Human brain stem structures respond differentially to noxious heat

Abstract

Concerning the physiological correlates of pain, the brain stem is considered to be one core region that is activated by noxious input. In animal studies, different slopes of skin heating (SSH) with noxious heat led to activation in different columns of the midbrain periaqueductal gray (PAG). The present study aimed at finding a method for differentiating structures in PAG and other brain stem structures, which are associated with different qualities of pain in humans according to the structures that were associated with different behavioral significances to noxious thermal stimulation in animals. Brain activity was studied by functional MRI in healthy subjects in response to steep and shallow SSH with noxious heat. We found differential activation to different SSH in the PAG and the rostral ventromedial medulla (RVM). In a second experiment, we demonstrate that the different SSH were associated with different pain qualities. Our experiments provide evidence that brainstem structures, i.e., the PAG and the RVM, become differentially activated by different SSH. Therefore, different SSH can be utilized when brain stem structures are investigated and when it is aimed to activate these structures differentially. Moreover, percepts of first pain were elicited by shallow SSH whereas percepts of second pain were elicited by steep SSH. The stronger activation of these brain stem structures to SSH, eliciting percepts of second vs. first pain, might be of relevance for activating different coping strategies in response to the noxious input with the two types of SSH.

Keywords: A-delta fiber; C-fiber; PAG; RVM; pain descriptors; periaqueductal grey; rostral ventromedial medulla; second pain.

Figure 1

Experimental paradigm. The fMRI experiment (Experiment 1) consisted of five stimulation blocks (SB). Each of the four stimulation conditions was presented once during each SB. Painful heat peaks of the steep SSH stimuli were applied with a frequency of 0.3 Hz whereas painful heat peaks of the stimuli with shallow SSH were applied with a frequency of 0.17 Hz. During Experiment 2, shallow and steep SSH were applied only for the hot temperature.

Figure 2

(A) Increased activation of both HOT conditions compared to baseline in the posterior cingulate cortex PCC (slice plane 1), amygdala (slice plane 2), and PAG/NRD (slice plane 3). (B) Increased activation to shallow SSH compared to baseline in superior part of the PAG (slice plane 1); Field of view (FOV) with coronal slices (C) Increased activation to steep SSH compared to baseline in inferior part of the PAG, NRD (slice plane 1), and RVM (slice plane 2). (D) Increased activation to steep SSH compared to shallow SSH in PAG, NRD (slice plane 1), and RVM (slice plane 2). Statistical parametric maps are overlaid on a T1 scan (neurological convention, left = left).

Figure 3

Schematic overview of the blood oxygen level dependent (BOLD) responses in the periaqueductal gray (PAG), the nucleus Raphe dorsalis (NRD), and the rostral ventromedial medulla (RVM) (steep vs. shallow SSH for T_hot and T_warm conditions). The figure depicts means ± SE of parameter estimates for the peak voxel of the structures.

Figure 4

Odds ratios and 95% confidence intervals of the three descriptors, sorted from left to right for increasing selectivity for second pain and decreasing selectivity for first pain.

Figure A1

Coronal slices (one volume) of fMRI data overlaid on a anatomical scan (neurological convention left = left).

Figure A2

Section (between green lines in mid – saggital view) of the functional mean BOLD – data coregistered to the anatomical scan (neurological convention left = left).