1. Using fMRI to Evaluate Working Memory Function of FASD Krisztina Malisza, PhD Institute for Biodiagnostics National Research Council of Canada

2. 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 Metabolism Blood Flow O2O2 O2O2

4. What do we measure with fMRI? Brain Activity Metabolism Blood Flow O2O2 O2O2 dHb Deoxyhemoglobin causes a variation in the local magnetic field on a macroscale

5. What do we measure with fMRI? Brain Activity Metabolism Blood Flow O2O2 O2O2 dHb T2*T2* T2*T2* T 2 * - transverse relaxation caused by variations in local field on a macroscale

6. What do we measure with fMRI? Brain Activity Metabolism Blood Flow O2O2 O2O2 dHb T2*T2* T2*T2* MR Signal

7. What do we measure with fMRI? Brain Activity Metabolism Blood Flow O2O2 O2O2 dHb T2*T2* T2*T2* MR Signal

8. fMRI Data Acquisition Hemodynamic Response Function

9. fMRI Data Acquisition Block Design

11. fMRI Background Physiological effects relating to changes in neuronal activity cause changes in the MR signal intensity By imaging a volume of the brain or spinal cord repeatedly during alternated “rest” and “task” periods, we can detect where the signal intensity changed in relation to the activity

12. Objectives: To determine FASD child/adult brain function in areas of attention, spatial memory and working memory 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

13. Methods Subjects: Child Control n=15Child FASD n=14 Adult Control n=10Adult FASD n=10 fMRI 1.5T GE Signa LX MRI system Gradient-Echo Echo Planar Imaging (EPI) 3 activation states alternated with 4 rest states (NR=56)

14. 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)

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

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

17. HUMAN BRAIN: PREFRONTAL CORTEX A. Spatial working memory A. Spatial working memory B. Spatial working memory, performance of self-ordered tasks B. Spatial working memory, performance of self-ordered tasks C. Spatial, object and verbal working memory, self-ordered C. Spatial, object and verbal working memory, self-ordered tasks, analytic reasoning tasks, analytic reasoning D. Object working memory, analytic reasoning D. Object working memory, analytic reasoning Scientific American, August 1997

18. Lobes of the Cerebral Cortex

19.  Prefrontal cortex (DLPFC)  working memory Anterior cingulate  attention, response selection Parietal lobe  discrimination, memory, spatial perception Insula  Visceral function, integrates autonomic info  Connections to temporal & parietal lobe  Response inhibition/selection  Executive function Brain Regions

20. 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

21. 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  Activations displayed on a T1 template Data Analysis

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

23. Adults Blank - simple FASD (25y,F) Control (26y, F) P=0.01 P=0.05 P=0.01 P=0.05 FASD (26y,F)

24. Adults 1-back - simple P=0.01 P=0.05 P=0.01 P=0.05 FASD, 26y and 25y, F Control, 26y, F

25. Mean Response Times Latency (s) Simple1-back blank2-back Task 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 *** Adult Control Adult FAS

26. Incorrect and No responses simple1-backblank2-back Task Average Number of Incorrect and No Responses 0 1 2 3 4 5 6 7 8 9 10 ** * Adult Control Adult FAS

27. Children S51 – FASD (11y, F) S45 – FASD (11y (just), F) Blank - simple S32 Control (11 y, F) S47 Control (10 y, F) P=0.01

28. Children 1-back - simple S32 Control (11 y, F) S47 Control (10 y, F) S51 – FASD (11y, F) S45 – FASD (11y (just), F) P=0.01

29. Response times simple1-backblank2-back Tasks Latency (s) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 *** ** Child FAS Child control

30. Average Number of Incorrect and No Responses Task simple1-backblank2-back Incorrect and No responses 0 2 4 6 8 10 12 14 * * ** Child FAS Child Control

31. fMRI Conclusions Adults & Children Consistent activations in brain regions associated with working memory (DLPFC) and attention (cingulate) Controls - increase in frontal activity with increasing task difficulty; not as consistent in FASD FASD – greater inferior frontal activation than controls Controls – activation in insula; very little if any in FASD  promising preliminary results - full study required

32. 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, S must touch a different picture

34. Wisconsin Card Sorting Task Successful performance requires »Planning ability »Cognitive flexibility »Working memory »Response inhibition »Concept formation and reasoning Kolb & Whishaw, 2001, p.541

35. WCST MeasureControlFAS Perseverative Responses SS 111.0 (17.5)93.4 (34.8) Perseverative Errors SS108.7 (14.4) 91.5 (31.6) Nonperseverative Errors SS *105.4 (7.4) 92.3 (15.6) % Conceptual Level Responses SS ** 104.7 (7.8) 88.0 (17.3) Number of Categories **5.9 (0.4) 3.9 (1.8) * p<.10; ** p<.05

36. Continuous Performance Task Detect the presence of targets in a series of trials that include distractors Measures: –# correct responses –correct response latency –probability of a hit –probability of a false alarm

37. * Group, F(1,14) = 10.14, p<.01

38. CPT Age main effect: Children performed worse than adults on all 4 indicies Group main effect: FAS 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.

39. Conclusions Adults and children with FASD show impaired performance relative to age- and sex-matched controls, on tasks tapping into executive function, sustained attention, and visual working memory Adults and children with FASD show impaired performance relative to age- and sex-matched controls, on tasks tapping into executive function, sustained attention, and visual working memory 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!! Not all exposed individuals show deficits Not all exposed individuals show deficits Studying unique neuroanatomical & neuropsychological profile of individuals with FASD is important for design of assessment tools, and development of support and intervention programs for patients and their families Studying unique neuroanatomical & neuropsychological profile of individuals with FASD is important for design of assessment tools, and development of support and intervention programs for patients and their families fMRI may prove helpful in this regard fMRI may prove helpful in this regard

40. Acknowledgements IBD - Ms A. Allman, Dr. D. Shiloff U of M, Psychology – Dr. L. Jakobson HSC – Dr. A. Chudley, Dr. S. Longstaffe child life specialists Ms D. Kuypers Ms S. Treichel Financial support Manitoba Medical Services Foundation Ava-Ann Allman - Women in Engineering and Science (WES) Award -NRC