imaging the developing brain in autism joseph piven, m.d. carolina institute for developmental...
TRANSCRIPT
Imaging the Developing Brain in Autism
Joseph Piven, M.D. Carolina Institute for Developmental Disabilities University of North Carolina
Sinneave Family Foundation/Hotchkiss Brain Institute New Developments in Autism Research
June 2009
Conclusions
• The brain in autism is too big.
• Overgrowth occurs around the time of onset of the defining features of autism.
• The timing and pattern of overgrowth provide clues to the underlying neurobiological and genetic mechanisms,
• and is of potential importance for early detection and intervention
MID-SAGITTAL BRAIN AREA in Adolescents and Adults with Autism
mean mm2 (SD) t (df=28) p
autistic (N=15) 12,773 (951)
control I (age/IQ) 11,608 (1075) 3.14 .002
control II (age/SES) 11,671 (956) 3.17 .002
mid-sagittal brain area
Piven et al., 1992
The finding of brain enlargement in autism has been replicated and is consistent with findings from head circumference and post mortem studies
MRI Studies Brain Finding Subject AgePiven et al. (1992) inc mid-sagittal area 18 - 53 yrs Piven et al (1995) inc total brain volume 14 – 29 yrsHazlett et al (2005) inc total brain volume (N=51) 2 yrsCourchesne et al (2001) inc cerebral. gray and white 2 – 4 yrs onlySparks et al (2002) inc total cerebral 3-4 yrsAylward et al (2002) inc TBV (HFA) under 12 yrsLotspeich et al (2004) inc cerebral gray(N=52) 7 – 18 yrPalmen et al (2005) inc TBV, cerebral gray (N=21) 7 – 15 yrs
Schultz et al (unpub) inc TBV, GM, WM (N=117) 7-36 yrs
Head Circumference Studies – Macrocephaly in ~ 20%Kanner (1943), Bailey et al (1995), Steg and Rapoport (1975); Woodhouse et al (1996); Greenstein and Holt (1994); Lainhart et al (1997, 2006); Bolton (1994); Stevenson et al (1997)
Post Mortem Studies – Increased brain weight
Bauman and Kemper, 1996; Bailey et al., 1998
Characterizing the Phenomenon
timing
pattern: regions structures
tissues
clinical correlates
pathogenesis
?brain enlargement is
a real phenomenon
in autism
Anatomy of the Brain
Gray and White Matter
EMS hard segmentations
EMS segmentations overlaid on MRI
cortical gray volume
cortical white volume
Pfefferbaum et al., (1994), A Quantitative MRI Study of Changes in Brain Morphology From Infancy to Late Adulhood, Arch of Neurol.
Age (years)(3 mos – 30 yrs)
in typically-developing individuals
total cerebral To total cerebral white matter
frontal gray parietal gray
temporal gray occipital gray
Age in years
Peak 12 y12 yrs 12 yrs
16 yrs20 yrs
4
more sensitive for detecting individual growth patterns, even in the presence of large inter-individual variationinter-individual variation and non-linear growthnon-linear growth
Longitudinal Methods
time 1 time 2
Giedd et al., Nature Neuroscience, 1999
Longitudinal MRI Study of 2 Year OldsHazlett et al, Arch Gen Psych (2005)
Sample
time 1 2 years of age
autistic 51
typical 14
25
dev. delay 11
age 4 years
Sample Characteristics (Time 1)
N % male years (SD) IQ-SS (SD)#
autism 51 88% 2.7 (0.3) 54.2 (9.4)
controls 25
DD 11 55% 2.7 (0.4) 59.7 (9.4)
TYP 14 64% 2.4 (0.4) 107.5 (18.7)
# IQ-SS = Mullen composite Standard Score
Longitudinal MRI Study of Autism:Brain Volume Adjusted for Gender and Age
autism controls
mean (SE) mean (SE) % diff p
TBV 1264.6 (13.4) 1208.1 (16.2) 4.7 0.008
Longitudinal MRI Study of Autism:
Regional Brain Volumes Adjusted for Gender and Age
autism controls
mean (SE) mean (SE) % diff p
TBV 1264.6 (13.4) 1208.1 (16.2) 4.7 0.008
cerebrum 941.5 (10.5) 890.5 (12.3) 5.7 0.002
cerebellum 114.1 (1.5) 114.4 (2.2) 0.3 0.9
Longitudinal MRI Study of Autism:Brain Volume Adjusted for Gender and Age
autism controls
mean (SE) mean (SE) % diff p
TBV 1264.6 (13.4) 1208.1 (16.2) 4.7 0.008
cerebrum 941.5 (10.5) 890.5 (12.3) 5.7 0.002
gray 676.7 (7.7) 644.2 (8.8) 5.0 0.005
white 264.7 (3.1) 246.2 (3.7) 7.5 0.0001
cerebellum 114.1 (1.5) 114.4 (2.2) 0.3 0.9
% increase in Autism vs. Controls
0.0%
1.0%
2.0%
3.0%
4.0%
5.0%
6.0%
7.0%
8.0%
9.0%
10.0%
% in
cre
ase
Parietal-Occipital Lobe Temporal Lobe Frontal Lobe
Gray Tissue
White Tissue
generalized enlargement of cerebral cortical gray and white matter
The Timing of Brain Enlargement: Clues from Head Circumference Studies
• macrocephalics had normal HC at birth. • macrocephaly noted by 3-4 years of age.
(Lainhart et al., 1997)
• 17/18 macrocephalics, normal HC at birth
(Stevenson et al., 1997)
• 14/15 2-5 year olds MRI subjects with normal HC at birth (Courchesne et al., 2001)
The Timing of Brain Enlargement: Clues from Head Circumference (Hazlett et al., 2005)
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0 3 6 9 12 15 18 21 24 27 30 33 36
Age (months)
He
ad
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cu
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ren
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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
Longitudinal Head Circumference
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0 3 6 9 12 15 18 21 24 27 30 33 36
Age (months)
He
ad
Cir
cu
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ren
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Combined Controls
Autism
brain enlargement detected on MRIonset of HC
enlargement
c/w J. Constantino (pers com)
The Timing of Brain Enlargement: Clues from Head Circumference (Hazlett et al., 2005)
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35
40
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0 3 6 9 12 15 18 21 24 27 30 33 36
Age (months)
He
ad
Cir
cu
mfe
ren
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Combined Controls
Autism
suggests onset of brain enlargement in the latter part of the first year
Longitudinal Trajectory of Brain (cortical WM) Volume Changes from 2 to 4 Years of Age
White
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360
380
1.5 2 2.5 3 3.5 4 4.5 5 5.5 6
Age (years)
Vo
lum
e
Autism
Typical
DD
c/w increased rate of brain growth in autism occurring prior to 2 years of age
time 1 time 2 (18-35 mos) (42-59 mos.)autistic 49 28 controls 36 16
Canadian ‘Infant Sib’ StudyZwaiggenbaum, Bryson, Roberts, Brian, Szatmari (2005)
• 10 of 74 siblings meet strict criteria for ASD at age 36-48 months (recurrence =13.5%)
Canadian ‘Infant Sib’ StudyZwaiggenbaum, Bryson, Roberts, Brian, Szatmari (2005)
• 10 of 74 siblings meet strict criteria for ASD at age 36-48 months (recurrence =13.5%)
• examined at 6, 12 and 18 months with
• 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
Autism Observation Scale for Infants (AOSI) Bryson (2005)
Children with Autism: Features at 12 months*
• poor visual tracking
• decreased eye contact
• do not ‘orient to name’
• decreased social behaviors (smiling, interest and
affect; e.g., peek-a-boo)
• lack basic imitation skills
• atypical reactivity (under- or over-reactive)
*sibs-ASD>sibs-N, controls; all p<.01
Zwaiggenbaum et al., 2005
18-months12-months6-months
10
8
6
4
2
0
control
non-ASD sib
Autism/ASD
3-yeardiagnosis
__
Autism Observation Scale for Infants: Scores ASD and Non ASD Siblings
(Zwaiggenbaum et al., 2005)
18-months12-months6-months
10
8
6
4
2
0
control
non-ASD sib
Autism/ASD
3-yeardiagnosis
__
Autism Observation Scale for Infants: Scores ASD and Non ASD Siblings
(Zwaiggenbaum et al., 2005)
?
consistent with Yirmiya et al 2006; and Landa et al 2007
Children with Autism: Features at 6 months
• many typical social behaviors– eye contact (100%)– reciprocal social smiling (88%)– social interest and affect (88%)
• subtle differences– visual tracking1
– anticipatory responses1
– motor control1,2
1Sibs-ASD>controls; 2Sibs-ASD>Sibs-N; p<.01
Zwaiggenbaum et al., 2005
AOSI Items: anticipatory response, eye contact, social interest and shared affect, reactivity
Social Behaviors Observable at Six Months
Social Behavior at 6, 12 and 18 months
Courtesy of Lonnie Zwaigenbaum, M.D.
18-months12-months6-months
10
8
6
4
2
0
control
non-ASD sib
Autism/ASD
3-yeardiagnosis
__
Autism Observation Scale for Infants: Scores ASD and Non ASD Siblings
(Zwaiggenbaum et al., 2005)
?
consistent with Yirmiya et al 2006; and Landa et al 2007
18-months12-months6-months
10
8
6
4
2
0
control
non-ASD sib
Autism/ASD
3-yeardiagnosis
__
Autism Observation Scale for Infants: Scores ASD and Non ASD Siblings
(Zwaiggenbaum et al., 2005)
onset of autism is post-natal occuring in the latter part of the first year
18-months12-months6-months
10
8
6
4
2
0
control
non-ASD sib
Autism/ASD
3-yeardiagnosis
Autism Observation Scale for Infants: Scores ASD and Non ASD Siblings
Zwaiggenbaum et al., 2005
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40
45
50
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0 3 6 9 12 15 18 21 24 27 30 33 36
Age (months)
Hea
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rcum
fere
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Combined Controls
Autism
Hazlett et al 2005
Onset of Autistic Behavior Onset of Brain Enlargement
head circumference
The convergence of evidence from infant sib behavioral and head
circumference studies suggests that the onset of autistic behavior is temporally related to the onset of brain enlargement in the latter part of the 1st year
AOSI
A Major Shift in Thinking About the Onset of Autism?
• child-rearing practices (1940’s – 1970’s)
A Major Shift in Thinking About the Onset of Autism?
• child-rearing practices (1940’s – 1970’s)
• biological disorder with roots in the brain (Folstein and Rutter, 1977)
A Major Shift in Thinking About the Onset of Autism?
• child-rearing practices (1940’s – 1970’s)
• biological disorder with roots in the brain (Folstein and Rutter, 1977)
• origins in the prenatal period with onset from the earliest possible ages (but not observed til age 2) (Bauman and Kemper)
A Major Shift in Thinking About the Onset of Autism?
• child-rearing practices (1940’s – 1970’s)
• biological disorder with roots in the brain (Folstein and Rutter, 1977)
• origins in the prenatal period with onset from the earliest possible ages (but not observed til age 2) (Bauman and Kemper)
• onset of autistic symptoms and changes in brain volume are both post-natal events occurring ~ the end of the first year of life
– primary vs secondary ?
– speculation: pre-symptomatic period where early intervention may have more potent effects on brain development/symptom emergence
Brain Volume Doubles in the First YearJ. Gilmore, G. Gerig (UNC)
Intracranial Volume
Neonate Year 10
250000
500000
750000
1000000
1250000
* p < 0.0001
Vo
lum
e m
m3
neonate 1 year old
Total Ventricle Volume
Neonate 1 year0
2500
5000
7500
10000
* p < 0.0001
Vo
lum
e m
m3
Total Intracranial Volume
Neonate One Two Four Adult0
250000
500000
750000
1000000
1250000
1500000
1750000
mm
3
2 Neuron and a Synapse in Between
axon dendrites
cell body
synapse
dendrites
Can changes in the size, shape and number of dendritic spines alter brain volume ?
Time Course of Critical Events in the Determination of Human Brain Morphometry
Pu
ber
ty
Bir
th
18 years1 year20 weeks
Rel
ativ
e V
olu
me/
Den
sity
10 years
Neurogenesis
Synaptogenesis
Dendritic and Axonal Development/Remodeling
Myelination
Synaptic Elimination
Synapses
White MatterWhite Matter
Gray Matter
Migration
Neurodevelopmental processes, cortical synapse density, and their relationship to gray and white matter volumes on MRI. Giedd et al. 1999, Sowell et al. 1999.
?
Development of Synapses in the Brain: overdevelopment following by cutting back
Mean synaptic density in human auditory (°); visual (); and , prefrontal (x) cortex as a function of postconceptual age
(from Huttenlocher and Dabholkar, 1997)
Prefrontal:
Visual:
Auditory:
Prefrontal
Visual
Auditory
Phase shift
Dendritic Development Regulated by CREST, a Calcium-Regulated Transcriptional Activator (pyramidal neurons of the hippocampus in mutant mice) Aizawa et al., Science 2004
Post-natal Neurodevelopmental Disorders: Meeting at the Synapse ? Zoghbi, Science 2003
– neuroligins (Nature Genetics, 2003; Science 2007)
– SHANK3 (Nat Genet 2007)
– PTEN (Butler 2005), social deficits in mice (Kwon 2006)
– neurexin (Nature Genetics, 2007)
Hinton VJ,et al (1991): Analysis of neocortex in three males with Fragile X Syndrome. .
Dendritic Pathology in Fragile X
Proteins that are integral to the structure and function of the cortical neuronal excitatory synapse. Proteins with mutations associated with autism are circled.
Serotonin
autism• hyperserotonemia (Schain and Freedman, 1961)• altered serotonin synthesis on PET (Chugani et al., 1997)• SSRI’s for stereotyped behavior (Hollander et al., 2003)• genetic association (Devlin et al., 2005; Sutcliffe et al 2005;
Cook et al 1997)
brain structure and function• fMRI response of amygdala to fear faces (Hariri et al, 2002)• amygdala volume on MRI (Pezawas et al., 2005)
brain development• neurogenesis (Lauder and Bloom, 1974; Gaspar et al 2003)
Serotonin Transporter Promoter Polymorphism (5-HTTLPR)
5-HTTLPR: The Serotonin Transporter Gene
Cerebral Cortical Gray Matter Overgrowth in Autism is Associated
with Functional Variation of the Serotonin Transporter Gene
Tom Wassink (Iowa); Heather Hazlett (UNC); Eric A. Epping (Iowa); Stephan Arndt (Iowa); Steve Dager (Washington); Jerry Schellenberg (Washington); Geri Dawson (Washington) and Joe Piven (UNC)
Archives of General Psychiatry, in press
Table 1. Demographic Data for UNC and UW Samples
Genotype All L/L L/S S/S All L/L L/S S/SNumber 29 11 12 6 15 4 8 3Age (years)* 2.7 ± 0.3 2.8 ± 0.3 2.6 ± 0.3 2.8 ± 0.2 4.0 ± 0.3 4.0 ± 0.4 3.8 ± 0.3 4.4 ± 0.1Head circumf (cm)† 51.2 ± 1.3 50.9 ± 1.2 51.4 ± 1.4 51.3 ± 1.3 52.1 ± 1.3 52.4 ± 0.6 51.7 ± 1.6 52.9 ± 1.3
UNC Sample UW Sample
-0.75
-0.50
-0.25
0.00
0.25
0.50
0.75
1.00
1.25
1.50
LL SL SS
Genotype
Least S
quare
s M
eans
Right Left Total amygdala
b
-0.75
-0.50
-0.25
0.00
0.25
0.50
0.75
1.00
1.25
1.50
LL SL SS
Genotype
Least S
quare
s M
eans
Frontal Gray Temporal Gray
Parietal-Occipital Gray Cortical gray
a
The Serotonin Transporter Polymorphism and Cerebral Cortical Gray Matter Volume in 2 Year olds with Autism
Larger gray matter volume on MRI with the “short” form of the gene
Monoamine Oxidase A and Brain Volume in 2 Year olds with Autism
(Davis, Hazlett, Nopoulos, Sheffield, Piven and Wassink, 2008)
• MAOA metabolizes brain neurotransmitters (serotonin, dopamine, norepinephrine)
• linked to brain structure and behavior
• expressed early in developing cortex
• low activity allele (in the promoter) associated with autism severity (Yirmiya et al 2002)
Association of MAOA Promoter and Cortical Volume 29 Two Year Old Males With Autism
Cerebral Gray Volume By MAOA Genotype In Children with Autism
500
600
700
800
900
Ad
just
ed V
olu
mes
in C
ub
ic C
enti
met
ers
Cerebral White Volume By MAOA Genotype In Children With Autism
200
225
250
275
300
325
Ad
just
ed
Volu
mes
in C
ub
ic C
en
tim
ete
rs high MAOA low MAOA high MAOA low MAOA
F=5.3; p=.01 F=4.8; p=.02
N=17 N=12N=17 N=12 N=17 N=12N=17 N=12
• MAO-L (low activity) allele associated with larger volume
• no association in (28 high and 11 low activity allele) typically developing children
• c/w hypothesis: secondary to increased extracellular serotonin levels
Davis et al, 2008, Amer J Med Genet (Neuropsyc Genet)
The Serotonin Transporter and the Brain in Autism: Evidence for a Modifier Role
• PTEN Mutation associated with ASD and macrocephaly Butler (2005)
The Serotonin Transporter and the Brain in Autism: Evidence for a Modifier Role
• PTEN Mutation associated with ASD and macrocephaly Butler (2005)
• PTEN regulates neuronal arborization (dendritic hypertrophy, inc. spine density) and social interaction in mice Kwon (2006)
The Serotonin Transporter and the Brain in Autism: Evidence for a Modifier Role
• PTEN Mutation associated with ASD and macrocephaly Butler (2005)
• PTEN regulates neuronal arborization and social interaction in mice Kwon (2006)
• Pten and Ser transporter each increase brain volume and alter social behavior in mice (Page et al; PNAS, 2009)
wt Pten (-) Sert (-) (-) (-)
The Serotonin Transporter and the Brain in Autism: Evidence for a Modifier Role
• PTEN Mutation associated with ASD and macrocephaly Butler (2005)
• PTEN regulates neuronal arborization and social interaction in mice Kwon (2006)
• Pten and Ser transporter each increase brain volume and alter social behavior in mice (Page et al; PNAS, 2009)
together interact to: increase brain size and alter social behavior in mice
wt Pten (-) Sert (-) (-) (-)
PUTATIVE AND KNOWN AUTISM-RELATED GENES: Common or Related Pathways from J. Sutcliffe; Science, July 2008 Synapse function and/or neuronal cell adhesion
FMR1A,B Fragile X mental retardation NLGN3B Neuroligin NLGN4B Neuroligin NRXN1B,C Neurexin SHANK3 B,C SH3 and mulitple ankyrin repeat domains CNTNAP2B,C,D Contactin-associated protein-like PCDH10C Protocadherin CNTN3C Contactin
Endosomal trafficking NHE9 (SLC9A9)B, C Na+/H+ exchanger isoform NHE6 (SLC9A6)B Na+/H+ exchanger isoform DIA1 (c3orf58)C Deleted in autism A2BP1C
Ataxin 2-binding protein
Neuronal activity regulation/expression FMR1A,B Fragile X mental retardation MECP2B,C Methyl CpG binding protein DIA1 (c3orf58)C Deleted in autism PCDH10C Protocadherin NHE9 (SLC9A9)B,C Na+/H+ exchanger isoform A2BP1C Ataxin 2-binding protein UBE3AB,C Ubiquitin protein ligase E3A
Implicated in related disorders FMR1A,B Fragile X mental retardation MECP2B,C Methyl CpG binding protein NHE6 (SLC9A6)C Na+/H+ exchanger isoform A2BP1C Ataxin 2-binding protein UBE3AB,C Ubiquitin protein ligase E3A
EN2D Engrailed homeobox 2 SLC6A4 Serotonin transporter MET
proto-oncogene SCN7 Na+ channel, voltage-gated RNF8 Ring finger protein
Other functions
Genes Implicated in Brain Size/ Cerebral Cortical Volume and Pattern of
Development
HOXA1 and Head circumference Conciatori M et al., (2004)
Microcephaly Genes Acquired During Human Evolution (Gilbert, Dobyns, Lahn 2005)
ASPM (abnormal spindle-like microcephaly associated protein) (Merkel-Bobrov et al., 2005)
MCPH1 (microcephalin) (Evans et al., 2005)
CDK5RAP2 (cyclin dependent kinase 5 regulatory assocated protein 2) (Bond et al, 2005)
CENPJ (centromere-associated protein J) (Bond et al, 2005)
Emx2, Pax6 – changes in anterior-posterior size gradients (Monuki and Walsh, 2001)
Ephrin signaling and cerebral cortical volume (Depaepe et al., 2005)
Mouse QTL’s associated with increased cortical volume (Beatty and Laughlin 2006)
It is likely that multiple genes interact to cause brain and behavior changes associated with autism
genes cells/metabolites brain behavior
Brain – Behavior Relationships: Amygdala
implicated in social cognition (orienting to faces)
Amygdala Enlargement at Age 2-4 Years
Right Amygdala
0.0
0.5
1.0
1.5
2.0
2.5
0 1 2 3 4 5 6
Age (years)
Vo
lum
e (
cm
3 )
Autism
Combined Controls
p < .001
Mosconi et al (2009) Archives General Psychiatry
Joint Attention and Amygdala Volume at Age 2-4 Years
social referencing between two individuals coordinating attention to an object
Joint Attention and Amygdala Volume at Age 2-4 Years
develops normally between 9 and 15 months of age
Joint Attention and Amygdala Volume at Age 2-4 Years
• critical for early social, language and cognitive development• abnormal in autism
Mosconi, Reznick, Mesibov, Piven; JADD (2009)
Joint attention (response to JA; initiating JA)
The Social Orienting Continuum and Response Scale (SOC-RS)
extracted/coded systematically from ADOS videotapes.
joint attention specifically associated with (R) amygdala volume but not associated with other social (e.g., social gestures) or repetitive
behaviors in autistic individuals at age 2-4.
Right Amygdala
0.0
0.5
1.0
1.5
2.0
2.5
0 1 2 3 4 5 6
Age (years)
Vo
lum
e (c
m3 )
Autism
Combined Controls
p < .001
Mosconi et al (2009) Archives General Psychiatry
Joint Attention associated with Amygdala Volume at Age 2-4 Years but not other social (e.g., social gestures) or repetitive behaviors.
Right Amygdala
0.0
0.5
1.0
1.5
2.0
2.5
0 1 2 3 4 5 6
Age (years)
Vo
lum
e (c
m3 )
Autism
Combined Controls
p < .001 consistent with Nacewitz et al (2006) suggesting early compensatory response (~ hypertrophy) of the amygdala
Bigger Amygdala ~ Better Joint Attention
Future Directions
Scanning Very Early Developmentin Infants and Toddlers at Risk for ASD
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0 3 6 9 12 15 18 21 24 27 30 33 36
Age (months)
Hea
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ceCombined Controls
Autism
IBIS (Infant Brain Imaging Study) Network IBIS (Infant Brain Imaging Study) Network
500 at-risk sibs examined longitudinally 6 24 months
NIH Autism Center of Excellence (www.ibis-network.orgwww.ibis-network.org )
Gogtay et al. (2004); N=13, 4-21 years of age; scans q2 years x 10 years
Cortical Cortical
CC
Development of Major Fiber Tracts using Diffusion Tensor Imaging (DTI)
Combination of Major Fiber Tracts:
DTI data: EPI 2x2x2mm3
Superior longitudinal (yellow)
Splenium/genu (red)
Cortico-spinal (blue)Fractional Anisotropy
illustrating strong fiber tracts
(Weili Lin, UNC)
Tractography showing major fiber tracts
(Fillard/Gerig, UNC)
3Tesla High-Resolution DTI
Development of the Corpus Callosum with Diffusion Tensor Imaging
neonate (2 wks) adultinfant (1 year)
Fractional anisotropy (FA) of DTI of neonate (left) and 1 yr old (second left) show tractography of the commissural bundle, cut at the midsagittal plane, with color-coding FA. The change of colors (blue = low fractional anisotropy) demonstrates the increased structuring of white matter over this early period.
Quantitative Tractography of the Motor Sensory Tract at Two weeks, One and Two Years of Age (Phenotype = Trajectory)
Motor-Sensory
0
1000
2000
3000
4000
5000
6000
7000
-20 -10 0 10 20
Location
FA
Neonate
1yr
2yrs
Fig. 8: Tractography of the motor-sensory tract colored with FA (left) and FA plotted along the curved tracts for neonates, 1 and 2 years olds (right). The coordinate origin is put into the axial plane through the internal capsule. Please note the significant increase of FA at all locations of the fiber tract and the very similar pattern for each age group.
SSSignificant increase of FA over time in all locations across the fiber tract and similar pattern for each age group
from G. Gerig and J. Gilmore (UNC Medical ImageAnalysis Laboratory)
The Trajectory of Brain and Behavior Development Over Time ?
Fiber Tracts
Can we measure the development of the fiber tracts associated with joint attention ?
Can we identify early changes (under 9 months) in children that go on to have ASD ?
PUTATIVE AND KNOWN AUTISM-RELATED GENES: Common or Related Pathways from J. Sutcliffe; Science, July 2008 Synapse function and/or neuronal cell adhesion
FMR1A,B Fragile X mental retardation NLGN3B Neuroligin NLGN4B Neuroligin NRXN1B,C Neurexin SHANK3 B,C SH3 and mulitple ankyrin repeat domains CNTNAP2B,C,D Contactin-associated protein-like PCDH10C Protocadherin CNTN3C Contactin
Endosomal trafficking NHE9 (SLC9A9)B, C Na+/H+ exchanger isoform NHE6 (SLC9A6)B Na+/H+ exchanger isoform DIA1 (c3orf58)C Deleted in autism A2BP1C
Ataxin 2-binding protein
Neuronal activity regulation/expression FMR1A,B Fragile X mental retardation MECP2B,C Methyl CpG binding protein DIA1 (c3orf58)C Deleted in autism PCDH10C Protocadherin NHE9 (SLC9A9)B,C Na+/H+ exchanger isoform A2BP1C Ataxin 2-binding protein UBE3AB,C Ubiquitin protein ligase E3A
Implicated in related disorders FMR1A,B Fragile X mental retardation MECP2B,C Methyl CpG binding protein NHE6 (SLC9A6)C Na+/H+ exchanger isoform A2BP1C Ataxin 2-binding protein UBE3AB,C Ubiquitin protein ligase E3A
EN2D Engrailed homeobox 2 SLC6A4 Serotonin transporter MET
proto-oncogene SCN7 Na+ channel, voltage-gated RNF8 Ring finger protein
Other functions
genetics of early brain and behavior development
30
35
40
45
50
55
0 3 6 9 12 15 18 21 24 27 30 33 36
Age (months)
He
ad
Cir
cu
mfe
ren
ce
Combined Controls
Autism
prediction ?
intervention ?
Contributors
UNC Heather Hazlett, Ph.D. Michele Poe, Ph.D. Matt Mosconi, Ph.D. Iowa
Tom Wassink, M.D.
U of UtahGuido Gerig, Ph.D.
U Washington McMaster Steve Dager, M.D. Lonnie Zwaigenbaum, M.D.Geri Dawson, Ph.D.
AcknowledgementsNIH (NICHD, NIMH), Autism Speaks, Simons FoundationAll of t he families that participated in our research.