1. Evaluation of Spatial Working Memory Function in Children and Adults with FASD : A Functional Magnetic Resonance Imaging Study Krisztina Malisza, PhD Institute for Biodiagnostics National Research Council of Canada

2. FMRI What are we trying to do? Neural Activity In Response to task Where Detection How Much Quantify

3. What do we measure with fMRI? Brain Activity Blood Flow O2O2 dHb MR Signal Blood Oxygenation Level-Dependent Imaging

4. fMRI Data Acquisition Block Design  =

6. Objectives: Develop MRI based techniques to aid diagnosis of FASDDevelop MRI based techniques to aid diagnosis of FASD To determine if there are different regions of fMRI activity in subjects with FASD than controls using a working memory taskTo determine if there are different regions of fMRI activity in subjects with FASD than controls using a working memory task

7. Psychological tests significant differences between children and adults (p < 0.05) significant differences between children and adults (p < 0.05) greater errors in FASD group than controls overall greater errors in FASD group than controls overall -Mean errors: (p < 0.05) -FASD =17.8 ± 8.6 -Controls = 13.1± 8.6 Self-Ordered Pointing Test of visual working memory and strategic memory Test of visual working memory and strategic memory Presented with n sets of n pictures Presented with n sets of n pictures (n = 6, 8, 10 or 12) In each sheet of a given set, subject must touch a different picture In each sheet of a given set, subject must touch a different picture

8. No statistically significant differences in children No statistically significant differences in children trends towards group differences favoring controls in adults (p < 0.1) trends towards group differences favoring controls in adults (p < 0.1) Wisconsin Card Sorting Task Successful performance requires Successful performance requires »Planning ability »Cognitive flexibility »Working memory »Response inhibition »Concept formation and reasoning

9. Continuous Performance Task Detect the presence of targets in a series of trials that include distracters Detect the presence of targets in a series of trials that include distracters Measures: # correct responses; correct response latency; probability of a hit; probability of a false alarm Measures: # correct responses; correct response latency; probability of a hit; probability of a false alarm FASD subjects performed similarly to controls on all measures except mean latencies of correct responses FASD subjects performed similarly to controls on all measures except mean latencies of correct responses  significantly longer than controls p <0.01  Indicates that group differences on other measures were unlikely due to group differences in ability to remain on task.010

10. N-BackTasks (n=0) Simple (2 1 4 3) (n=1) One-back (NR 2 1 4) (n=2) Two-back (NR NR 2 1)

11. (n=1) Blank (NR 2 NR 4) N-BackTasks

12. 4 fMRI tasks: 4 fMRI tasks:  Saccadic eye movement  Finger movement  Working memory (spatial, object)  Procedural learning  Attention

13. Lobes of the Cerebral Cortex In: Psychology, Canadian Edition. Ed. C. Wade, C. Tavris, D. Saucier, L. Elias, 2004, Prentice Hall, Toronto Attention Response selection Working memory Memory Spatial perception Discrimination

14. MethodsSubjects: Children (7-12 years); Adults (18-33 years) Child FASD n=14 Child Control n=15 5 ARND, 6 pFAS, 3 FAS5 ARND, 6 pFAS, 3 FAS Adult FASD n=10 Adult Control n=10 6 ARND, 1 pFAS, 3 FAS6 ARND, 1 pFAS, 3 FASfMRI 1.5T GE Signa LX MRI system Gradient-Echo Echo Planar Imaging (EPI)Gradient-Echo Echo Planar Imaging (EPI) 3 activation states alternated with 4 rest states (NR=56)3 activation states alternated with 4 rest states (NR=56)

15. Data Analysis  50% correct responses on fMRI tasks  50% correct responses on fMRI tasks  Children (FASD: Control):  Blank: 9:14  1-Back: 7:13  Adults (FASD: Control):  Blank: 10:10  1-Back: 6:9

16. SPM 99 (computer program)  Images corrected for motion, normalised to a adult or child template then smoothed  Individual activations in more difficult tasks (n=1) subtracted from simple (n=0) task Data Analysis

17. Open bars: Controls; Filled bars: FAS participants Combined adult and child fMRI task performance

18. Children (11 yr female) Blank-Simple FAS pFAS control

19. Children (11 yr female) One-Back-Simple FAS pFAS control

20. Adult (female) Blank-Simple ARND 26 yrs FAS 25 yrs Control 26 yrs

21. Adult (female) One-Back -Simple ARND 26 yrs FAS 25 yrs Control 26 yrs

22. One sample t-test (p <0.01) Group activity in Children a) a)Blank - Simple FASD (n=9) b) b)Blank - Simple Control (n=8) c) c)One-Back - Simple FASD (n=7) d) d)One-Back - Simple Control (n=8)

23. a) a)Blank - Simple FASD (n=10) b) b)Blank - Simple Control (n=9) c) c)One-Back - Simple FASD (n=6) d) d)One-Back - Simple Control (n=6) One sample t-test (p <0.01) Group activity in Adults

24. fMRI All Adults & Children : Consistent activations in brain regions associated with working memory (bilateral DLPFC) and attention (cingulate)Consistent activations in brain regions associated with working memory (bilateral DLPFC) and attention (cingulate) increased parietal and frontal cortex activity at superior slices with increasing task difficultyincreased parietal and frontal cortex activity at superior slices with increasing task difficulty All FASD participants: Greater Orbital and inferior-middle frontal activations observed than control subjects (particularly Blank)Greater Orbital and inferior-middle frontal activations observed than control subjects (particularly Blank) Structural brain abnormalities (reduction in orbito- frontal size) previously observed (Sowell Cereb cortex 2002; 12:856)Structural brain abnormalities (reduction in orbito- frontal size) previously observed (Sowell Cereb cortex 2002; 12:856)

25. ChildrenFASD: -greater cingulate cortex at inferior brain slices -less activity in frontal cortex with increased task difficulty Control children: - greater cingulate and frontal activation at more superior slice levels - more parietal activity - increased frontal functional activity with increasing task difficulty (opposite of FASD) fMRI

26. AdultsFASD: - greater cingulate cortex at inferior brain slices - greater cingulate cortex at inferior brain slices - greater superior frontal cortex activity than control - overall less activity in FASD compared to controls fMRI

27. Anatomical Images No statistically significant differences observed in: No statistically significant differences observed in: T1 or T2 relaxation times T1 or T2 relaxation times Magnetization contrast images Magnetization contrast images corpus callosum volumes (normalized to cerebrum) - but there are trends. corpus callosum volumes (normalized to cerebrum) - but there are trends. Examine corpus callosum shape and location within brain and between FASD classifications in both children and adults. Examine corpus callosum shape and location within brain and between FASD classifications in both children and adults. Previous studies shown abnormalities in this area (Bookheimer et al) Previous studies shown abnormalities in this area (Bookheimer et al)

28. Conclusions Significant latency of response for FASD subjects compared to controls – but both groups paying attention!! Significant latency of response for FASD subjects compared to controls – but both groups paying attention!! Variability between subjects and small subject numbers necessitates comparisons on an individual subject basis. Variability between subjects and small subject numbers necessitates comparisons on an individual subject basis. At least 2 different brain regions show distinct patterns of activity in FASD compared to control subjects. This suggests fMRI may be an adjunctive tool for diagnostics. At least 2 different brain regions show distinct patterns of activity in FASD compared to control subjects. This suggests fMRI may be an adjunctive tool for diagnostics.

29. Future Studies and Pilot Study Limitations FMRI: Large sample size required to enable group comparisonsLarge sample size required to enable group comparisons Event-related design required for dealing with an affected population such as FASDEvent-related design required for dealing with an affected population such as FASD Effective distinction between classifications requires considerations of co-morbidities (ADHD)Effective distinction between classifications requires considerations of co-morbidities (ADHD) Need for matching on socio-economic basisNeed for matching on socio-economic basis Anatomical Data: Closer examination of striatal and cortical structures within sub classifications of FASDCloser examination of striatal and cortical structures within sub classifications of FASD Complete 3D volumetric acquisition at high spatial resolutionComplete 3D volumetric acquisition at high spatial resolution

30. Ethical considerations in pediatric neuroimaging - CIHR New Emerging Team in Neuroethics Legal and ethical standards in Canada (U.S.) Legal and ethical standards in Canada (U.S.) Understanding the risks and benefits of Neuroimaging Understanding the risks and benefits of Neuroimaging Reduction of stress and motion through training Reduction of stress and motion through training Sedation in Imaging Sedation in Imaging Development of guidelines Development of guidelines Dissemination of Information Dissemination of Information research and medical professionals, and ethics boards of risks and benefits of pediatric neuroimaging research studies research and medical professionals, and ethics boards of risks and benefits of pediatric neuroimaging research studieswww.neuroethics.ca Current Studies

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34. Acknowledgements IBD - Dr. D. Shiloff, Ms A. Allman, Mr. K. Paulson, Mr. B. Meek U of M, Psychology – Dr. L. Jakobson U of M Medicine and HSC: Dr. A. Chudley, Dr. S. Longstaffe child life specialists: Ms D. Kuypers, Ms S. Treichel Photographs by: Dr. M. Malainey Financial support Manitoba Medical Services Foundation Ava-Ann Allman - Women in Engineering and Science (WES) Award -NRC