Transcript Document

Multiple mediators of expectancy effects on pain perception:
Interactions among higher-order brain regions and the pain matrix
Lauren Y.
Columbia Psychology SCAN group
http://www.scan.psych.columbia.edu/
1
Atlas ,
Niall
1
Bolger ,
Martin
2
Lindquist ,
324 Schermerhorn Hall
Department of Psychology
1190 Amsterdam Ave.
New York, NY 10027
1
Wager
Tor D.
1Columbia University Department of Psychology, 2Columbia University Department of Statistics
Contact: [email protected]
Reprints: http://www.columbia.edu/cu/psychology/tor/
INTRODUCTION
RESULTS
N
CB Vermis
Y
Y
Y
R. SII
Y
N
N
R. Thalamus*
Y
N
Y
R. Anterior Insula†
Y
Y
N
L. Anterior Insula
Y
Y
Y
R. Middle Insula
Y
N
N
7
L. Middle Insula
Y
N
N
6
dACC*
N
Y
Y
PAG
N
N
N
Pons*
Y
N
Y
LM
4
3
2
0
Brain Mediators
HH
Path a
•18 subjects (mean age = 25.3, 9 females)
•Thermal stimulation to 4 sites on left forearm with 16mm thermode (Medoc, Inc.))
•FMRI acquisition: 1.5T GE scanner, Spiral In-Out, 29 slices, 2s TR
TPJ
L. Ant. Insula
L. Putamen,
Caudate
PAIN PERIOD ACTIVATION
Left Anterior Insula
Right Thalamus
High pain
cue
High pain
cue
+
CUE
Delay
Low Pain (Level 2)
LL
Med Pain (Level 5)
LM
Med Pain (Level 5)
HM
High Pain (Level 8)
HH
•Voxelwise single trial analysis
1. Fit basis functions
trial-by-trial
2. Estimate trial-by-trial
area under the
curve (AUC)
3. Use trial level
parameters in multilevel mediation
14s
+
+
HEAT
ISI
LE-Med > HE-Med
HE-Med > LE-Med
Left DLPFC
Left Amygdala
Medial OFC
Basis functions
Expectancy
(HM-LM)
Pons
Expectancy
(HM-LM)
L. Anterior Insula
Perceive
d Pain
SII
Trial-by-trial estimates
0.20 (0.08)**
Mid. Cingulate
5
4
3
Cerebellum
5
4
3
5
4
3
2
2
2
2
1
1
1
1
Right IFG
Right latPFC
Perceived
Pain
Region
L VS
L Amyg
R SII
mOFC
Perceived
Pain
b
Medial OFC
A*B
0.4333(.21)*
0.5039 (.25)*
0.3749(.11)**
0.2468(.18)*
*:Activity averaged across pain matrix mediators.
Report Region
Thick arrows depict paths identified in
primary mediation (Hypoth IV).
Dashed arrows depict effects
potentially being mediated.
Perceived
Pain
Right
dmPFC
Expectancy
Pain Matrix
Mediators
Medial
OFC
•Nearly all pain matrix regions are modulated by expectancy during noxious thermal stimulation (all except dACC, PAG).
•Some pain matrix regions (Insula, dACC) predict perceived pain controlling for expectancy and temperature.
•A key subset of pain matrix regions (insula, thalamus, dACC, pons, cerebellum) mediate expectancy effects on perceived
pain.
•Amygdala, striatum, and medial OFC mediate expectancy effects on pain matrix mediators.
•R. dmPFC mediates expectancy effects on pain independent of pain matrix activity.
Secondary mediation 1
Secondary mediation 2
Independent of pain matrix
a
Perceived
Pain
Positive path coefficients
Negative path coefficients
References
SUMMARY
Three linear equations:
1. y = cx + ey
2. m = ax + em
3. y = bm + c'x + e'y
3
R. Ant. Insula
b
Expectancy Region
Pain Matrix
Mediators
Expectancy
42.52 (6.18)***
•Whole-brain multi-level mediation
A test for mediation should satisfy the following criteria:
1. M should be related to X (a effect)
2. M should be related to Y after controlling for X
(b effect)
3. The indirect relationship (a*b)should be significant
2.24 (0.77)**
4
a
Left Ventral
Striatum
Trial level parameters
Expectancy
(HM-LM)
b.
5
Pain Matrix
Mediators*
Path c
Mediating expectancy effects on
pain matrix
Left
Amygdala
6.25 (1.72) ***
PERCEIVED PAIN
VI. Secondary mediation analysis: Expectancy-based interactions between pain matrix
and higher-order mediators contribute to perceived pain.
R. Thalamus
CB Vermis
rdACC
Right DMPFC
ISI
Contrast HM vs LM
during pain period:
identical stimulation, high
vs low pain expectancy
R sgACC
Right VLPFC
dACC
+
rdACC
IV, V. Mediation effect: Pain matrix regions and higher order
regions mediate expectancy effects on reported pain.
IV. Pain matrix mediators
8s
Vermis
Pons
4s
How
Painful?
Mid. Cing
R.
Thalamus
b.
2. Learning Task: Tones predict low or high pain, counterbalanced
across subjects; S informed of cue-pain pairings, must correctly
identify 90% of tones to proceed 2s
6s
3. Two conditioning runs + fMRI
+
10s
R (Contralateral)
Pons
pgACC
Pons
PAIN PERIOD ACTIVATION
a.
dACC
R. dmPFC
Right SII
1. Pain calibration
Low pain
cue
Low pain
cue
Middle Occipital
Gyrus
L (Ipsilateral)
•Experimental design
4. Six experimental runs + fMRI
Path b
Pain Regions
a.
EXPECTANCY
III. Path b: Controlling for
expectancy and
temperature, brain activity
predicts perceived pain.
L. DLPFC
Reported Pain
HM
Negative effect
LM
Reported Pain
LL
II. Path a: Expectancies
modulate brain activity
during pain.
Level 8 (Max
tolerable pain)
Perceived
Pain (Pain
Reports)
HM
A*B: Which brain regions
mediate expectancy effects on
pain perception?
1
METHODS
Level 5
(Moderate pain)
LM
Path c/c’
5
I.
II.
III.
IV.
Level 2 (Slightly
painful)
HM
8
•Hypotheses
Expectancies modulate pain reports.
Expectancies modulate pain matrix activity (Path a).
Pain matrix activity affects perceived pain (Path b).
Expectancy effects in pain matrix regions lead to changes in
perceived pain (Mediation effect, A*B).
V. Higher order regions involved in cognitive control and value
processing also mediate expectancy effects on perceived pain.
VI. Interactions among these mediators predict perceived pain.
Expectanc
y (HM-LM)
HM>LM (p<.0001), allowing
us to examine mediators of
expectancy effects on
reported pain within a single
**** stimulation.
level of noxious
Reported Pain
•We used multi-level mediation (M3) software to test this compound
hypothesis, and to locate regions that formally mediate the relationship
between experimentally manipulated expectancy and reported pain.
Y
Reported Pain
a) be influenced by expectancy.
b) predict trial-by-trial changes in reported pain, even within a single
level of noxious stimulation.
c) statistically explain a significant portion of expectancy effects on
trial-by-trial reported pain.
Y
Pain Regions
•For a brain region or pathway to mediate expectancy effects on reported
pain, its activity must:
Bilateral
Cerebellum†
Positive effect
–Have not examined relationship between brain and pain reports.
A? B? AB?
Pain Rating
–Event-related (cue-based) expectancy manipulations: modulation of
pain matrix and striatal regions5,6
Pain Localizer - HH>LL
Region
Pain Rating
–Placebo analgesia brain-behavior correlations = between-subjects only.
WHOLE BRAIN MULTI-LEVEL MEDIATION ANALYSIS
I. Expectancies
modulate perceived
pain.
Perceived Pain
•Expectancies modulate both reported pain and responses in some brain
regions, yet the key brain circuitry that mediates expectancy effects on pain
experience has not been identified.
–Placebo expectancy manipulations: decreases in “pain matrix”
regions1,2, increases in control regions, particularly rACC2,3,4
1.
2.
3.
4.
DD Price et al. Pain, 127, 63-72 (2007).
TD Wager et al. Science, 303, 1162-7 (2004).
U Bingel et al. Pain, 120, 8-15 (2006).
P Petrovic, E Kalso, KM Petersson, M Ingvar. Science,
295, 1737-40, (2002).
5. T Koyama, JG McHaffie, PJ Laurienti, RC Coghill. PNAS,
102, 12950-12955 (2005).
6. JR Keltner et al. JNeuroscience, 26, 4437-4443 (2006).