Washington State FAS Diagnostic & Prevention Network (FAS DPN) University of Washington Susan J. Astley Ph.D. Profes

1. MRI, MRS, and fMRI in Children with FAS/D Washington State FAS Diagnostic & Prevention Network (FAS DPN) University of Washington Susan J. Astley Ph.D. Professor and Director www.fasdpn.org

2. FASD MRI, MRS, fMRI Study Institution: University of Washington, FAS Diagnostic & Prevention Network Investigators Susan Astley Ph.D., Principal Investigator Elizabeth Aylward, PhD, neuroimaging psychologist Todd Richards, PhD, physicist Ken Maravilla, MD, radiologist Julian Davies, MD, pediatrician Heather Carmichael Olson, PhD, psychologist Kimberly Kerns, PhD, neuropsychologist Allison Brooks, PhD, psychologist Susan Dorn, MS, school psychologist Tracy Jirikowic, OT, PhD, occupational therapist Truman Coggins, PhD, speech language pathologist Funding Agency NIAAA

3. FASD MRI, MRS, fMRI Study: Hypotheses • Primary Hypotheses • The following will differ between children with FAS/D and typically developing children: • neuro-structure (size of specific brain structures) • neuro-function (as measured by psychological, psychiatric, and fMRI assessment) • neuro-chemistry (neurometabolites: choline and n-acetyl-aspartate) • Long-range Clinical Question • Can MRI, MRS, and/or fMRI improve the accuracy of a FASD diagnostic evaluation?

4. FASD MRI, MRS, fMRI Study: Population • STUDY POPULATION • Four groups (8-15 years old) • FAS / Partial FAS (n = 20) • Static Encephalopathy / Alcohol Exposed(SE/AE) (n = 24)(Severe “ARND” with no FAS face) • Neurobehavioral Disorder / Alcohol Exposed(ND/AE) (n = 21)(Mild “ARND” with no FAS face) • Controls (n = 16)(typical development, No alcohol exposure)

5. CNS Damage Diagnostic Method: FASD 4-Digit Diagnostic Code Training4-Digit Online CourseDiagnostic Team Training All Diagnostic Tools and Courses available on the web.www.fasdpn.org

6. 3 4 4 4 significant severe definite 4 moderate moderate probable 3 mild mild possible 2 none none unlikely 1 Growth FAS Facial CNS DeficiencyFeatures Damage 4 high risk 3 some risk 2 unknown 1 no risk Prenatal Alcohol Growth Face CNS Alcohol The FASD 4-Digit Diagnostic Code Function

7. FASD MRI, MRS, fMRI Study: Population Increasing severity of FASD across the 4 study groups

8. FAS The Three FAS Facial Features • Short PFL <= -2 SD • 2) Smooth Philtrum Rank 4 or 5 • 3) Thin Upper Lip Rank 4 or 5

9. FASD MRI, MRS, fMRI Study: Methods • METHODS • Five days of participation over the course of 1 month • Comprehensive psychological / psychiatric assessment • MRI, MRS, fMRI in scanner

10. FASD MRI, MRS, fMRI Study: Methods PSYCHOLOGICAL / PSYCHIATRIC ASSESSMENTS: Cognition, executive function, language, memory, achievement, attention, sensory-motor, inhibitory control, adaptive and maladaptive behavior. Neuropsych.LanguageExperimentalBehavioral/Parent Report WISC-III TLC Arrows Game BRIEF CVLT-C TOLD Colored Boxes CBCL DKEFS TOWK Fire Fighting Game C-DISC RCFT Letters Game VABS WCST Shapes Game Key Math Child Size Ordering Test QNST N-Back Faces IVA CPT VMI

11. FASD MRI, MRS, fMRI Study: Methods MRI: Structure Volumes caudate putamen hippocampus frontal lobe frontal gray matter frontal white matter total brain Midsaggital Area corpus callosum cerebellar vermis total brain

12. FASD MRI, MRS, fMRI Study: Methods • fMRI: Functional Assessment in the Scanner • Whole brain scan for activity levels while child is participating in a N-back working memory task. • Child is presented photos of faces while in the scanner. • Child responds to task by pushing a button. • 0-Back Task • Push the button when you see a man’s face. • 1-Back Task • Push the button when the face you are looking at matches the face you saw one slide back. • 2-Back Task • Push the button when the face you are looking at matches the face you saw two slides back.

13. white matter voxel FASD MRI, MRS, fMRI Study: Methods • MRS: Spectroscopy • Three locations scanned. • White matter voxel (1 cm cube) • Hippocampus voxel (1 cm cube) • Whole brain slice above the ventricles • Choline , N-acetyl-aspartate , Creatine

14. Proportion of subjects with scores 2 SDs below the mean

15. Mild ARND Severe ARND FAS / PFAS Control ND/AE SE/AE FAS/PFAS FASD MRI, MRS, fMRI Study: Results Key Structural Findings All brain regions become progressively smaller (absolute size) as you advance across the 4 Diagnostic Groups from Controls to FAS / PFAS.

16. Frontal Lobe (adjusted for brain size) Across 4 Groups FAS/PFAS SE/AE ND/AE Control FASD MRI, MRS, fMRI Study: Results Key Structural Findings The frontal lobe is significantly smaller in FAS/PFAS relative to Severe ARND, Mild ARND, and Controls, even after adjustment for overall brain size.

17. Caudate Size (adjusted for brain size) across the 4 Groups FAS/PFAS SE/AE ND/AE Control FASD MRI, MRS, fMRI Study: Results Key Structural Findings The caudate is significantly smaller in both FAS/PFAS and Severe ARND, relative to Mild ARND and Controls, even after adjustment for overall brain size.

18. FASD MRI, MRS, fMRI Study: Results Key Structural Findings NO significant group differences between 4 study groups for mean midsagittal area of corpus callosum. Mean corpus callosum lengthdiffered between FAS/pFAS and Control groups Of 207 FASD with clinical MRIs, only 2 cases (1%) with hypogenesis or agenesis of corpus callosum. Variability in Shape of CC among Controls

19. FASD MRI, MRS, fMRI Study: Results Key Structural Findings Percent of subjects with one or more brain regions significantly smaller than control group: ▪ FAS/PFAS (CNS Rank 3-4 with FAS facial features)70 % ▪SE/AE (CNS Rank 3, No FAS facial features) 58 % ▪ND/AE (CNS Rank 2, No FAS facial features) 43 % ▪Controls (CNS Rank 1, No FAS facial features) 0 % Even subjects with neurobehavioral disorder (ND/AE) have underlying structural alterations!

20. When will MR technology enter the FASD Diagnostic Clinic? Before MRI can be used diagnostically, we need population-based norms (not research study norms) to compare against. What is the normal size of a frontal lobe in a 10 yr old boy? If the frontal lobe is small, are there functional consequences? The NIH MRI Study of Normal Brain Development. Documenting normal MRI, MRS, and neuropsychological development in a population-based sample of healthy individuals (birth to 18 years old). Waber et al., 2007 J Internationall Neuropsychological Society

21. FASD MRI, MRS, fMRI Study: Results • Key Structural-Functional Findings • Brain function decreases with decreasing size of brain regions. • One global measure of brain function is the 4-Digit CNS Ranks: • Rank 1 (normal function) • Rank 2 (mild impairment) • Rank 3 (severe impairment)

22. FASD MRI, MRS, fMRI Study: Results Key Structural-Functional Findings Some functional impairments appear correlated with reduction in size of specific brain regions.

23. FASD MRI, MRS, fMRI Study: Results • Key Structural-Functional Findings • Hippocampal volume • significantly smaller in all FASD groups • significantly correlated with performance on CVLT-C (r = .336, p < 0.01)

24. 5 week 10 week FASD MRI, MRS, fMRI Study: Results Key Facial Findings The frontal lobe decreases in size as the 4-Digit FAS face becomes more severe. Frontal lobe and the FAS face both share the same embryologic origin (frontonasal prominence).

25. FASD MRI, MRS, fMRI Study: Results Key Facial Findings The more severe the FAS facial features, the more severe the impairment in brain function.

26. FASD MRI, MRS, fMRI Study: Results One of Several Key Alcohol Findings The frontal lobe volume decreases significantly with increasing duration of prenatal alcohol exposure. Trimester of Exposure

27. FASD MRI, MRS, fMRI Study: Results • Key MR Spectroscopy Finding • Choline is significantly lower among FAS / PFAS (may be marker for white matter deficit). • Choline lower among those with alcohol exposure through the 2nd or 3rd trimester. Choline and Group Choline and Trimester of Alcohol

28. Number of Correct Responses on N-Back Level of Activation in Dorsolateral Prefrontal Cortex Key: 1-Back (simple task) 2-Back (difficult task) FASD MRI, MRS, fMRI Study: Results One of Several fMRI Findings: Activation and Working Memory

29. FASD MRI, MRS, fMRI Study: Key Outcomes • Three clinically distinct groups can be constructed with the FASD 4-Digit Code (FAS, SE/AE, ND/AE). FAS is unique from ARND. ARND has 2 distinct subgroups (SE/AE and ND/AE). • Children across the full spectrum of FASD have evidence of structural brain alterations, not just those with FAS. • The FAS facial phenotype (as defined by the 4-Digit Code) is an external biomarker for underlying alteration in brain structure / function. • As dysfunction increases from mild, moderate, to severe, the prevalence / severity of underlying structural brain alteration increases linearly. • Frontal lobe, caudate, and hippocampus appeared most impacted. • Choline is significantly lower in FAS. May be a marker for white matter deficits. • Poor working memory performance was associated with lower activation on fMRI among FASD.

30. For Further Information FASD Screening, Surveillance, Diagnosis, Intervention, Prevention, Training, Research, PublicationsGo to our websitewww.fasdpn.orgOr contact Susan Astley, Ph.D. astley@u.washington.edu