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

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

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

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?

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

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)

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) P120-150 Novel Object recognition (learning and memory) P60 T-maze (working memory) P75-105 Compete for chocolate P110-113 Collect brain, blood, liver at PN 1, 8, 13, 21, 41, 48, 150 for hormone & epigenetic analyses

Social status influences neurobehavioural outcomes in PAE animals.

>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

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

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

Ethanol-induced cell death in E9 mouse embryos

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

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

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

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

Multi-Site Imaging

Multi-Site Imaging

Tractography of the Corpus Callosum

Direction errors in the antisaccade task were negatively correlated to FA score in the splenium of the control group (r= -0.83, p< 0.0001)

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

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

Resting State fMRI Control FASD

Natural Viewing Experiment

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)

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

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

Questions?