mdacc mr research 1 functional mri study of pressure pain and its modulation using mental imagery...

MDACC MR ResearchMDACC MR Research

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Functional MRI study of pressure

pain and its modulation using mental imagery

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

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


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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 disso-ciation 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.

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 disso-ciation 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.

IntroductionIntroduction


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Methods and MaterialsMethods 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.

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.


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Paradigm: Five repeated trials (18 s stimulus / 27 s rest) acquired per run. Each run time was 3:39 min.

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

Paradigm: Five repeated trials (18 s stimulus / 27 s rest) acquired per run. Each run time was 3:39 min.

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

Methods and MaterialsMethods and Materials

StimulusStimulus Rest Rest

12s12s 18s 27s … 9s18s 27s … 9s


55

Methods and MaterialsMethods 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.

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.


66

Methods and MaterialsMethods 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 (corres-ponding 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.

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 (corres-ponding 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.


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ResultsResults

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 0-10 with 10 being the “worst pain imaginable”). As a comparison, the mean rating in the pre-imaging session (without verbal cueing to focus toward or away from the pain) was 5.4.

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 0-10 with 10 being the “worst pain imaginable”). As a comparison, the mean rating in the pre-imaging session (without verbal cueing to focus toward or away from the pain) was 5.4.


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ResultsResults Mean Activation Map for Control State

(N = 8, p 0.05, tmin = 2.08)

Mean Activation Map for Control State (N = 8, p 0.05, tmin = 2.08)

z=+25z=+25

z=+10z=+10

z= - 5z= - 5

z=+40z=+40


99

ResultsResults Mean Activation Map for Away State

(N = 8, p 0.05, tmin=2.08, Mean Pain Intensity Rating: 2.9)

Mean Activation Map for Away State (N = 8, p 0.05, tmin=2.08, Mean Pain Intensity Rating: 2.9)

z=+25z=+25

z=+10z=+10

z= - 5z= - 5

z=+40z=+40


1010

ResultsResults Mean Activation Map for Toward State

(N = 8, p 0.05, tmin=2.08, Mean Pain Intensity Rating: 6.5)

Mean Activation Map for Toward State (N = 8, p 0.05, tmin=2.08, Mean Pain Intensity Rating: 6.5)

z=+25z=+25

z=+10z=+10

z= - 5z= - 5

z=+40z=+40


1111

ResultsMean State Activation Volumes


DDeessccrriippttiioonn BBrrooddmmaannnn’’ssAArreeaa

MMeeaannpp--vvaalluuee

LL--RR((mmmm))

PP--AA((mmmm))

II--SS((mmmm))

VVoolluummee((ll))

RR mmiiddddlleetteemmppoorraall ggyyrruuss

2222,, 4422 00..000077 --5555 --3300 66 1144993366

LL mmiiddddlleetteemmppoorraall ggyyrruuss

2222,, 4422 00..000099 5599 --2255 66 1122558800



LL--RR((mmmm))

PP--AA((mmmm))

II--SS((mmmm))

VVoolluummee((ll))

LL ssuuppeerriioorrtteemmppoorraall ggyyrruuss

2222,, 4422 00..000099 --5500 --1155 1100 2277445511

RR ssuuppeerriioorrtteemmppoorraall ggyyrruuss

2222,, 4422 00..000077 --5588 --1188 66 1177005533

LL cciinngguullaatteeggyyrruuss

2244 00..001166 --44 --44 4400 11996633

LL ppoosstteerriioorrcciinngguulluumm

2299,, 3300 00..002266 --55 --5511 77 11001144

RR iinnffeerriioorrffrroonnttaall ggyyrruuss

4455 00..001133 4444 2211 1122 11000077

RR pprree--cceennttrraallggyyrruuss

66 00..000099 4466 --11 3322 881144

Mean Control State:Mean Control State:

Mean Away State:Mean Away State:

Total Volume: 49.3 mlTotal Volume: 49.3 ml



1212





LL--RR((mmmm))

PP--AA((mmmm))

II--SS((mmmm))

VVoolluummee((ll))

LL iinnssuullaarr aannddLL ssuuppeerriioorr

tteemmppoorraall ggyyrrii

11332222,, 4422

00..001111 --4455 --1166 99 3311003355

RR ssuuppeerriioorrtteemmppoorraall ggyyrruuss

2222,, 4422 00..000077 5577 --1177 88 2266117788

MMiiddlliinneecciinngguullaattee ggyyrruuss

3322 && 2244 00..001177 44 1100 3377 33336600

MMiiddlliinneetthhaallaammuuss aanndd

RR ccaauuddaattee

00..001133 1144 --44 1122 33335577

LL ssuuppeerriioorrffrroonnttaall ggyyrruuss

1100 00..001177 --3377 7700 --22 887777


2299 00..002211 --66 --4400 1100 661166

RR mmiiddddlleeoocccciippiittaall ggyyrruuss

3377 00..002266 4466 --6677 22 552222

LL mmiiddddlleeoocccciippiittaall ggyyrruuss

3377 00..003322 --3300 --6677 88 552266

Mean Toward State:Mean Toward State:



1313

ResultsResults Mean Difference Maps

(N = 8, p 0.05, tmin = 2.08)

Mean Difference Maps (N = 8, p 0.05, tmin = 2.08)

z=+25z=+25

z=+10z=+10

z= - 5z= - 5

z=+40z=+40

z=+25z=+25

z=+10z=+10

z= - 5z= - 5

z=+40z=+40

Away - ControlAway - Control Toward - ControlToward - Control


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ResultsMean Difference Map Activation Volumes




LL--RR((mmmm))

PP--AA((mmmm))

II--SS((mmmm))

VVoolluummee((ll))


2299,, 3300 00..002211 --55 --5522 77 22555511


2244 00..001177 --66 00 3388 22003399

LL iinnssuullaarr aannddpprree--cceennttrraall ggyyrrii

11334444

00..001177 --4455 22 88 11995577

LL mmiiddddlleeffrroonnttaall ggyyrruuss

4466 00..002266 --4477 3344 1166 11440011

LL ppoosstt--cceennttrraallggyyrruuss

33 00..001133 --6666 --1100 2233 11331166


33 00..001133 3322 --1122 3388 11223377

LL tthhaallaammuuss 00..002211 --2233 --2266 99 11114499

LL ppoosstt--cceennttrraallggyyrruuss

44 00..002211 --2266 --66 4411 11005522

RR iinnssuullaa 1133 00..002211 4455 --11 44 999955

LL iinnffeerriioorrppaarriieettaall

4400 00..003322 --4455 --2288 2255 881166

RR ppoosstt--cceennttrraallggyyrruuss

66 00..001111 4466 --33 3322 777711

LL ppaarriieettaall 3399 00..002266 --4433 --7711 1144 668855

LL iinnssuullaa 1133 00..002266 --3388 2288 1133 660066

Mean Away Minus Control Map:Mean Away Minus Control Map:



1515





LL--RR((mmmm))

PP--AA((mmmm))

II--SS((mmmm))

VVoolluummee((ll))

LL iinnssuullaa 1133 00..001177 --3333 --55 1188 99661122

LL mmiiddddlleeffrroonnttaall ggyyrruuss

1100 00..002266 --3300 5577 1100 22446600

RR iinnssuullaa 1133 00..002211 4499 66 55 22339922

RR iinnffeerriioorrppaarriieettaall

4400 00..001177 5522 --3300 2266 22226600

MMiiddlliinneecciinngguullaattee ggyyrruuss

2244 00..002211 11 --55 4422 11666633

RR ssuuppeerriioorrppaarriieettaall

77 00..002211 2233 --6666 4477 11550055

RR ccaauuddaattee //tthhaallaammuuss

00..002211 88 44 1100 11116699

LL ssuuppeerriioorrppaarriieettaall

77 00..001133 --2200 --6644 4499 11116688


3322 00..002266 --77 1199 4400 775555

LL ccaauuddaattee 00..002211 --1100 --1155 2211 664422

LL ssuuppeerriioorrffrroonnttaall ggyyrruuss

88 00..001177 --1133 4422 4411 557755


66 00..001111 4466 --77 2255 555566

Mean Toward Minus Control Map:Mean Toward Minus Control Map:



1616

DiscussionMean State Activation Volumes

DiscussionMean 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 post-experiment 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.

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 post-experiment 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.


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DiscussionMean Difference Map Activation Volumes

DiscussionMean 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.

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.


1818

Discussion Mean Difference Map Activation Volumes

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.

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.


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ConclusionConclusion

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 non-pharmacological interventions should provide a powerful tool for studying the poorly understood mechanisms responsible for the effects of these interventions.

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 non-pharmacological interventions should provide a powerful tool for studying the poorly understood mechanisms responsible for the effects of these interventions.


2020

References and AcknowledgmentsReferences 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).

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 1 functional mri study of pressure pain and its modulation using mental imagery...

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