fmri & children clinical applications? daniel s. pine, md emotion & development branch
DESCRIPTION
Outline Introduction Diagnostic Specificity Risk versus Disorder Novel TherapeuticsTRANSCRIPT
fMRI & Children Clinical Applications?
DEPARTMENT OF
HEA
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 O
nset
Dis
tribu
tion
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 O
nset
Dis
tribu
tion
Separation Anxiety Disorder*Specific 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 Selection9 Months: EEG14 Months: Behavioral Inhibition24 Months: Behavioral Inhibition4 Years: Quartet Peer Interaction7 Years: Quartet Peer Interaction14 Years: Clinical Assessment, fMRI17 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
Med
ium
Larg
e
Sm
all
Med
ium
Larg
e
Sm
all
Med
ium
Larg
e
Sm
all
Med
ium
Larg
e
Caudate Putamen NucleusAccumbens
Amygdala
% s
igna
l cha
nge
InhibitedNon-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
Med
ium
Larg
e
Sm
all
Med
ium
Larg
e
Sm
all
Med
ium
Larg
e
Sm
all
Med
ium
Larg
e
Caudate Putamen NucleusAccumbens
Amygdala
% s
igna
l cha
nge
InhibitedNon-inhibited
Behavioral Inhibition Guyer et al. 2006
Anxiety Guyer et al. 2012
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 Selection9 Months: EEG14 Months: Behavioral Inhibition24 Months: Behavioral Inhibition4 Years: Quartet Peer Interaction7 Years: Quartet Peer Interaction14 Years: Clinical Assessment, fMRI18 Years: Clinical Assessment, fMRI
Fox et al. 2006
Study Design
4 Months: Recruitment and Selection9 Months: EEG14 Months: Behavioral Inhibition24 Months: Behavioral Inhibition4 Years: Quartet Peer Interaction7 Years: Quartet Peer Interaction14 Years: Clinical Assessment, fMRI18 Years: Clinical Assessment, fMRI
Fox et al. 2006
***-assessment of attention
***
***
***
Study Design
4 Months: Recruitment and Selection9 Months: EEG14 Months: Behavioral Inhibition24 Months: Behavioral Inhibition4 Years: Quartet Peer Interaction7 Years: Quartet Peer Interaction14 Years: Clinical Assessment, fMRI18 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
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 asAdolescents?
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 asAdolescents?
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 asAdolescents?
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 asAdolescents?
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 asAdolescents?
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 CONDITIONINGCS 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 CONDITIONINGCS 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
Outline
• Introduction
• Diagnostic Specificity
• Risk versus Disorder
• Novel Therapeutics
CollaboratorsNIMH-SDANJennifer BrittonMonique ErnstAmanda GuyerJen LauChris MonkEric NelsonRoxanne Roberson-NayTomer Shechner
NIMH-MAPEllen LeibenluftChristian GrillonShmuel LissekKen TowbinBrenda Benson
NIMH-IRPPeter BandettiniSean MarrettJim WinslowPam Noble
U MarylandNathan FoxJillian HardeeKoraly PerezJenna Suway
U SouthamptonBrendan BradleyKarin Mogg
Tel Aviv UniversityYair Bar-HaimSharon EldarIlan Wald
Griffith UniversityAllison Waters
Institute for Child & Adolescent PsychiatryGiovanni SalumGisele ManfroLuis Rhode