Sackler Institute for Developmental PsychobiologyWeill Medical College of Cornell University

BJ Casey, Ph.D., Sackler Professor and Director

Sackler Institute for Developmental Psychobiology

Weill Medical College of Cornell University

Pediatric Imaging

Functional changes with development

A B C

MRI fMRI DTI

Structure Function Connectivity

For recent reviews: Casey, Tottenham, Liston & Durston (2005). Trends in Cognitive ScienceCasey, Galvan & Hare (2005). Current Opinions in NeurobiologyAmso & Casey (in press). Current Directions in Psychological Science

Magnetic Resonance Imaging (MRI)of the Developing Human Brain

Structural MRI to track changes in size and shape

of neuroanatomicalstructures with development

Functional MRI (fMRI) to track changes in brain and behavior with development

Casey et al 2005 Current Opinions in Neurobiology

A B C

Diffusion Tensor Imaging (DTI) to track

strengthening of connectivity of fiber tracts

with development

Pediatric Issues(Precision of Measurement)

• Hemodynamic Response

• Spatial Normalization

• Age-Appropriate Tasks

• Behavioral Performance Differences

Average timecourses for each region

Right SM lateral

-0.2

0

0.2

0.4

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0.8

1

1 2 3 4 5 6 7

time (frame #)

Adult

Child

Right SM medial

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0

0.2

0.4

0.6

0.8

1

1.2

1 2 3 4 5 6 7

time (frame #)

Adult

Child

Left SM medial

-0.2

0

0.2

0.4

0.6

0.8

1 2 3 4 5 6 7

time (frame #)

Adult

Child

Left SM lateral

-0.2

0

0.2

0.4

0.6

0.8

1

1 2 3 4 5 6 7

time (frame #)

Adult

Child

Left SMA

-0.2

0

0.2

0.4

0.6

0.8

1

1 2 3 4 5 6 7

time (frame #)

Adult

Child

Right SMA

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0

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1

1 2 3 4 5 6 7

time (frame #)

Adult

Child

Left visual

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0

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1.2

1 2 3 4 5 6 7

time (frame #)

Adult

Child

Right visual

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1.2

1 2 3 4 5 6 7

time (frame #)

Adult

Child

p= .04 p= .06

p= .34

p= .45

p= .02

p= .0001 p= .0008

p= .51 p= .10

Uncorrected p-values arein black, significantcorrected p-value in red.

Time courses are similar for children and adultsKang et al, Neuroimage 2003

Superior Temporal Sulcus, x = 51

-10 -15 -20 -25 -30

•• •••

plottedz values

predeterminedy values

y value

-20

-15

-10

-5

0

-10 -15 -20 -25 -30

Adult

Child

There are only small differences between adults and children in sulcus location

Burgund et al Neuroimage 2002

Common Stereotactic Space

Age Appropriate Paradigms

What is changing with development?

-behavioral level

-neural level

Immature cognition is characterized by greater susceptibility to interference

Ability to suppress inappropriate thoughts and actions in favor of appropriate ones (cognitive control).

- adjust/alter thoughts and actions when predictions are violated (flexible rules use, E. Miller)

Casey et al. 2000, 2002, 2005a, b,c

Spiderman NoGo Task

“Try to catch Spiderman, but no, no, never catch the Green Goblin or you’ll be sorry!”

Shultz, et al. 2003

Recruitment of Prefrontal Cortex across age

Casey et al. 1997 JCN

Children Adults

1800

1500

1200

900 600

300

0

Dorsolateral PFC Activity

Vol

ume

of A

ctiv

ity

*

* p < .05 Casey et al. 1997

Age vs Performance

• Correlation of age and performance with brain activity– Partial out age and performance

7 8 9 10 11 12 21

Age in Years

2400

2000

1600

1200

800

400

Vo

lum

e o

f A

ctiv

atio

n in

MF

G (

mm

3)

Prefrontal Activity as a function of Age

Adapted from Casey et al., 1997 JoCN

Neuroanatomical correlates of go no/go performance

Sackler Institute

Durston et al (2002)Developmental Science

Age vs Performance

• Correlation of age and performance with brain activity– Partial out age and performance – Assumes linearity

Age vs Performance

• Correlation of age and performance with brain activity– Partial out age and performance – Assumes linearity

• Parametric manipulation of task difficulty

% M

R S

ign

al C

ha

ng

e

1 3 5 1 3 5

Ventral Prefrontal Activityduring Go/Nogo Task

Adults Children

number of go trials preceding a nogo trial

Parametric Manipulation: vary # of preceding Gos before a NoGo

Time

Level 1

Level 2

Level 3

Nu

mb

er

of

Fa

lse

Ala

rms

1 3 5 1 3 5

Behavioral Performanceduring Go/Nogo Task

Adults Children

number of go trials preceding a nogo trial

% M

R S

ign

al C

ha

ng

e

1 3 5 1 3 5

Ventral Prefrontal Activityduring Go/Nogo Task

Adults Children

number of go trials preceding a nogo trial

Parametric Manipulation:vary # of preceding Gos before a NoGo

Time

Level 1

Level 2

Level 3

Nu

mb

er

of

Fa

lse

Ala

rms

1 3 5 1 3 5

Behavioral Performanceduring Go/Nogo Task

Adults Children

number of go trials preceding a nogo trial

Age vs Performance

• Correlation of age and performance with brain activity– Partial out age and performance – Assumes linearity

• Parametric manipulation of task difficulty

• Matching performance (pre and post scan)

1 2 3 4 5

100 -

80 -

60 -

Runs

Per

cent

Acc

urac

y

Performance over Time

Adults

Children

Adapted from Thomas et al 1999

Age vs Performance

• Correlation of age and performance with brain activity– Partial out age and performance – Assumes linearity

• Parametric manipulation of task difficulty

• Matching performance (pre and post scan)– Ages differ with time on task (pre-matching)

Schlaggar et al 2002

Area is active regardless of age or performance

Activity differs as a function of performance rather than age

Activity differs as a function of age, regardless of performance

Schlaggar et al 2002

Area is active regardless of age or performance

Activity differs as a function of performance rather than age

Activity differs as a function of age, regardless of performance

Schlaggar et al 2002

Area is active regardless of age or performance

Activity differs as a function of performance rather than age

Activity differs as a function of age, regardless of performance

What is changing with development?Diffuse/focal Progressive/Regressive

Brown et al 2005 Neuroimage

Casey et al. 2005 TICS

Cortical Changes with development

on a variety of cognitive controltasks

Longitudinal Study (7-12 years)Cortical regions that are recruited more

(in red) and less (in blue) with development

Sackler Institute, Cornell MedicalDurston et al in press Dev Science

Durston et al. in press Developmental Science

Longitudinal fMRI in typical development(Whole brain analyses based 21 scans)

Within Ss Analysis Between Ss Analysis Between Ss Analysisat different ages of different ages of same ages

Durston et al in press Dev Science

Fine-tuning of neural systems with development

A B C

MRI fMRI DTI

Structure Function Connectivity

Sowell et al., 1999

Developmental Differences in Frontostriatal structure

Basal Ganglia Prefrontal Cortex

Developmental Differences in Frontostriatal Activity

Neuroimage 2002Dev Science 2002

Prefrontal Cortex

Basal Ganglia

Developmental Differences in Frontostriatal Activity

• Preliminary data suggest dissociation between allelic variants in dopamine genes expressed predominantly in prefrontal cortex and basal ganglia, respectively.

Brightness corresponds to the relative anisotropy and color is direction of greatest diffusion (red = right-left, green = anterior-posterior, blue = superior-inferior). Boxes representing prefrontal white matter ROIs

Mean prefrontal white matter Dav in children (7-10 years old) and adults (22-31 years old). Average diffusion is 7.7% lower in adults than in children (t = 3.17, p<.01).

Children Adults

Mea

n D

av

750

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650

Development of Frontal and Posterior Tracts

Task Specific Connectivity

Liston et al. submitted

Prefrontal Cortex

Striatum

Fiber tracts connecting Prefrontal and striatum

Frontostriatal connectivity

correlated with frontostriatal

activity, especially in the striatum.

PFC

Striatum

% M

R S

IGN

AL

CH

AN

GE

Frontostriatal connectivity in correlated with how well the individuals with ADHD performed the go/nogo task.

In ADHD parents - as

frontostriatal connectivity increased -

performance approached

that of parents w/o ADHD.

Traditionally, the focus of biological research on ADHD has been on neurotransmitters within prefrontal circuitry like dopamine and norepinephrine.

The findings highlight the need to also consider genetic and environmental factors that may alter myelin and axonal migration (e.g. neurotrophin factors and white matter injury).

The imaging data suggests a fine-tuning of neural systems with development (MRI, fMRI and DTI).

Brain regions associated with more basic functions such as sensorimotor processes, mature first.

This development is followed by association areas involved in top-down control of behavior (e.g., cognitive control and frontostriatal circuitry).

(shift from concrete rule learning to flexible & abstract)

Conclusions

Sackler Institute For Developmental PsychobiologyWeill Medical College of Cornell University

Fellows Adriana Galvin

Todd Hare Conor Liston Sumit Niogi

StaffJason Buhle

Marcella Nurse

Faculty Dima Amso

Matthew DavidsonJohn Fossella

Nim TottenhamHenning Voss

Sarah Durston (Utrecht/Sackler) Richard Watts (New Zealand)

Gary Glover (Stanford)

Acknowledgments:Work funded in part by R01 MH63255, P50 MH62196, R01 DA018879, R21 DA15882 and the Mortimer Sackler family.