FMRI & Children Clinical Applications? Daniel S. Pine, MD Emotion & Development Branch.
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Transcript of FMRI & Children Clinical Applications? Daniel S. Pine, MD Emotion & Development Branch.
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