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Uncertainty modulates an6cipatory anterior insula ac6vity in generalized anxiety disorder
Dan W. Grupe, Desmond J. Oathes, Dan R. McFarlin, and Jack B. Nitschke
Waisman Laboratory for Brain Imaging & Behavior and Departments of Psychology and Psychiatry
University of Wisconsin-‐Madison
What is anxiety?
An emo6onal state characterized by an#cipatory affec6ve, cogni6ve, and behavioral changes in response to uncertainty about poten6al future threat
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An6cipa6on of aversion in healthy controls
Grupe et al., Cer. Cort., 2012
PHASIC SUSTAINED
Sustained differences for an6cipa6on of aversive vs. neutral pictures
Grupe et al., Cer. Cort., 2012
R Anterior Insula Midbrain/PAG R BNST L Anterior Insula
AVERSIVE ANTICIPATION NEUTRAL ANTICIPATION
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An6cipa6on of aversion in GAD
• Sustained an6cipa6on under condi6ons of threat uncertainty is par6cularly relevant for GAD
?
• Individuals with GAD may show heightened anterior insula ac6vity during uncertain an6cipa6on
Methods
• 57 par6cipants with GAD (43 F, mean age 27.5 ± 10.6 years)
• 43 healthy controls (22 F, mean age 24.2 ± 6.7 years)
• Four 11-‐minute fMRI runs of Emo6onal An6cipa6on task
• Group analysis: Group (GAD,CON) x Condi6on (X,O,?) ANOVA for sustained an6cipatory period – Whole-‐brain voxelwise analysis conducted at p < 0.05 (corrected using clustering and Monte Carlo simula6on)
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Results: main effects of condi6on
x=-2
-‐0.1
-‐0.08
-‐0.06
-‐0.04
-‐0.02
0
43 Controls 57 GAD
Aversive Uncertain Neutral
y=24 y=-2 R
Results: main effects of condi6on
x=-2
-‐0.12
-‐0.1
-‐0.08
-‐0.06
-‐0.04
-‐0.02
0
43 Controls 57 GAD
Aversive Uncertain Neutral
y=24 y=-2 R
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Heightened anterior insula responses to uncertain an6cipa6on in GAD
Group x Condition Interaction p < 0.05 (corrected)
-‐0.25
-‐0.2
-‐0.15
-‐0.1
-‐0.05
0
43 Controls 57 GAD
Aversive Uncertain Neutral
y=24 R
Heightened anterior insula responses to uncertain an6cipa6on in GAD
Group x Condition Interaction p < 0.05 (corrected)
-‐0.25
-‐0.2
-‐0.15
-‐0.1
-‐0.05
0
43 Controls 57 GAD
Uncertain Neutral
y=24
p = 0.004
R
z=-6
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But what does it mean? • Relate anterior insula ac6vity during sustained, uncertain an6cipa6on to self-‐reported Intolerance of Uncertainty (IU).
Anterior insula ac6vity posi6vely correlated with Intolerance of Uncertainty in GAD
Regression of whole-‐brain ac6vity (contrast of uncertain–neutral an6cipa6on) on Intolerance of Uncertainty scores p < 0.05, corrected
y=18 -‐0.6
-‐0.4
-‐0.2
0
0.2
0.4
0.6
50 70 90 110 130 150
57 GAD
r=0.53
(?-‐O An#
c. Ac#vity)
IU Scores
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But what does it mean? • Anterior insula ac6vity during sustained, uncertain an6cipa6on is correlated with self-‐reported Intolerance of Uncertainty (IU) in GAD.
• Elevated ac6vity in the anterior insula during sustained, uncertain an6cipa6on may reflect altered parasympathe6c func6on in GAD • Measure of parasympathe6c tone: high-‐frequency heart-‐rate variability (HRV)
• HRV correlated with cardiac health • HRV as a marker of adap6ve emo6onal responses to stress
Anterior insula ac6vity inversely correlated with HRV in GAD
Regression of whole-‐brain ac6vity (contrast of uncertain–neutral an6cipa6on) on average HF-‐HRV; p < 0.05, corrected
y=16
-‐0.4
-‐0.2
0
0.2
0.4
3 5 7 9 11
38 Con 51 GAD
(?-‐O An#
c. Ac#vity)
Heart-‐rate variability scores
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Anterior insula ac6vity inversely correlated with HRV in GAD
Regression of whole-‐brain ac6vity (contrast of uncertain–neutral an6cipa6on) on average HF-‐HRV; p < 0.05, corrected
Increased AI ac#vity during uncertain an#cipa#on may reflect deficient inhibitory parasympathe#c control
y=16
-‐0.4
-‐0.2
0
0.2
0.4
3 5 7 9 11
51 GAD
r=-0.34
(?-‐O An#
c. Ac#vity)
Heart-‐rate variability scores
Summary • Individuals with GAD show heightened sustained anterior insula ac6vity in response to uncertain threat an6cipa6on
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Summary • Individuals with GAD show heightened sustained anterior insula ac6vity in response to uncertain threat an6cipa6on
• Anterior insula ac6vity in GAD correlated with: – Greater intolerance of uncertainty – Lower high-‐frequency heart-‐rate variability (i.e., reduced parasympathe6c tone)
Thank you!
Collaborators
Jack Nitschke Desmond Oathes Dan McFarlin
Technical Support and Consulta#on Tammi Kral Melissa Schmidt Dave Perlman Aaron Heller Michael Anderle Ron Fisher
Funding
NSF Graduate Research Fellowship
NIMH (R01-‐MH74847, K02-‐MH082130, K08-‐MH63984) NICHD core grant to the Waisman Center (P30-‐HD03352).