imaging the developing brain in autism joseph piven, m.d. carolina institute for developmental...

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

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

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

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

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

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)

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

Age (months)

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

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

Age (months)

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)

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

Age (months)

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

1.5 2 2.5 3 3.5 4 4.5 5 5.5 6

Age (years)

Autism

Typical

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

control

non-ASD sib

Autism/ASD

3-yeardiagnosis

Autism Observation Scale for Infants: Scores ASD and Non ASD Siblings

(Zwaiggenbaum et al., 2005)

control

non-ASD sib

Autism/ASD

3-yeardiagnosis

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

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.

control

non-ASD sib

Autism/ASD

3-yeardiagnosis

consistent with Yirmiya et al 2006; and Landa et al 2007

control

non-ASD sib

Autism/ASD

3-yeardiagnosis

onset of autism is post-natal occuring in the latter part of the first year

control

non-ASD sib

Autism/ASD

3-yeardiagnosis

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

Age (months)

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

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

neonate 1 year old

Total Ventricle Volume

Neonate 1 year0

* p < 0.0001

Total Intracranial Volume

Neonate One Two Four Adult0

250000

500000

750000

1000000

1250000

1500000

1750000

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

18 years1 year20 weeks

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

LL SL SS

Genotype

Least S

Right Left Total amygdala

LL SL SS

Genotype

Least S

Frontal Gray Temporal Gray

Parietal-Occipital Gray Cortical gray

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

Cerebral White Volume By MAOA Genotype In Children With Autism

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)

• PTEN regulates neuronal arborization (dendritic hypertrophy, inc. spine density) and social interaction in mice Kwon (2006)

• 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 (-) (-) (-)

• 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 1 2 3 4 5 6

Age (years)

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

develops normally between 9 and 15 months of age

• 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 1 2 3 4 5 6

Age (years)

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 1 2 3 4 5 6

Age (years)

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

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

Age (months)

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

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

-20 -10 0 10 20

Location

Neonate

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

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

Age (months)

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.

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