# Presentation: 486921

## 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_

## 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

## 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?

## 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)

## Diagnostic Method: FASD 4-Digit Diagnostic Code

- All Diagnostic Tools and Courses available on the web.www.fasdpn.org

- _Training_4-Digit Online CourseDiagnostic Team Training

## The FASD 4-Digit Diagnostic Code

| severe |
| --- |
| mild |
| none |

|  |
| --- |
|  |
|  |

- Function

## FASD MRI, MRS, fMRI Study: Population

| 4 Study Groups | FAS Face | Brain |  |  |  | Alcohol |
| --- | --- | --- | --- | --- | --- | --- |
| 1.  FAS / PFAS | face | severe |  |  |  | alc |
| 2.  SE/AE    (severe ARND) |  | severe |  |  |  | alc |
| 3.  ND/AE       (mild ARND) |  |  |  | moderate |  | alc |
| 4.  Control |  |  |  |  |  |  |

- Increasing severity of FASD across the 4 study groups

## The Three FAS Facial Features

- Short PFL  	<= -2 SD
- 2)   Smooth Philtrum 	Rank 4 or 5
- 3)   Thin Upper Lip 	Rank 4 or 5

## 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

## 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._          _Language_              _Experimental_	   _Behavioral/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

## 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

## 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_.

## 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

## Proportion of subjects with scores 2 SDs below the mean

| Selected Psychological Outcomes | FAS/PFAS | SE/AE | ND/AE | Control |
| --- | --- | --- | --- | --- |
| WISC FSIQ | 20 | 25 | 0 | 0 |
| WIAT Basic Reading | 5 | 21 | 5 | 0 |
| Key Math | 20 | 13 | 0 | 0 |
| VMI | 33 | 8 | 0 | 0 |
| Rey Complex Figure Test Copy | 85 | 88 | 48 | 0 |
| Rey Delayed Recall | 55 | 54 | 29 | 0 |
| D-KEFS: Tower, Total Rule Violation | 25 | 21 | 0 | 0 |
| CVLT-C, Total Trials # Correct | 50 | 63 | 14 | 0 |
| IVA Continuous Performance Test | 75 | 54 | 29 | 13 |
| TOWK: Conjunctions & Transitions | 43 | 39 | 7 | 0 |
| Vineland Adaptive Behavior, Composite | 75 | 83 | 67 | 6 |
| CBCL: Internalizing Problems | 60 | 46 | 38 | 0 |
| BRIEF: Gen Executive Composite | 85 | 92 | 76 | 0 |
| ADHD | 63 | 71 | 67 | 0 |

- _Proportion_ of subjects with scores 2 SDs below the mean

## 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.

## 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.

## 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.

## 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 length differed between FAS/pFAS and Control groups

- Variability in Shape of CC among _Controls_

- Of 207 FASD with clinical MRIs, only 2 cases (1%) with hypogenesis or agenesis of corpus callosum.

##          Percent of subjects with one or more brain regions                                      

-          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!*

- FASD MRI, MRS, fMRI Study: Results

- _Key Structural Findings_

## 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

## 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)

## FASD MRI, MRS, fMRI Study: Results

- _Key Structural-Functional Findings_
- Some functional impairments appear correlated with reduction in size of specific brain regions.

## 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)

## 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).

## FASD MRI, MRS, fMRI Study: Results

- _Key Facial Findings_
- The more severe the FAS facial features, the more severe the impairment in brain function.

## Trimester of Exposure

- _One of Several Key Alcohol Findings_
- The frontal lobe volume decreases significantly with increasing duration of prenatal alcohol exposure.

- FASD MRI, MRS, fMRI Study: Results

## 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

## FASD MRI, MRS, fMRI Study: Results

- _One of Several fMRI Findings: Activation and Working Memory_

## 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.

## FASD Screening, Surveillance, Diagnosis, Intervention, Prevention, Training, Research, PublicationsGo to our websitewww.fasdpn.orgOr contact Susan Astley, Ph.D. astley@u.washington.edu

- FASD Screening, Surveillance, Diagnosis, Intervention, Prevention, Training, Research, PublicationsGo to our website_www.fasdpn.org_Or contact Susan Astley, Ph.D. _astley@u.washington.edu_