Sackler Institute for Developmental Psychobiology Weill 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 FunctionConnectivity For recent reviews: Casey, Tottenham, Liston & Durston (2005). Trends in Cognitive Science Casey, Galvan & Hare (2005). Current Opinions in Neurobiology Amso & 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 neuroanatomical structures 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

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

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 JCN

Children Adults Dorsolateral PFC Activity Volume of Activity * * p <.05 Casey et al. 1997

Age vs Performance Correlation of age and performance with brain activity –Partial out age and performance

Age in Years Volume of Activation in MFG (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

% MR Signal Change Ventral Prefrontal Activity during 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 Number of False Alarms Behavioral Performance during Go/Nogo Task Adults Children number of go trials preceding a nogo trial

% MR Signal Change Ventral Prefrontal Activity during 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 Number of False Alarms Behavioral Performance during 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)

Runs Percent Accuracy 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 TICS Cortical Changes with development on a variety of cognitive control tasks

Longitudinal Study (7-12 years) Cortical regions that are recruited more (in red) and less (in blue) with development Sackler Institute, Cornell Medical Durston 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 Analysis at 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 FunctionConnectivity

Sowell et al., 1999 Developmental Differences in Frontostriatal structure Basal GangliaPrefrontal Cortex

Developmental Differences in Frontostriatal Activity Neuroimage 2002 Dev 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). ChildrenAdults Mean Dav 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 % MR SIGNAL CHANGE

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 Psychobiology Weill Medical College of Cornell University Fellows Adriana Galvin Todd Hare Conor Liston Sumit Niogi Staff Jason Buhle Marcella Nurse Faculty Dima Amso Matthew Davidson John Fossella Nim Tottenham Henning 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.