Evaluation of Spatial Working Evaluation of Spatial Working Memory Function in Children Memory Function in Children

and Adults with FASD : A and Adults with FASD : A Functional Magnetic Functional Magnetic

Resonance Imaging StudyResonance Imaging Study

Krisztina Malisza, PhDKrisztina Malisza, PhDInstitute for Biodiagnostics Institute for Biodiagnostics

National Research Council of CanadaNational Research Council of Canada

FMRIFMRIWhat are we trying to do?What are we trying to do?

Neural Activity In Response to task

WhereDetection

How MuchQuantify

What do we measure with fMRI?What do we measure with fMRI?

BrainActivity

Blood Flow

O2 dHb MR Signal

Blood Oxygenation Level-Dependent Imaging Blood Oxygenation Level-Dependent Imaging

fMRI Data Acquisition Block DesignfMRI Data Acquisition Block Design

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Objectives:Objectives:

• Develop MRI based techniques to aid Develop MRI based techniques to aid diagnosis of FASDdiagnosis of FASD

• To determine if there are different To determine if there are different regions of fMRI activity in subjects with regions of fMRI activity in subjects with FASD than controls using a working FASD than controls using a working memory taskmemory task

Psychological testsPsychological tests

• significant differences between children and significant differences between children and adults (p < 0.05)adults (p < 0.05)• greater errors in FASD group than controls greater errors in FASD group than controls overalloverall

-Mean errors: (p < 0.05)Mean errors: (p < 0.05)-FASD =17.8 ± 8.6FASD =17.8 ± 8.6-Controls = 13.1± 8.6Controls = 13.1± 8.6

Self-Ordered PointingSelf-Ordered Pointing Test of visual working memory and Test of visual working memory and strategic memorystrategic memory

Presented with Presented with nn sets of sets of nn pictures pictures((nn = 6, 8, 10 or 12) = 6, 8, 10 or 12)

In each sheet of a given set, subject In each sheet of a given set, subject must touch a different picture must touch a different picture

• No statistically significant differences in childrenNo statistically significant differences in children• trends towards group differences favoring controls trends towards group differences favoring controls in adults (p < 0.1)in adults (p < 0.1)

Wisconsin Card Sorting TaskWisconsin Card Sorting Task Successful performance requiresSuccessful performance requires

» Planning abilityPlanning ability» Cognitive flexibilityCognitive flexibility» Working memoryWorking memory» Response inhibitionResponse inhibition» Concept formation and reasoningConcept formation and reasoning

Continuous Performance TaskContinuous Performance Task Detect the presence of targets in a series of trials that Detect the presence of targets in a series of trials that

include distractersinclude distracters Measures: # correct responses; correct response latency; Measures: # correct responses; correct response latency;

probability of a hit; probability of a false alarmprobability of a hit; probability of a false alarm

• FASD subjects performed similarly to controls on all FASD subjects performed similarly to controls on all measures except mean latencies of correct responsesmeasures except mean latencies of correct responses

significantly longer than controls p <0.01significantly longer than controls p <0.01 Indicates that group differences on other Indicates that group differences on other measures were unlikely due to group differences measures were unlikely due to group differences in ability to remain on task.010in ability to remain on task.010

N-BackTasksN-BackTasks(n=0) Simple (2 1 4 3)(n=0) Simple (2 1 4 3)

(n=1) One-back (NR 2 1 4)(n=1) One-back (NR 2 1 4)

(n=2) Two-back (NR NR 2 1)(n=2) Two-back (NR NR 2 1)

(n=1) Blank (NR 2 NR 4)(n=1) Blank (NR 2 NR 4)

N-BackTasksN-BackTasks

• 4 fMRI tasks:4 fMRI tasks:

Saccadic eye movementSaccadic eye movement Finger movementFinger movement Working memory (spatial, object)Working memory (spatial, object) Procedural learningProcedural learning AttentionAttention

Lobes of the Cerebral CortexLobes of the Cerebral Cortex

In: Psychology, Canadian Edition. Ed. C. Wade, C. Tavris, D. Saucier, L. Elias, 2004, Prentice Hall, Toronto

AttentionAttentionResponse selectionResponse selection

Working Working memorymemory

MemoryMemory

Spatial perceptionSpatial perception

DiscriminationDiscrimination

MethodsMethodsSubjects:Subjects:

Children (7-12 years); Adults (18-33 years)Children (7-12 years); Adults (18-33 years)

Child FASD n=14 Child FASD n=14 Child Control n=15Child Control n=15

• 5 ARND, 6 pFAS, 3 FAS5 ARND, 6 pFAS, 3 FAS

Adult FASD n=10 Adult FASD n=10 Adult Control n=10Adult Control n=10

• 6 ARND, 1 pFAS, 3 FAS6 ARND, 1 pFAS, 3 FAS

fMRIfMRI

1.5T GE Signa LX MRI system1.5T 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 3 activation states alternated with 4 rest states (NR=56)(NR=56)

Data AnalysisData Analysis

50% correct responses on fMRI tasks50% correct responses on fMRI tasks

Children (FASD: Control):Children (FASD: Control): Blank: 9:14Blank: 9:141-Back: 7:131-Back: 7:13

Adults (FASD: Control): Adults (FASD: Control): Blank: 10:10Blank: 10:101-Back: 6:91-Back: 6:9

SPM 99 (computer program)SPM 99 (computer program)

Images corrected for motion, Images corrected for motion, normalised to a adult or child template normalised to a adult or child template then smoothedthen smoothed

Individual activations in more difficult Individual activations in more difficult tasks (n=1) subtracted from simple (n=0) tasks (n=1) subtracted from simple (n=0) tasktask

Data AnalysisData Analysis

Open bars: Controls; Filled bars: FAS participants

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Combined adult and child fMRI task performance Combined adult and child fMRI task performance

Children (11 yr female) Blank-SimpleChildren (11 yr female) Blank-Simple

FAS

pFAS

control

Children (11 yr female) One-Back-SimpleChildren (11 yr female) One-Back-Simple

FAS

pFAS

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Adult (female) Adult (female) Blank-SimpleBlank-Simple

ARND26 yrs

FAS25 yrs

Control26 yrs

Adult (female) One-BackAdult (female) One-Back-Simple-Simple

ARND26 yrs

FAS25 yrs

Control26 yrs

One sample t-test (p <0.01) Group activity in ChildrenOne sample t-test (p <0.01) Group activity in Children

a) Blank - Simple FASD (n=9)b) Blank - Simple Control (n=8)c) One-Back - Simple FASD (n=7)d) One-Back - Simple Control (n=8)

a) Blank - Simple FASD (n=10)b) Blank - Simple Control (n=9)c) One-Back - Simple FASD (n=6)d) One-Back - Simple Control (n=6)

One sample t-test (p <0.01) Group activity in AdultsOne sample t-test (p <0.01) Group activity in Adults

fMRIfMRIAll Adults & ChildrenAll Adults & Children::• Consistent activations in brain regions associated with Consistent activations in brain regions associated with

working memory (bilateral DLPFC) and attention working memory (bilateral DLPFC) and attention (cingulate) (cingulate)

• increased parietal and frontal cortex activity at superior increased parietal and frontal cortex activity at superior slices with increasing task difficultyslices with increasing task difficulty

All FASD participants:All FASD participants:• Greater Orbital and inferior-middle frontal activations Greater Orbital and inferior-middle frontal activations

observed than control subjects (particularly Blank)observed than control subjects (particularly Blank)• Structural brain abnormalities (reduction in orbito-Structural brain abnormalities (reduction in orbito-

frontal size) previously observed frontal size) previously observed (Sowell Cereb cortex 2002; 12:856)(Sowell Cereb cortex 2002; 12:856)

ChildrenChildrenFASD: FASD: -greater cingulate cortex at inferior brain slicesgreater cingulate cortex at inferior brain slices-less activity in frontal cortex with increased task difficultyless activity in frontal cortex with increased task difficulty

Control children:Control children:

- greater cingulate and frontal activation at more superior - greater cingulate and frontal activation at more superior slice levels slice levels

- more parietal activity- more parietal activity

- increased frontal functional activity with increasing task - increased frontal functional activity with increasing task difficulty (opposite of FASD)difficulty (opposite of FASD)

fMRIfMRI

AdultsAdultsFASD:FASD:

- greater cingulate cortex at inferior brain slices- greater cingulate cortex at inferior brain slices

- greater superior frontal cortex activity than control- greater superior frontal cortex activity than control

- overall less activity in FASD compared to controls- overall less activity in FASD compared to controls

fMRIfMRI

Anatomical ImagesAnatomical Images• No statistically significant differences observed in:No statistically significant differences observed in:

• T1 or T2 relaxation timesT1 or T2 relaxation times• Magnetization contrast imagesMagnetization contrast images• corpus callosum volumes (normalized to cerebrum) - corpus callosum volumes (normalized to cerebrum) - but there are trends.but there are trends.

• Examine corpus callosum shape and location within brain Examine corpus callosum shape and location within brain and between FASD classifications in both children and and between FASD classifications in both children and adults.adults.

• Previous studies shown abnormalities in this area Previous studies shown abnormalities in this area (Bookheimer et al)(Bookheimer et al)

ConclusionsConclusions Significant latency of response for FASD subjects Significant latency of response for FASD subjects

compared to controls – but both groups paying compared to controls – but both groups paying attention!!attention!!

Variability between subjects and small subject numbers Variability between subjects and small subject numbers necessitates comparisons on an individual subject basis.necessitates comparisons on an individual subject basis.

At least 2 different brain regions show distinct patterns At least 2 different brain regions show distinct patterns of activity in FASD compared to control subjects. This of activity in FASD compared to control subjects. This suggests fMRI may be an adjunctive tool for diagnostics.suggests fMRI may be an adjunctive tool for diagnostics.

Future Studies and Pilot Study LimitationsFuture Studies and Pilot Study LimitationsFMRI:FMRI:•Large sample size required to enable group comparisons Large sample size required to enable group comparisons •Event-related design required for dealing with an Event-related design required for dealing with an affected population such as FASDaffected population such as FASD•Effective distinction between classifications requires Effective distinction between classifications requires considerations of co-morbidities (ADHD) considerations of co-morbidities (ADHD) •Need for matching on socio-economic basisNeed for matching on socio-economic basis

Anatomical Data:Anatomical Data:•Closer examination of striatal and cortical structures Closer examination of striatal and cortical structures within sub classifications of FASDwithin sub classifications of FASD•Complete 3D volumetric acquisition at high spatial Complete 3D volumetric acquisition at high spatial resolutionresolution

Ethical considerations in pediatric neuroimaging - CIHR Ethical considerations in pediatric neuroimaging - CIHR New Emerging Team in NeuroethicsNew 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 trainingReduction of stress and motion through training• Sedation in ImagingSedation in Imaging• Development of guidelinesDevelopment of guidelines• Dissemination of InformationDissemination of Information

• research and medical professionals, and ethics research and medical professionals, and ethics boards of risks and benefits of pediatric boards of risks and benefits of pediatric neuroimaging research studiesneuroimaging research studies

www.neuroethics.cawww.neuroethics.ca

Current StudiesCurrent Studies

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AcknowledgementsAcknowledgementsIBD - IBD - Dr. D. Shiloff, Ms A. Allman, Mr. K. Paulson, Dr. D. Shiloff, Ms A. Allman, Mr. K. Paulson,

Mr. B. MeekMr. B. MeekU of M, Psychology –U of M, Psychology – Dr. L. Jakobson Dr. L. JakobsonU of M Medicine and HSC: U of M Medicine and HSC: Dr. A. Chudley, Dr. S. Dr. A. Chudley, Dr. S.

Longstaffe Longstaffe child life specialists: child life specialists: Ms D. Kuypers, Ms S. TreichelMs D. Kuypers, Ms S. TreichelPhotographs by:Photographs by: Dr. M. Malainey Dr. M. MalaineyFinancial supportFinancial supportManitoba Medical Services Foundation Manitoba Medical Services Foundation Ava-Ann AllmanAva-Ann Allman - Women in Engineering and Science - Women in Engineering and Science

(WES) Award -NRC (WES) Award -NRC