Krisztina Malisza, PhD Institute for Biodiagnostics National Research Council of Canada

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

3. What do we measure with fMRI? Blood Oxygenation Level-Dependent Imaging Blood Flow O2 MR Signal Brain Activity dHb

4. fMRI Data Acquisition Block Design = 

6. Objectives: • Develop 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 task

7. Psychological tests Self-Ordered Pointing • Test of visual working memory and strategic memory • 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 • significant differences between children and adults (p < 0.05) • greater errors in FASD group than controls overall • Mean errors: (p < 0.05) • FASD =17.8 ± 8.6 • Controls = 13.1± 8.6

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

9. Continuous Performance Task • 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 • 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-BackTasks (n=1) Blank (NR 2 NR 4)

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

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

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

15. Data Analysis •  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. Data Analysis • 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

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

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 Blank - Simple FASD (n=9) Blank - Simple Control (n=8) One-Back - Simple FASD (n=7) One-Back - Simple Control (n=8)

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

24. fMRI • All Adults & Children: • 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 difficulty All FASD participants: • 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)

25. fMRI • Children • FASD: • 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)

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

27. Anatomical Images • No statistically significant differences observed in: • T1 or T2 relaxation times • Magnetization contrast images • 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. • 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!! • 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.

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

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

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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