Functional MRI
study of pressure
pain and its
modulation using
mental imagery
Edward F. Jackson1, Charles S. Cleeland2,
Karen O. Anderson2, Robert R. Allen2, Tito R.
Mendoza2, Richard Payne2, Guadalupe Palos2
Department of Radiology1 and
Pain Research Group, Department of
Symptom Control and Palliative Care
The University of Texas
M. D. Anderson Cancer Center
MDACC MR Research
1
Introduction
Recent PET and fMRI studies have
demonstrated the involvement of cortical
structures of the limbic system, i.e., the
anterior cingulate cortex and the insular
cortex, as well as sensory cortex areas SI
and SII in the perception of pain1,2. In
addition, studies have implicated a dissociation of the affective component of pain
(unpleasantness) from the intensity of
pain3. The present study utilized fMRI to
map areas of pain-evoked activation and
to quantitate the changes in the levels of
activation to further evaluate whether
such a dissociation of the two
components of pain could be observed
when the perceived level of pain was
modulated by mental imagery.
MDACC MR Research
2
Methods and Materials
Scanner and Acquisition Parameters: All
images were acquired on a GE 1.5 T Signa Horizon
EchoSpeed scanner (v5.6). The fMRI images were
acquired using a gradient-echo EPI sequence with
TE/TR = 60/3000 ms, Flip angle = 60o, 32 cm FOV,
64x64 matrix, and 95 kHz bandwidth (ramp
sampled). Seven 7 mm sections were acquired.
Following the EPI acquisitions, 3D FSPGR volume
scans and venous and arterial MRA scans were
acquired for anatomical-functional overlays and
transformations to Talairach coordinates4.
Stimulus: An MR-compatible pressure algometer5
placed between the first and second joints of the
index finger provided the painful stimulus. Weight
loads ranged from 1.0 - 2.5 kg, and were chosen
prior to the fMRI study to generate a mean pain
intensity rating of 5.4 on a 0 - 10 scale.
Subjects: Eight normal, right-handed subjects (7
females, 1 male) participated in the study after
providing written informed consent.
MDACC MR Research
3
Methods and Materials
Paradigm: Five repeated trials (18 s stimulus / 27 s
rest) acquired per run. Each run time was 3:39 min.
12s 18s 27s …
9s
Stimulus
Rest
Three runs were acquired with the last two runs
randomized to minimize order effect bias:
– Control
(State “C”)
Subject was verbally instructed to imagine the
non-weighted pressure algometer as painful
during each 18 s stimulus period
– “Toward State” (State “T”)
Subject was verbally instructed to focus on the
pain resulting from the application of the
weighted algometer during each stimulus period
– “Away State”
(State “A”)
Subject was distracted from the pain using
verbally-cued mental imagery during the
application of the weighted algometer
MDACC MR Research
4
Methods and Materials
Post-Acquisition Processing:
The fMRI, anatomical, and MRA data were
processed using AFNI6 version 2. For each run,
2D image registration was performed on all fMRI
data to decrease the effects of involuntary motion.
The fMRI activation maps were generated using a
multiple cross-correlation algorithm, and the
activation maps were transformed to Talairach
coordinate space.
The resulting 24 fMRI activation maps (8 subjects,
3 runs each) were then analyzed using a 3D
ANOVA to generate mean activation maps for the
control state, toward state, and away state, as well
as the difference maps toward minus control (T-C)
and away minus control (A-C). The “treatment
effects” map was also generated to test the
hypothesis C=A=T.
MDACC MR Research
5
Methods and Materials
Post-Acquisition Processing (cont):
For each mean or difference map, a 3D cluster
analysis program was used to compute the
volumes of connected activated voxels in the
fMRI maps subject to a p-value threshold of 0.05
and a minimum cluster size of 525 l (corresponding to three connected voxels in the original
EPI datasets).
The center of mass of the identified clusters was
determined in Talairach coordinates, and the
volume of each cluster was computed.
MDACC MR Research
6
Results
Subjective Pain Ratings:
The subjective mean post-experiment rating
of pain intensity was 2.9 in the away state
and 6.5 in the toward state (on a scale of 010 with 10 being the “worst pain imaginable”).
As a comparison, the mean rating in the preimaging session (without verbal cueing to
focus toward or away from the pain) was 5.4.
MDACC MR Research
7
Results
Mean Activation Map for Control State
(N = 8, p  0.05, tmin = 2.08)
z= - 5
z=+10
z=+25
z=+40
MDACC MR Research
8
Results
Mean Activation Map for Away State
(N = 8, p  0.05, tmin=2.08, Mean Pain Intensity Rating: 2.9)
z= - 5
z=+10
z=+25
z=+40
MDACC MR Research
9
Results
Mean Activation Map for Toward State
(N = 8, p  0.05, tmin=2.08, Mean Pain Intensity Rating: 6.5)
z= - 5
z=+10
z=+25
z=+40
MDACC MR Research
10
Results
Mean State Activation Volumes
Mean Control State:
Description
Brodmann’s
Area
R middle
temporal gyrus
L middle
temporal gyrus
22, 42
0.007
-55
-30
6
14936
22, 42
0.009
59
-25
6
12580
Mean
L-R
P-A
I-S
p-value (mm) (mm) (mm)
Volume
(l)
Total Volume: 27.5 ml
Mean Away State:
Description
L superior
temporal gyrus
R superior
temporal gyrus
L cingulate
gyrus
L posterior
cingulum
R inferior
frontal gyrus
R pre-central
gyrus
Brodmann’s
Area
22, 42
Mean
L-R
P-A
I-S
p-value (mm) (mm) (mm)
0.009
-50
-15
10
Volume
(l)
27451
22, 42
0.007
-58
-18
6
17053
24
0.016
-4
-4
40
1963
29, 30
0.026
-5
-51
7
1014
45
0.013
44
21
12
1007
6
0.009
46
-1
32
814
Total Volume: 49.3 ml
MDACC MR Research
11
Results
Mean State Activation Volumes
Mean Toward State:
Description
L insular and
L superior
temporal gyri
R superior
temporal gyrus
Brodmann’s
Area
13
22, 42
Mean
L-R
P-A
I-S
p-value (mm) (mm) (mm)
0.011
-45
-16
9
Volume
(l)
31035
22, 42
0.007
57
-17
8
26178
Midline
cingulate gyrus
Midline
thalamus and
R caudate
L superior
frontal gyrus
32 & 24
0.017
4
10
37
3360
0.013
14
-4
12
3357
10
0.017
-37
70
-2
877
L posterior
cingulum
R middle
occipital gyrus
L middle
occipital gyrus
29
0.021
-6
-40
10
616
37
0.026
46
-67
2
522
37
0.032
-30
-67
8
526
Total Volume: 66.5 ml
MDACC MR Research
12
Results
Mean Difference Maps
(N = 8, p  0.05, tmin = 2.08)
Away - Control
Toward - Control
z= - 5
z= - 5
z=+10
z=+10
z=+25
z=+25
z=+40
z=+40
MDACC MR Research
13
Results
Mean Difference Map Activation Volumes
Mean Away Minus Control Map:
Description
Brodmann’s
Area
L posterior
cingulum
L cingulate
gyrus
29, 30
0.021
-5
-52
7
2551
24
0.017
-6
0
38
2039
L insular and
pre-central gyri
L middle
frontal gyrus
L post-central
gyrus
13
44
46
0.017
-45
2
8
1957
0.026
-47
34
16
1401
3
0.013
-66
-10
23
1316
R pre-central
gyrus
L thalamus
3
0.013
32
-12
38
1237
0.021
-23
-26
9
1149
L post-central
gyrus
R insula
4
0.021
-26
-6
41
1052
13
0.021
45
-1
4
995
L inferior
parietal
R post-central
gyrus
L parietal
40
0.032
-45
-28
25
816
6
0.011
46
-3
32
771
39
0.026
-43
-71
14
685
L insula
13
0.026
-38
28
13
606
Mean
L-R
P-A
I-S
p-value (mm) (mm) (mm)
MDACC MR Research
14
Volume
(l)
Total Volume: 16.6 ml
Results
Mean Difference Map Activation Volumes
Mean Toward Minus Control Map:
Description
L insula
Brodmann’s
Area
13
Mean
L-R
P-A
I-S
p-value (mm) (mm) (mm)
0.017
-33
-5
18
Volume
(l)
9612
L middle
frontal gyrus
10
0.026
-30
57
10
2460
R insula
13
0.021
49
6
5
2392
R inferior
parietal
Midline
cingulate gyrus
40
0.017
52
-30
26
2260
24
0.021
1
-5
42
1663
R superior
parietal
R caudate /
thalamus
L superior
parietal
L cingulate
gyrus
L caudate
7
0.021
23
-66
47
1505
0.021
8
4
10
1169
7
0.013
-20
-64
49
1168
32
0.026
-7
19
40
755
0.021
-10
-15
21
642
8
0.017
-13
42
41
575
6
0.011
46
-7
25
556
L superior
frontal gyrus
R pre-central
gyrus
Total Volume: 24.8 ml
MDACC MR Research
15
Discussion
Mean State Activation Volumes
The number and total volume of activated regions
increased from the control (27.5 ml) to the away
(49.3 ml) to the toward (66.5 ml) states, and this
increase correlated with the subjective postexperiment pain intensity ratings.
Other than
auditory cortex, the activated regions of greatest
volume were the anterior cingulate and insular
cortex. The volume of activation in the cingulate
increased significantly in the toward state and
involved BA24 and 32 as compared to only BA24 in
the away state. The auditory cortex activation
prevented quantitative assessment of the insular
cortex activation volumes, but qualitatively the
volume increased in the toward state relative to the
away state. Other areas of activation were also
significant but were of less volume.
Interestingly, the volume of activated auditory
cortex increased from the control to the away to the
toward conditions. The reason for the modulation of
the auditory cortex activation is unknown.
MDACC MR Research
16
Discussion
Mean Difference Map Activation Volumes
The auditory cortex activation due to the verbal
cueing tended to limit the quantitative assessment
of the volume of activation within the insular
cortex. To improve the visualization of the insular
cortex activation, the difference maps were
computed. As in the mean state maps, the total
volume of activation increased from the away
(16.6 ml) to the toward (24.8 ml) states, with the
primary areas of activation being in the anterior
cingulate cortex and insular cortex. Again, the
volumes of activation increased in the anterior
cingulate cortex and insular cortex in the toward
state relative to the away state. The insular cortex
activation was more clearly visualized in the
difference maps, but probable residual auditory
cortex activation remained and prevented
accurate assessment of the activation volumes.
Minor activation volumes in the caudate,
thalamus, and other areas were also noted.
MDACC MR Research
17
Discussion
Mean Difference Map Activation Volumes
While they more clearly showed the activation of
the insular cortex and allowed improved
qualitative assessment of the degree of activation,
the use of the difference maps is not the optimal
means of suppressing the auditory cortex
activation.
This is particularly true with the
relatively small number of subjects and the spatial
variation in auditory cortex activation in the control
vs away vs toward conditions. The auditory
cortex activation with verbal cueing might be
decreased in the fMRI maps by the presentation
of tones having sound pressure levels
comparable to those presented during the
auditory cueing but presented within the control
states.
MDACC MR Research
18
Conclusion
This study demonstrates the utility of fMRI
for the evaluation of the cortical
representation of pain and its modulation
by mental imagery, and reinforces the
previous studies that have demonstrated
the involvement of the anterior cingulate
cortex and insular cortex in the processing
of painful stimuli. The use of fMRI in
studies of pharmacological and nonpharmacological interventions should
provide a powerful tool for studying the
poorly
understood
mechanisms
responsible for the effects of these
interventions.
MDACC MR Research
19
References and
Acknowledgments
References:
1) Craig AD, Reiman EM, Evans A, et al. Nature
384:258-260, 1996.
2) Davis KD, Taylor SJ, Crawley AP, et al.
J
Neurophysiol 77:3370-3380, 1997.
3) Rainville P, Duncan GH, Price DD, et al. Science
277: 968-971, 1997.
4) Talairach J and Tournoux P. Co-Planar Stereotaxic
Atlas of the Human Brain, Thieme Medical Publishers,
Inc. New York, 1988.
5) Rainwater AJ, McNeil DW. Behav Res Methods
23:486-492, 1991.
6) Cox RW. Comput Biomed Res 29:162-173, 1996.
Acknowledgments:
This work was supported in part by a grant from the
National Cancer Institute to C.S.C. (RO1-CA73005).
MDACC MR Research
20