Pain Affect Encoded in Human Anterior Cingulate But Not Somatosensory Cortex

R. Melzack and K. L. Casey, in The Skin Senses, D. R. Kenshalo, Ed. (Thomas, Springfield, IL, 1968), pp. 423–443.

H. L. Fields, Pain (McGraw-Hill, New York, 1987).

Foltz E. L., White E. W., J. Neurosurg. 19, 89 (1962);

; Int. J. Neurol.6, 353 (1968);

Hurt R. W., Ballantine H. T., Clin. Neurosurg. 21, 334 (1973);

; S. Corkin and N. Hebben, Pain (suppl. 1) 150 (1981).

Gingold S. I., Greenspan J. D., Apkarian A. V., J. Comp. Neurol. 308, 467 (1991);

Stevens R. T., London S. M., Apkarian A. V., Brain Res. 631, 241 (1993) .

Talbot J. D., et al., Science 251, 1355 (1991);

Jones A. K. P., Brown W. D., Friston K. J., Qi L. Y., Frackowiak R. S. J., Proc. R. Soc. London Ser. B 244, 39 (1991);

Casey K. L., et al., J. Neurophysiol. 71, 802 (1994);

Coghill R. C., et al., J. Neurosci. 14, 4095 (1994).

Vogt B. A., Rosene D. L., Pandya D. N., Science 204, 205 (1979);

Sikes R. W., Vogt B. A., J. Neurophysiol. 68, 1720 (1992);

; J. O. Dostrovsky and A. D. Craig, Soc. Neurosci. Abstr.22, 111 (abstr. 51.16) (1996); A. D. Craig and E.-T. Zhang, ibid., (abstr. 51.18); E. Rausell and E. G. Jones, J. Neurosci. 11, 226 (1991);

Kenshalo D. R., Chudler E. H., Anton F., Dubner R., Brain Res. 454, 378 (1988).

Suggestions for increased and decreased unpleasantness were adapted from

Kiernan B. D., Dane J. R., Phillips L. H., Price D. D., Pain 60, 39 (1995).

, validated for separating sensory and affective pain perception [B. Carrier, P. Rainville, G. H. Duncan, M. C. Bushnell, in abstracts of the Eighth World Congress on Pain, International Association for the Study of Pain, Vancouver, British Columbia, Canada, 17 to 22 August 1996 (IASP Press, Seattle, WA, 1996), abstr. 132, p. 478], and confirmed in the individuals chosen for these imaging experiments.

A preliminary report has appeared as an abstract [

Rainville P., Duncan G. H., Price D. D., Bushnell M. C., Soc. Neurosci. Abstr. 22, 117 (1996)].

Before the experiment a group of volunteers were tested with the noxious stimuli and hypnotic induction and suggestion procedures. From that group three female and five male participants, 19 to 53 years in age, who displayed moderate to high hypnotic suggestibility (Stanford Suggestibility Scale Form A) and robust modulation of pain unpleasantness were chosen for the PET study. Experimental sessions (12 scans) were administered once to each of five participants and twice to three other participants. Because of possible residual effects of hypnotic suggestions, the alert control conditions were always presented first, followed by hypnotic control (without suggestions of altered perception), and finally suggestions for increased (↑UNP) or decreased (↓UNP) unpleasantness. “Neutral” (35°C) and “painfully hot” (46.5° to 47.5°C) stimuli were counterbalanced across individuals within the alert and hypnotic control states, as were the blocks of two ↑UNP and two ↓UNP scans.

This 75-s hand immersion stimulus was chosen on the basis of our previous findings that tonic pain has a stronger affective component than phasic pain [

Rainville P., Feine J. S., Bushnell M. C., Duncan G. H., Somatosens. Mot. Res. 9, 265 (1992);

]. Temperatures were adjusted individually to obtain pain ratings of 40 to 80 on a scale of 0 to 100 [see (11)]; resulting temperatures ranged from 46.5° to 47.5°C.

Participants rated pain intensity and unpleasantness using separate numerical scales of 0 to 100. The intensity scale endpoints were “no burning, pricking, stinging sensation,” the most frequently chosen words describing the sensory aspect of heat pain in an independent study [

Morin C., TenBokum L., Bushnell M. C., Soc. Neurosci. Abstr. 20, 127 (1994);

], and “extremely intense sensation.” The unpleasantness scale endpoints were “not at all unpleasant” and “extremely unpleasant.” To avoid ceiling effects, we instructed participants that responses could surpass 100 if larger values were needed to describe sensations relative to those previously rated.

PET data (63 slices) were acquired with a Siemens ECAT HR⁺ camera. Participants lay immobile in the scanner, eyes closed, with inserted earphones connected to a microphone through which they received instructions or hypnotic suggestions before each scan. Stimulus onset was simultaneous with bolus injection (10 mCu of H₂¹⁵O, half-life of 123 s, without arterial blood sampling) to synchronize the increase in pain sensation with brain uptake of H₂¹⁵O. Scans began 15 s after the injection, and data were collected in two sequential frames of 40 and 20 s (data presented are derived from the 40-s frame, which yielded the better signal-to-noise ratio). Scans were separated by 12 to 15 min to allow tracer decay to background levels.

MRI scans (160 contiguous 1-mm-thick slices) were acquired on a Philips 1.5T Gyroscan system. Each participant's PET and MRI volumes were transformed into the Talairach coordinate system [J. Talairach and P. Tournoux, Co-Planar Stereotaxic Atlas of the Human Brain (Thième, New York, 1988)] by using the automated methods of D. L. Collins, P. Neelin, T. M. Peters, and A. C. Evans, [J. Comput. Assisted Tomogr. 18, 192 (1994)]. PET and MRI volumes were resampled to obtain voxels of 1.34 mm by 1.72 mm by 1.50 mm in the x, y, and z planes, respectively.

Worsley K. J., Evans A. C., Marrett S., Neelin P., J. Cereb. Blood Flow Metab. 12, 900 (1992).

With four target foci, the search volume of 4 resels yields a threshold for statistical significance of t = 2.55 (P < 0.05, one-tailed t-test corrected for multiple comparisons).

VOIs were centered independently at the point of maximum pain-related increase in rCBF within each of the three pain sites identified in the two comparison conditions. This procedure ensured that the maximum activation observed in ↑UNP was directly compared with the corresponding point of maximum activation obtained in ↓UNP. To further verify the robustness of these comparisons, we tested different VOI radii (from 10 to 20 mm) for each structure, with similar results for all values.

In monkeys, responses of single neurons probably in the spino-thalamo-ACC pathway are modulated by cognitive factors that change both the perception of and reaction to pain [

Bushnell M. C., Duncan G. H., Exp. Brain Res. 78, 415 (1989);

___, Dubner R., He L. F., J. Neurophysiol. 52, 170 (1984)].

Corbetta M., Miezin F. M., Dobmeyer S., Shulman G. L., Petersen S. E., J. Neurosci. 11, 2383 (1991);

Pardo J. V., Pardo P. J., Janer K. W., Raichle M. E., Proc. Natl. Acad. Sci. U.S.A. 87, 256 (1990);

Paus T., Petrides M., Evans A. C., Meyer E., J. Neurophysiol. 70, 453 (1993);

Paus T., et al., Cereb. Cortex 6, 207 (1996);

; N. Picard and P. L. Strick, ibid., p. 342.

R. Bandler and M. T. Shipley, Trends Neurosci.17 (no. 9), 379 (1994).

D. P. Friedman, A. E. Murray, J. B. O'Neill,

Mishkin M., J. Comp. Neurol. 252, 323 (1986) ;

Mufson E. J., Mesulam M.-M., ibid. 212, 23 (1982);

; B. A. Vogt and D. N. Pandya, ibid.262, 271 (1987).

D. D. Price, Psychological and Neural Mechanisms of Pain (Raven, New York, 1988).