1. NeuroDevNet: Opportunities in Brain Development Across Canada James N
NeuroDevNet: Opportunities in Brain Development Across Canada James N. Reynolds, PhD January 9, 2013

3. NeuroDevNet Research Operations
Developing
Brain
ASD CP
FASD
Opportunities
PROJECTS
Animal Models
COMMON
PLATFORMS
Genetics
Imaging
Neuroethics
Neuroinformatics
KNOWLEDGE TRANSFER & EXCHANGE
INDIVIDUAL OUTCOMES & PRACTICE CHANGE
EVALUATION / METRICS

4. Fetal Alcohol Spectrum Disorder: Gene-environment interactions; predictive biomarkers; and the relationship between structural alterations in the brain and functional outcomes

5. Research Questions
Are there genetic and/or epigenetic modifications that could be predictive of outcomes in children impacted by prenatal alcohol exposure?
What is the relationship between structural and functional alterations in the brain induced by gestational alcohol exposure and functional outcomes in offspring?

6. Genetic Susceptibility
Brain Connectivity
NeuroDevNet Initiative on FASD
Genetic Susceptibility
Eye Tracking
Animal Models
Fetal Alcohol
Spectrum Disorder
(FASD)
Brain Volume
Cognition & Behaviour
Cortical Thickness 6

7. FASD Team Dr. James Reynolds, Queen’s University (Project Lead)
Dr. Joanne Weinberg, University of British Columbia (Co-Lead, neurobehavioural and epigenetic effects of prenatal ethanol exposure in the rat)
Ab Chudley, University of Manitoba (Co-Lead, Clinical genetics study)
Dr. Christian Beaulieu, University of Alberta (Multi-site acquisition and analysis of MRI data)
Dr. Dan Goldowitz, University of British Columbia (Ethanol-induced neuronal cell death in genetically defined mouse lines)
Dr. Carmen Rasmussen, University of Alberta (Clinical neurobehavioural studies)
Dr. Dawa Samdup, Queen’s University (Clinical neurobehavioural studies)
Dr. Sarah Nikkel, Children’s Hospital of Eastern Ontario (Clinical neurobehavioural studies)
Dr. Ana Hanlon-Dearman, University of Manitoba (Clinical neurobehavioural studies)
Dr. Gail Andrew, University of Alberta (Clinical neurobehavioural studies)
Dr. Tim Oberlander, University of British Columbia (Clinical neurobehavioural studies)
Dr. Michael Kobor, University of British Columbia (Human and rat epigenetic studies)
Dr. Marie-Pierre Dube, University of Montreal (Clinical genetics statistical analysis)

8. Rat Model: Study Overview
Compete for chocolate
P25-28
Motor Behaviour
P27-29
Play Behaviour P29/36
Chronic Mild Stress
(Adolescence)
PRE
Corticosterone
Dominance
Status
Social Behaviour
POST
Activity (Anxiety)
Prenatal Treatment
G1- G20
Motor Behaviour
P41/ P48
Dominance
Status
Radial Arm
Mace
(working
memory) P
Novel Object recognition (learning and memory)
P60
T-maze
(working memory)
P75-105
Compete for chocolate P
Collect brain, blood, liver at PN 1, 8, 13, 21, 41, 48, 150 for hormone & epigenetic analyses

9. Social status influences neurobehavioural outcomes in PAE animals.

10. >200 “Biological Processes” altered in the brain of rats after PAE
Hippocampus
Prefrontal cortex
Neurological processes
Immune processes
Neurodevelopment
Glucocorticoid biosynthesis
Stress-activated MAPK cascade
Neurological processes
Immune processes
Candidate FASD genes
Regulation of lymphocyte differentiation
Regulation of neuron differentiation
Circadian rhythm

11. Mouse Model: Study Design
Strains used: C57BL/6, DBA/2, panel of 25 BXD recombinant inbred strains
Pregnant mice treated with ethanol or an isocaloric dose of maltose-dextrin at embryonic day (E)9, embryos harvested 8 hours later and cell death in brainstem and forebrain assessed by TUNEL
Neonatal mice treated on postnatal day (P) 7 with ethanol or an isocaloric dose of maltose-dextrin, brain harvested 8 hours later and cell death in forebrain assessed by anti-caspase 3 IHC
QTL analysis planned

12. Recombinant inbred strains of mice exhibit differences in ethanol-induced cell death
BXD51
BXD80

13. Ethanol-induced cell death in E9 mouse embryos

15. FASD Clinical Project Outline
Target Recruitment: 100 FASD, 100 Control
Actual Recruitment: 91 FASD, 31 PAE, 116 Control
Clinics Engaged
Kingston
Ottawa
Winnipeg
Edmonton
Cold Lake
Vancouver
Database Creation: (1) RedCAP; (2) LORIS

16. PSYCHOMETRIC TESTS:
Woodcock Reading Mastery Tests
NEPSY II
Animal Sorting
Arrows
Auditory Attention
Response Set
Inhibition
Memory for Names
Woodcock-Johnson Tests of Achievement
Quantitative Concepts
Working Memory Test Battery for Children
Digit Recall
Block Recall

17. EYE MOVEMENT TASKS:
Prosaccade
Antisaccade
Memory Guided
Free Viewing
Antisaccade Task
Memory Guided Saccade Task 1 2

18. PHYSIOLOGICAL, GENETIC & EPIGENETIC MARKERS:
Buccal Swabs – Epigenetic Analysis
Saliva Samples – Cortisol, Gene Expression
BRAIN IMAGING:
Structural MRI
DTI
Resting State fMRI

19. Multi-Site Imaging

20. Multi-Site Imaging

21. Tractography of the Corpus Callosum

22. Direction errors in the antisaccade task were negatively correlated to FA score in the splenium of the control group
(r= -0.83, p< )

23. retino-geniculo-cortical pathway
Neural Circuitry Controlling Saccade Production
Frontal Cortex
SEF
Parietal
DLPFC
Cortex
FEF
Visual Cortex CD
Thalamus
LGN
retino-geniculo-cortical pathway
direct pathway
GPe
indirect pathway
STN
SNr
SCi
SCs
Retina
Basal Ganglia
retinotectal pathway
retinotectal pathway
Cerebellum
Saccade
PPRF

24. Antisaccade direction errors correlate to deficits in response inhibition in children with FASD
NEPSY II Inhibition Task

25. Resting State fMRI
Control
FASD

28. Natural Viewing Experiment

29. Performance of the Classifier
Overall Accuracy: 77.3%
Control
ADHD
FASD
0.77
0.12
0.11
0.81
0.08
0.20
0.09
0.71
Sensitivity Specificity
0.77
0.85
0.81
0.89
0.71
0.91
Tseng et al., J. Neurol. (2012)

30. Looking Forward…
Integrate analyses across all of the experimental platforms (imaging – genetics – neurobehavioural phenotypes) as well as between the clinical and animal model studies
Evaluate the efficacy of intervention strategies
Develop new, cross-cutting research themes to address common co-morbidities in neurodevelopmental disorders
Form new national and international partnerships that will accelerate the pace of discovery and open up new research directions

31. Intervention Research
Strongest Families: FASD
A family-centered intervention designed for parents/caregivers of children with FASD between the ages of 4 and 12 years
Neurofeedback
Evaluate the efficacy of neurofeedback (EEG biofeedback) training in a cohort of children with FASD and their parents/caregivers
Exergames
Aerobic exercise and computer gaming linked with social networking

32. Questions?