fMRI & Children Clinical Applications?

DEPARTMEN

T O

F H

EA

LTH

& H

UM AN SE RV I CE S U SA

Daniel S. Pine, MDEmotion & Development Branch

Outline

• Introduction

• Diagnostic Specificity

• Risk versus Disorder

• Novel Therapeutics

Outline

• Introduction

• Diagnostic Specificity

• Risk versus Disorder

• Novel Therapeutics

Pediatric Mental Illnesses

• Extremely Common

• Usually Transient– But…predicts long-term problems

• Prediction, Therapeutics

Pediatric Mental Illnesses

• Ground research in Neuroscience

• Unique role of fMRI

• Integration of clinical & basic

Clinical Features

Disruption in Core

Psychological ProcessesFear Circuit

Amygdala & Prefrontal Cortex

(PFC)

Genetic influences

Environmental influences

Anxiety Disorders

Disorder-Specific Processes: Appraisal, Memory Bias, Reward Processing

Disorder-Common Processes: Attention Disruption, Conditioning & Extinction

Attention & Memory

A Focus on Trajectories

Outline

• Introduction

• Diagnostic Specificity

• Risk versus Disorder

• Novel Therapeutics

Outline

• Introduction

• Diagnostic Specificity

• Risk versus Disorder

• Novel Therapeutics

Outline

• Introduction

• Diagnostic Specificity Nosology

• Risk versus Disorder

• Novel Therapeutics

Diagnostic Specificity

• Unique, stable patterns manifest

• Comorbidity is rampant

• Vexing questions on anxiety

Males

0.00

0.25

0.50

0.75

1.00

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Age in years

Cum

ulat

ive

Age

of

Ons

et D

istr

ibut

ion

Separation Anxiety Disorder*Specif ic PhobiaSocial PhobiaAgoraphobiaPanic DisorderGAD

Females

0.00

0.25

0.50

0.75

1.00

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Age in years

Cum

ulat

ive

Age

of

Ons

et D

istr

ibut

ion

Separation Anxiety Disorder*Specif ic PhobiaSocial PhobiaAgoraphobiaPanic DisorderGAD

* Separation Anxiety Disorder has been assessed only in a subsample at T1

Age of Onset of Specific Anxiety Disorders

Separation Anxiety Disorder & Specific Phobia

Panic Disorder/Agoraphobia & Generalized Anxiety Disorder

Social Phobia

Specificity?

Behavioral Inhibition and AnxietySpecificity?

Behavioral Inhibition and Anxiety

Chronis-Tuscano et al, 2009

**

Specificity?

Assessing Reward Systems Function

BEHAVIORAL INHIBITION

4 Months: Recruitment and Selection

9 Months: EEG

14 Months: Behavioral Inhibition

24 Months: Behavioral Inhibition

4 Years: Quartet Peer Interaction

7 Years: Quartet Peer Interaction

14 Years: Clinical Assessment, fMRI

17 Years: Clinical Assessment, fMRI

Fox et al. 2006

Behavioral Inhibition, Anxiety, & Reward Processing

The MID Task

(a) (b) (c)

L R

(a) (b) (c)

L R

-0.1-0.05

00.05

0.10.15

0.20.25

0.30.35

0.4

Sm

all

Me

diu

m

La

rge

Sm

all

Me

diu

m

La

rge

Sm

all

Me

diu

m

La

rge

Sm

all

Me

diu

m

La

rge

Caudate Putamen NucleusAccumbens

Amygdala

% s

ign

al

ch

an

ge

Inhibited

Non-inhibited

Behavioral Inhibition Guyer et al. 2006

Behavioral Inhibition, Anxiety, & Reward Processing

The MID Task

(a) (b) (c)

L R

(a) (b) (c)

L R

-0.1-0.05

00.05

0.10.15

0.20.25

0.30.35

0.4

Sm

all

Me

diu

m

La

rge

Sm

all

Me

diu

m

La

rge

Sm

all

Me

diu

m

La

rge

Sm

all

Me

diu

m

La

rge

Caudate Putamen NucleusAccumbens

Amygdala

% s

ign

al

ch

an

ge

Inhibited

Non-inhibited

Behavioral Inhibition Guyer et al. 2006

Anxiety Guyer et al. 2012

Biswal et al. 1995

Fair, Schlagger, Peterson & others

Birn et al. 2014

Fair, Schlagger, Peterson & others

Outline

• Introduction

• Diagnostic Specificity

• Risk versus Disorder

• Novel Therapeutics

Outline

• Introduction

• Diagnostic Specificity

• Risk versus Disorder

• Novel Therapeutics

Behavioral Inhibition and Anxiety

Chronis-Tuscano et al, 2009

**

VISUALVISUALCORTEXCORTEX

AMYGDALAAMYGDALA

HEART RATE

BLOOD PRESSUREBLOOD PRESSURE MUSCLEMUSCLE

VISUAL THALAMUS

LeDoux. LeDoux. Sci AmSci Am. 1994;270:50.. 1994;270:50.

14 ms

*

17-1250 ms

+

Bar-Haim et al. (2007)

d=0.45

time

The Dot-Probe Task

Mogg & Bradley

+

time

The Dot-Probe Task

+

time

The Dot-Probe Task

*

+

14 ms

*time

The Dot-Probe Task

+

14 ms

*time

The Dot-Probe Task

Vigilance for threat = Faster RTs to probes replacing threat vs. neutral faces

+

Study Design

4 Months: Recruitment and Selection

9 Months: EEG

14 Months: Behavioral Inhibition

24 Months: Behavioral Inhibition

4 Years: Quartet Peer Interaction

7 Years: Quartet Peer Interaction

14 Years: Clinical Assessment, fMRI

18 Years: Clinical Assessment, fMRI

Fox et al. 2006

Study Design

4 Months: Recruitment and Selection

9 Months: EEG

14 Months: Behavioral Inhibition

24 Months: Behavioral Inhibition

4 Years: Quartet Peer Interaction

7 Years: Quartet Peer Interaction

14 Years: Clinical Assessment, fMRI

18 Years: Clinical Assessment, fMRI

Fox et al. 2006

***-assessment of attention

***

***

***

Study Design

4 Months: Recruitment and Selection

9 Months: EEG

14 Months: Behavioral Inhibition

24 Months: Behavioral Inhibition

4 Years: Quartet Peer Interaction

7 Years: Quartet Peer Interaction

14 Years: Clinical Assessment, fMRI

18 Years: Clinical Assessment, fMRI

Fox et al. 2006

***-assessment of attention

***

***

***

Persistent Anxiety Emerges Over Time

Perez-Edgar et al. 2010

14 ms

time

The Dot-Probe Task

68 ms

+

17 ms

Attention, PFC-Amygdala-Circuitry, and Pediatric Anxiety

Monk et al. 2006, 2008

VLPFCVLPFC

Attention, PFC-Amygdala-Circuitry, and Pediatric Anxiety

Monk et al. 2006, 2008

Brief Subliminal Threat: Amygdala instantiates anxiety

VLPFCVLPFC

68 ms

17 ms

Attention, PFC-Amygdala-Circuitry, and Pediatric Anxiety

Prolonged Threat: PFC regulates attention in anxiety

Monk et al. 2006, 2008

Brief Subliminal Threat: Amygdala instantiates anxiety

VLPFCVLPFC

68 ms

500 ms

17 ms

From: Differences in White Matter Fiber Tract Development Present From 6 to 24 Months in Infants With Autism

Am J Psychiatry. 2012;169(6):589-600. doi:10.1176/appi.ajp.2011.11091447

Autism Spectrum Disorder

• Onset in first year of life

• Siblings at high risk

• Less than half will be affected

Wolff et al. 2012

Outline

• Introduction

• Diagnostic Specificity

• Risk versus Disorder

• Novel Therapeutics

Outline

• Introduction

• Diagnostic Specificity

• Risk versus Disorder

• Novel Therapeutics

Any Adolescent Anxiety Disorder & Any Adult Mood/Anxiety Disorder

Disorder as Adults?

Disorder as

Adolescents?No Yes

No 390 36 426

Yes 191 62 253

581 98 679

Pine et al. 1998, 2001, 2002

Any Adolescent Anxiety Disorder & Any Adult Mood/Anxiety Disorder

Disorder as Adults?

Disorder as

Adolescents?No Yes

No 390 36 426

Yes 191 62 253

581 98 679

Pine et al. 1998, 2001, 2002

Any Adolescent Anxiety Disorder & Any Adult Mood/Anxiety Disorder

Disorder as Adults?

Disorder as

Adolescents?No Yes

No 390 36 426

Yes 191 62 253

581 98 679

Pine et al. 1998, 2001, 2002

Any Adolescent Anxiety Disorder & Any Adult Mood/Anxiety Disorder

Disorder as Adults?

Disorder as

Adolescents?No Yes

No 390 36 426

Yes 191 62 253

581 98 679

Pine et al. 1998, 2001, 2002

Any Adolescent Anxiety Disorder & Any Adult Mood/Anxiety Disorder

Disorder as Adults?

Disorder as

Adolescents?No Yes

No 390 36 426

Yes 191 62 253

581 98 679

Pine et al. 1998, 2001, 2002

Ressler & Davis 2003Ressler & Davis 2003

Ressler & Davis 2003Ressler & Davis 2003

Extinction Recall: Extinction Recall: Remembering the Boundary Remembering the Boundary Between Danger and SafetyBetween Danger and Safety

Ressler & Davis 2003

NMDA manipulation

Ressler & Davis 2003NMDA manipulations?

Insights on Therapeutics

EXTINCTION

How do we study How do we study fear learning in youth?fear learning in youth?

30 CS- trials

3 seconds

3 seconds

0 100

How nervous are you?

15 Paired CS+ trials

0 100

1 second scream

3 seconds

3 seconds

How nervous are you?

15 Unpaired CS+ trials

3 seconds

3 seconds

0 100

How nervous are you?

Acquisition (60 trials)

Conditioning of Fear Reactions:Neutral Face CS; Screaming Lady UCS

FACE-SCREAM CONDITIONING

CS MINUS CS PLUS

30 CS- trials

3 seconds

3 seconds

0 100

How nervous are you?

15 Paired CS+ trials

0 100

1 second scream

3 seconds

3 seconds

How nervous are you?

15 Unpaired CS+ trials

3 seconds

3 seconds

0 100

How nervous are you?

Acquisition (60 trials)

Conditioning of Fear Reactions:Neutral Face CS; Screaming Lady UCS

FACE-SCREAM CONDITIONING

CS MINUS CS PLUS (paired) CS PLUS

Lau et al. (2011)

Attention-State & Anxiety:

The importance of threat appraisal

Adolescents

Adults

Lau et al. (2011)

Attention-State & Anxiety:

The importance of threat appraisal

Lau et al. (2011)

Day 1 – Conditioning/Extinction

Day 2 – Extinction Recall

Day 15 - 400

Britton et al. 2013

Outline

• Introduction

• Diagnostic Specificity

• Risk versus Disorder

• Novel Therapeutics

CollaboratorsNIMH-SDAN

Jennifer Britton

Monique Ernst

Amanda Guyer

Jen Lau

Chris Monk

Eric Nelson

Roxanne Roberson-Nay

Tomer Shechner

NIMH-MAP

Ellen Leibenluft

Christian Grillon

Shmuel Lissek

Ken Towbin

Brenda Benson

NIMH-IRP

Peter Bandettini

Sean Marrett

Jim Winslow

Pam Noble

U Maryland

Nathan Fox

Jillian Hardee

Koraly Perez

Jenna Suway

U Southampton

Brendan Bradley

Karin Mogg

Tel Aviv University

Yair Bar-Haim

Sharon Eldar

Ilan Wald

Griffith University

Allison Waters

Institute for Child & Adolescent Psychiatry

Giovanni Salum

Gisele Manfro

Luis Rhode