaigenbaum et al., 2005)
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Gaze to Faces Social Smiles
Social Engagement Directed Vocalizations
A Prospective Study of the Emergence of Early Behavioral Signs of Autism Ozonoff et al (2010) JAACAP
25 high risk sibs who developed ASD vs. 25 low risk sibs who did not have ASD
differences remain after covarying for developmental level (Mullen)
Trajectories for Social Communication Behaviors and Overall Ratings of Social Engagement. ASD = autism spectrum disorders; TD = typically developing children.
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Zwaiggenbaum et al., 2005
10
8
6
4
2
0
AOSI
suggests onset of autistic (social) behavior in the latter part of the first year
3-year diagnosis Autism/ASD non-ASD sib control
6-months 12-months 18-months
Hazlett et al 2005
55
50
45
40
35
30
Combined Controls
Autism head circumference
suggests onset of brain overgrowth in latter part of first year
Head Circumference
0 3 6 9 12 15 18 21 24 27 30 33 Age (months)
36
Autism Observation Scale for Infants: The convergence of evidence from infant sib behavioral studies, head circumference studies and MRI studies suggests that:
Scores ASD and Non ASD Siblings the onset of autistic behavior is temporally related to the onset of brain enlargement in the latter part of the 1st year
Onset of Autistic Behavior Onset of Brain Enlargement
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Head Circum
ference
55 Combined Controls
Autism
50
45
40
35
map brain-behavior trajectories during this window
30 0 3 6 9 12 15 18 21 24 27 30 33 36
Age (months)
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55ned Control
30
35
40
45
50
Head Circum
ference
Combi s
Autism
prediction ? intervention ?
map brain-behavior trajectories during this window
pathogenesis
0 3 6 9 12 15 18 21 24 27 30 33 Age (months)
36
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age
Studying Development
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age
Studying Development
Cross-sectional Study A, B, C, D, E …
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Studying Development
Cross-sectional Study A, B, C, D, E …
Longitudinal Study A1A2; B1 B2 B3
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Studying Development
Cross-sectional Study A, B, C, D, E …
Longitudinal Study AA; B B; C C C
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Studying Development
Cross-sectional Study A, B, C, D, E …
Longitudinal Study AA; B B; C C C
• when you have ‘heterogeneity’ (apples and oranges),
• and, when you have non-linear development
LONGITUDINAL STUDIES
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Studying Development
Cross-sectional Study A, B, C, D, E …
Longitudinal Study AA; B B; C C C
• when you have ‘heterogeneity’ (apples and oranges),
• and, when you have non-linear development
LONGITUDINAL STUDIESrather than measure change across different individuals
at different ages; measure change in the same individual over time.
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Studying Development
Cross-sectional Study A, B, C, D, E …
Longitudinal Study AA; B B; C C C
longitudinal studies take a long time and are expensive
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IBIS (Infant Brain Imaging Study) Network NIH Autism Center of Excellence (www.ibis-network.org )
Sullivan, Wright
* *
*
*
*
*
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IBIS (Infant Brain Imaging Study) Network NIH Autism Center of Excellence (www.ibis-network.org )
400 HIGH RISK infants at 6 months of age
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IBIS (Infant Brain Imaging Study) Network NIH Autism Center of Excellence (www.ibis-network.org )
400 HIGH RISK infants at 6 months of age
+
100 HIGH RISK infants at 12 months of age
500 H IGH R ISK infants
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IBIS (Infant Brain Imaging Study) Network NIH Autism Center of Excellence (www.ibis-network.org )
400 HIGH RISK infants at 6 months of age
+
100 HIGH RISK infants at 12 months of age
500 HIGH RISK infants
+
150 LOW RISK controls
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longitudinal
500 HIGH RISK infants
+
150 LOW RISK controls 6 months 12 months 24 months
brain imaging and behavior assessments
650 infants
IBIS (Infant Brain Imaging Study) Network NIH Autism Center of Excellence (www.ibis-network.org )
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IBIS (Infant Brain Imaging Study) Network
Final Sample Expected ~ 15 – 20% high risk ~ 60 – 75* meet criteria for ASD: ~ 50% high risk symptomatic/subthreshold
~ 120-140 * * after attrition, poor quality scan etc. ~ 50% high risk ~ 200 *
asymptomatic:
low risk controls ~ 150
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IBIS (Infant Brain Imaging Study) Network
Final Sample Expected ~ 15 – 20% high risk ~ 60 – 75* meet criteria for ASD: ~ 50% high risk symptomatic/subthreshold
~ 120-140 * * after attrition, poor quality scan etc. ~ 50% high risk ~ 200 *
asymptomatic:
low risk controls ~ 150
infants with 36 (PI: Heather Hazlett) Fragile X Syndrome
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Progress To Date (3/17/2011)
• 780 scans have been completed
• 266 high risk subjects have been enrolled
High Risk
6 months 217
12 months 225
24 months 126
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Progress To Date (3/17/2011)
• 780 scans have been completed
• 266 high risk subjects have been enrolled
High Risk
6 months 217
12 months 225
24 months 126
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6 months 217
12 months 225 49
24 months 126
Progress To Date (3/17/2011)
• 780 scans have been completed
• 266 high risk subjects have been enrolled
High Risk
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6 months 217
12 months 225
24 months 126
Progress To Date (3/17/2011)
• 780 scans have been completed
• 266 high risk subjects have been enrolled
High Risk
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Progress To Date (3/17/2011)
• 780 scans have been completed
• 266 high risk subjects have been assessed (brain imaging and behavior)
• 104 low risk controls have entered the study
High Risk Low Risk Controls
6 months 217 6 months 104
12 months 225 12 months 74
24 months 126 24 months 34
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clinical research
time1
time1
time2
time2
Phantom1
Phantom2
~ 2000 scans across four sites over three different ages
chop Seattle UNC WashU WashU
IBIS (Infant Brain Imaging Study) Network: Image Quality Control
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Potential Impact of this Research
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6 months 12 months 24 months
1. What brain changes are associated with behavioral changes during this window ?
Brain – Behavior Relationships
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6 months 12 months 24 months
neural circuits
1. What brain changes are associated with behavioral changes during this window ?
global volume tissue volume substructures networks
Brain-Behavior Relationships
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autism social deficits social cognition attention
diagnosis
onset
6 months 12 months 24 months
neural circuits
1. What brain changes are associated with behavioral changes during this window ?
global volume tissue volume substructures networks
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autism social deficits social cognition attention
diagnosis
onset
6 months 12 months 24 months
Changes over time will allow us to make inferences about mechanisms.
neural circuits
1. What brain changes are associated with behavioral changes during this window ?
global volume tissue volume substructures networks
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2. Disease Specific or Associated With Genetic Liability ?
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Rate of macrocephaly (percent) in “autism families” (Lainhart et al., 2006)
2. Disease Specific or Associated With Genetic Liability ?
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Rate of macrocephaly (percent) in “autism families” (Lainhart et al., 2006)
High Risk Infant Sibs
autism
milder cognitive/behavioral deficits
typical development
2. Disease Specific or Associated With Genetic Liability ?
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Rate of macrocephaly (percent) in “autism families” (Lainhart et al., 2006)
High Risk Infant Sibs
autism
milder cognitive/behavioral deficits
typical development
2. Disease Specific or Associated With Genetic Liability ?
Which brain changes are specific to the presence of autistic disorder and which ones are associated with genetic liability only (i.e., necessary but not sufficient) ?
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prediction
brain changes typically precede behavioral changes ex. Parkinson’s Disease
6 months 12 months 24 months
3. Prediction/Early Detection
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6 months 12 months 24 months
joint attention
3. Prediction/Early Detection
Hypothesis:
delayed maturation of the uncinate fasciculus predicts abnormal joint attention ?
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6 months 12 months 24 months
3. Prediction/Early Detection
early brain + behavior trajectories (6, 12 and 18 months) predicting later diagnosis (24, 36 months)
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4. Pathogenesis (Causes/Neurobiological Mechanisms Underlying the Development of Autism)
1. particular brain changes narrow the search for causes
- cortical overgrowth due to increased surface area (Hazlett et al, in press)
- suggests proliferation of progenitor cells/ suggests specific genes (e.g., GSK) (Kim et al, 2010)
?
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4. Pathogenesis (Causes/Neurobiological Mechanisms Underlying the Development of Autism)
1. particular brain changes narrow the search for causes
- cortical overgrowth due to increased surface area (Hazlett et al, in press)
- suggests proliferation of progenitor cells/ suggests specific genes (e.g., GSK)
2. molecular genetic basis underlying brain and behavior trajectories - brain-behavior trajectories constitute ‘new phenotypes’ or definitions of autism - Autism Speaks; partnership with NIH EARLI ACE Network - DNA NIMH Genetics Repository - candidates and genetic signatures (ex. cancer)
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4. Pathogenesis (Causes/Neurobiological Mechanisms Underlying the Development of Autism)
1. particular brain changes narrow the search for causes
- cortical overgrowth due to increased surface area (Hazlett et al, in press)
- suggests proliferation of progenitor cells/ suggests specific genes (e.g., GSK)
2. molecular genetic basis underlying brain and behavior trajectories - Autism Speaks; partnership with NIH EARLI ACE Network - DNA NIMH Genetics Repository - candidates and genetic signatures (ex. cancer)
3. contrast with Fragile X (PI: Hazlett Hazlett, UNC) same behavior / different brains (Hazlett et al., 2009; Hoeft et al., 2011) specific and non-specific effect of background genes (Wassink, in prep)
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- early behavior and - phenotypes trajectories over time - early detection
- mechanisms - prevention - trajectories of brain - pathogenesis
development - treatment
- genetic signatures
Impact of Longitudinal Studies of Early Behavior x Brain x Gene Interactions
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- early behavior and - phenotypes trajectories over time - early detection
- mechanisms - prevention - trajectories of brain - pathogenesis
development - treatment
- genetic signatures
Impact of Longitudinal Studies of Early Behavior x Brain x Gene Interactions
Major understanding of autism will require going beyond single points in time; single brain structures and single genes to predict trajectories of development (particularly around the time of onset of the disorder), to elucidate underlying pathogenetic mechanisms and to develop rational approaches to treatment and prevention.
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Acknowledgements
• funding: NICHD Autism Speaks Simons Foundation LENA Foundation
• IBIS Network Collaborators
• and the contribution of participating families
www.ibis-network.org
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IBIS (Infant Brain Imaging Study) Network
University of North Carolina Joe Piven Heather Cody Hazlett Martin Styner Hongbin Gu Jed Elison Clement Vachet Zhexing Liu Chad Chappell
University of Washington Annette Estes Dennis Shaw Stephen Dager
Washington University Kelly Botteron J Constantino Bob McKinstry John Pruett
Children’s Hospital of Philadelphia Robert Schultz Sarah Paterson
University of Alberta Lonnie Zwaigenbaum
University of Utah Guido Gerig Sylvain Gouttard
McGill University, Montréal Alan Evans Louis Collins Vladimir Fonov Reza Adalat Bruce Pike Penelope Kostopoulos Samir Das
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Acknowledgements
• funding: NICHD Autism Speaks Simons Foundation LENA Foundation
• IBIS Network Collaborators
• and the contribution of participating families
www.ibis-network.org