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
0.6
0.8
1
1 2 3 4 5 6 7
time (frame #)
Adult
Child
Right SM medial
-0.2
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
-0.2
0
0.2
0.4
0.6
0.8
1
1 2 3 4 5 6 7
time (frame #)
Adult
Child
Left visual
-0.2
0
0.2
0.4
0.6
0.8
1
1.2
1 2 3 4 5 6 7
time (frame #)
Adult
Child
Right visual
-0.2
0
0.2
0.4
0.6
0.8
1
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
700
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.