Passport control

a bit carried away….

appreciated the advice…

forgot to talk to the manager, next thing I know – my fMRI…

thankfully, when aroused…

things – back to normal…

Inattentive impaired children and adolescents: how helpful are working memory paradigms?

Professor Alasdair Vance and teamAcademic Child PsychiatryDepartment of PaediatricsUniversity of MelbourneRoyal Children’s Hospital

Outline of presentation

1. ‘Inattentive and impaired’: definition2. Our research approach3. Key current findings4. Future directions

Prof. A. Vance

1. ADHD: definition

DSM-IV: a clinically significant behavioural patterninattention and/or hyperactivity/impulsiveness

associated with impairment in one or more areas of functioning

Questionnaires: >/= 1.5 SD above the mean for age, genderand IQ

Prof. A. Vance

2. Our research approach

Constrain measurement error

* clinical phenotyping: ‘pure’ versus comorbid disorderscategorical and dimensional definitionparticipants’ developmental stage, gender, IQ

* cognitive neuroscience: optimal brain behaviour relationships

* functional neuroimaging: task selection; within subject andbetween subject analysis

Prof. A. Vance

2. Our research approach

-‘pure’ ADHD inattentive dimension-defined structured clinical interview and parent/teacher ‘gold standard’ questionnaires-pre-pubertal children or post-pubertal adolescents

-visuospatial not verbal domain-non-human primate derived tests

-defined fMRI task components, block/event design-FSL (GLM) versus SPM

Prof. A. Vance

ADHD, combined type group: definition DSM-IV CRITERIA

-inattention dimension and hyperactivity-impulsivity dimension-evident in at least two settings-onset before seven years of age-impairment in social, academic, occupational functioning-FSIQ > 80-excluded: comorbid conduct disorder, major depressive disorder, learning disorders, speech/language disorders,

developmental coordination disorder, tic disorders

Prof. A. Vance

3. Our current findings

mental rotation task 10s/1s ISI block design

Prof. A. Vance

Prof. A. Vance

Silk, Vance et al, B J Psych 2005 N=14, CBCL inattention subscale T score: 72.23 (10.72)

Dysthymic disorder definition: DSM-IV criteria

-1 year or more (most of the day, for more days than not), <2 months absence in a given year

-depressed and/or irritable mood predominant-2 or more of the following: feelings of hopelessness, low self-esteemappetite change, in/hyper somnia, anergia (fatigue), decreased concentration or decisiveness-FSIQ > 80-excluded: comorbid ADHD-CT, conduct disorder, major depressive disorder, learning disorders, speech/language disorders,developmental coordination disorder, tic disorders

Prof. A. Vance

ControlDD

Control>DD

z-score 1

5

Dysthymic disorder

Control group: significant activation

Region BA x y zBilateral Parietal Lobe

R Interior Parietal Lobule 40 40 -58 44R Superior Parietal Lobule 7 36 -74 44R Precuneus 19 36 -76 38R Interior Parietal Lobule 40 38 -50 40R Precuneus 19 34 -66 36R Precuneus 7 16 -72 54L Precuneus 7 -20 -80 44R Cuneus 18 26 -78 20L Inferior Parietal Lobule 40 -44 -46 42L Precuneus 19 -34 -80 -40

Bilateral Frontal LobeR Middle Frontal Gyrus 6 28 2 46R Middle Frontal Gyrus 6 24 -10 50R Middle Frontal Gyrus 6 26 16 36R Inferior Frontal Gyrus 9 42 10 22R Middle Frontal Gyrus 46 46 40 14R Middle Frontal Gyrus 10 32 44 10R Middle Frontal Gyrus 46 36 32 20R Middle Frontal Gyrus 10 40 38 22R Middle Frontal Gyrus 46 52 28 26R Inferior Frontal Gyrus 47 40 22 -8R Inferior Frontal Gyrus 47 36 20 -8L Cingulate Gyrus 32 -2 22 34L Middle Frontal Gyrus 6 -30 4 48L Precentral Gyrus 6 -24 -14 48L Middle Frontal Gyrus 6 -34 -6 46L Middle Frontal Gyrus 6 -34 -4 46L Middle Frontal Gyrus 6 -40 4 44L Inferior Frontal Gyrus 9 -60 6 26

Bilateral Limbic LobeR Cingulate Gyrus 32 22 8 48L Cingulate Gyrus 32 -4 12 42

Left OccipitalL Cuneus 7 -20 -80 30L Cuneus 19 -26 -82 30

*No associated Brodmann area

ControlDD

Control>DD

z-score 1

5

Control

ControlDD

Control>DD

z-score 1

5

Control > Dysthymic disorder

N=14, CBCL inattention subscale T score: 70.88 (9.75)

Prof. A. Vance

Region of activation BA C (mm) ZControl Group greater than ADHD-CT GroupParieto-Occipital

R Precuneus 19 24 -70 32 3.53R Cuneus 19 32 -90 28 2.82

Posterior ParietalR Inf. Parietal 40 36 -40 50 2.82

Frontal/SubcorticalR Caudate Nucleus, Body 18 -12 22 2.82

Vance et al, Mol Psych 2007 N=24, CBCL inattention subscale T score: 72.14 (9.43)

Control>Dysthymic disorder

Dysthymic disorder Control

z-score 1

5

Dysthymic disorder

Control>Dysthymic disorder

Dysthymic disorder Control

z-score 1

5

Control

Control>Dysthymic disorder

Dysthymic disorder Control

z-score 1

5

Control > Dysthymic disorder

N=16, CBCL inattention subscale T score: 70.68 (9.44)

OCD: definitionDSM-IV criteria

-obsessions: intrusive, repetitive, involuntary, recognized as silly, senseless, purposeless by a given child and/or their parents, associated with increased physiological arousal, anxiety, distress-compulsions: intrusive, repetitive, involuntary ritualized actions that are designed to minimize the increased physiological arousal, anxiety, distress associated with the above obsessions-FSIQ > 80-excluded: comorbid ADHD-CT, conduct disorder, major depressive disorder, learning disorders, speech/language disorders,developmental coordination disorder, tic disorders

Prof. A. Vance

N=16, CBCL inattention subscale T score: 69.17 (9.23)

Region of activation BA C (mm) sizeControl group greater than OCD group

Right Precuneus 7 26 -74 56 993Left Precuneus 7 -10 -54 42 1236

Right DLPFC 9 54 -2 42 956Left DLPFC 9 -36 4 36 3870

Left lateral globus pallidus -22 -4 -6 763

3. Our current findings

General Summary

ADHD DD OCDParietal/Precuneus A /C A/C A /C

Basal ganglia A /C C A /C

Prefrontal cortex A A /C A /C

Prof. A. Vance

Prof. A. Vance

3. Our current findingsSpecific Summary

ADHD Parietal/Precuneus R>LDD Parietal/Precuneus R>LOCD Precuneus R=L

ADHD Caudate nucleus R>LDD Caudate/Putamen R (C only)OCD Globus pallidus L>R

ADHD Sup/Inf FG R=L (A only)DD Mid/Inf FG R OCD DLPFC R=L

4. Future clinical directions

- biomarker for clinical inattention- biomarker-developmental stage independent- target for medication and/or specific psychologicaltreatment

- target for monitoring of the above treatment- ADHD: parietal lobe main risk factor site?- OCD: global pallidus main risk factor site?- DD: insula main risk factor site?

NB: methodological problems of parsing neural network components

4. Future research directions

-interpretation: the ‘problem’ of epiphenomena-comorbidity-developmental stage; age; gender-more specific cognitive neuroscience constructs

. VSWM – capacitance versus strategy

. VSM – encoding versus retrieval -more specific fMRI tasks

. Parietal BG PFC-multiple neuroimaging modalities

. Oculomotor MRS DTI- ‘target’ phenotypes for mol gen studies Prof. A. Vance

Prof. A. Vance