Neurofeedback of the difference in activation of the anterior cingulate cortex and posterior insular cortex: two functionally connected areas in the processing of pain

Abstract

The aim of this study was the analysis of the effect of a learned increase in the dissociation between the rostral anterior cingulate cortex (rACC) and the left posterior insula (pInsL) on pain intensity and unpleasantness and the contribution of each region to the effect, exploring the possibility to influence the perception of pain with neurofeedback methods. We trained ten healthy subjects to increase the difference in the blood oxygenation level-dependent response between the rACC and pInsL to painful electric stimuli. Subjects learned to increase the dissociation with either the rACC (state 1) or the pInsL (state 2) being higher. For feedback we subtracted the signal of one region from the other and provided feedback in four conditions with six trials each yielding two different states: [rACC-pInsL increase (state 1), rACC-pInsL decrease (state 2), pInsL-rACC increase (state 2), pInsL-rACC decrease (state 1)]. Significant changes in the dissociation from trial one to six were seen in all conditions. There were significant changes from trial one to six in the pInsL in three of the four conditions, the rACC showed no significant change. Pain intensity or unpleasantness ratings were unrelated to the dissociation between the regions and the activation in each region. Learning success in the conditions did not significantly correlate and there was no significant correlation between the two respective conditions of one state, i.e., learning to achieve a specific state is not a stable ability. The pInsL seems to be the driving force behind changes in the learned dissociation between the regions. Despite successful differential modulation of activation in areas responsive to the painful stimulus, no corresponding changes in the perception of pain intensity or unpleasantness emerged. Learning to induce different states of dissociation between the areas is not a stable ability since success did not correlate overall or between two conditions of the the same state.

Keywords: anterior cingulate cortex; connectivity; neuromodulation; pain; posterior insula; real-time fMRI.

Figure 1

Course of one training trial for one target region. Over the course of one training trial (290 echo planar imaging (EPI) sequences) the participants attempted either up- or downregulation of the difference in the activation of the rostral anterior cingulate cortex (rACC) and the left posterior insula (pInsL) during 6 regulation phases each lasting 45 s (gray) while receiving painful electrical stimulation. Between the regulation phases, i.e., in the non-regulation phases (white), each lasting 22.5 s, the subjects performed mental arithmetic. An exemplary blood oxygenation level-dependent (BOLD) time course of one target area is superimposed in black.

Figure 2

(A,B) Offline statistical parametric mapping of the baseline run. Significant activations during the stimulation phases are superimposed over an averaged brain consisting of the ten T₁-weighted anatomical scans of the subjects, sagittal view (SAG). Red to yellow indicates significant activation in the regulation phases. Individual anatomical and functional scans were transformed into Talairach space. Average activation of the rostral anterior cingulate cortex (A) and the left posterior insula (B).

Figure 3

Unrelated region corrected (urc) percent signal change of all ten subjects of the rostral anterior cingulate cortex (rACC), the left posterior insula (pInsL) and the feedback percent signal change consisting of the activation difference between the regions for the two directions of the two states. Black lines indicate the change of the feedback signal, red lines the change in the pInsL only, and the blue line the change in the rACC only. Significant changes in the feedback, rACC, and pInsL activation are indicated in brackets of the same color. A significant difference between the activation in the two regions is indicated by a green bracket. The first column depicts the development from the baseline run to the first and the last training trial for all ten subjects, the second for the learners (L) and the third for the non-learners (NL) only. A positive training effect is seen in the significant change of the differences between the regions (feedback) from the first to the last training trial in the right direction.

Figure 4

Box plot showing the median, interquartile range, sample minimum and maximum of the direction independent magnitude of the training effect in the four conditions calculated from the unrelated region corrected (urc) difference of the rostral anterior cingulate gyrus (rACC) and the left posterior insula (pInsL) blood oxygenation level-dependent (BOLD) percent signal change.

Figure 5

Pain intensity and unpleasantness ratings in the baseline, on the first and last training trials (trials 1 and 6) and on average over all six training trials. The pain intensity and pain unpleasantness ratings relate to a verbal rating scale (VRS) with pain intensity ranging from 0 = no pain to 10 = strongest imaginable pain and pain unpleasantness ranging from 0 = not unpleasant to 10 = extremely unpleasant. State 1A, rostral anterior cingulate cortex (rACC) − left posterior insula (pInsL) increase condition; state 1B, pInsL − rACC decrease condition; state 2A, pInsL − rACC increase condition; state 2B, rACC − pInsL decrease condition.