Filling-in, spatial summation, and radiation of pain: evidence for a neural population code in the nociceptive system

Abstract

The receptive field organization of nociceptive neurons suggests that noxious information may be encoded by population-based mechanisms. Electrophysiological evidence of population coding mechanisms has remained limited. However, psychophysical studies examining interactions between multiple noxious stimuli can provide indirect evidence that neuron population recruitment can contribute to both spatial and intensity-related percepts of pain. In the present study, pairs of thermal stimuli (35 degrees C/49 degrees C or 49 degrees C/49 degrees C) were delivered at different distances on the leg (0, 5, 10, 20, 40 cm) and abdomen (within and across dermatomes) and subjects evaluated pain intensity and perceived spatial attributes of stimuli. Reports of perceived pain spreading to involve areas that were not stimulated (radiation of pain) were most frequent at 5- and 10-cm distances (chi(2) = 34.107, P < 0.0001). Perceived connectivity between two noxious stimuli (filling-in) was influenced by the distance between stimuli (chi(2) = 16.756, P < 0.01), with the greatest connectivity reported at 5- and 10-cm separation distances. Spatial summation of pain occurred over probe separation distances as large as 40 cm and six dermatomes (P < 0.05), but was maximal at 5- and 10-cm separation distances. Taken together, all three of these phenomena suggest that interactions between recruited populations of neurons may support both spatial and intensity-related dimensions of the pain experience.

Figures

Fig. 1.

Stimulated areas in the abdomen. A: using anatomical references, pairs of stimuli were delivered across dermatomes. The superior probe was positioned 5 cm below the xiphoid process in an area approximating the T6 dermatome, whereas the inferior probe was positioned 5 cm above the iliac spine in the vicinity of the T11/T12 dermatome. B: the distance “X” was used to place the probes in a horizontal orientation where spatial summation was evaluated within dermatomes. C: pairs of stimuli were also delivered side by side to evaluate the influence of separation of stimuli during spatial summation of pain (SSP) (B vs. C).

Fig. 2.

The perception of radiation of pain and pain sensitivity. A: during 35°C/49°C stimulus pairs, subjects reported pain from the neutral probe (35°C) at all distances. The most frequent reports of pain radiation occurred at separation distances of 5 and 10 cm. B: individual differences in the perceptions of radiation of pain were not influenced by individual differences in pain sensitivity.

Fig. 3.

The relationship between spatial perceptions of pairs of noxious stimuli (49°C/49°C) and stimulus separation distance on the leg (A–C) and within and across dermatomes on the abdomen (D). A: frequency of reports of only one probe activated. B: frequency of reports that the perceived pain was not restricted to the area under the activated probes but extended to connect the 2 stimuli. The highest reports of connectivity were found at 10 cm (χ2 = 17.149, P < 0.01). These reports are consistent with the filling-in phenomenon found in other systems. C: frequency of reports of 2 separate painful stimuli. D: connectivity perceived during pairs of noxious stimuli delivered on the abdomen. There was no difference on the perception of connectivity, irrespective of whether the stimuli were delivered within or across dermatomes (χ2 = 3.7, P < 0.1).

Fig. 4.

SSP at different distances. A: on the leg, SSP was found ≤40-cm distance between stimuli (P < 0.05) and was maximal at 10 cm (P < 0.01). There was no difference in SSP at 0-, 20-, and 40-cm separation distances (P = 0.8). B: pain sensitivity and SSP. There was no correlation between individual differences in pain sensitivity and SSP during pairs of noxious stimuli.

Fig. 5.

SSP on the abdomen. SSP was present when stimuli were delivered ≤6 dermatomes apart from each other. There was no difference between and across dermatomes (P = 0.5). However, SSP was greater when stimuli were separated vertically and horizontally than when they were side by side (P < 0.01 and P < 0.05, respectively).

Fig. 6.

Pain intensity was not modulated by the presence of a neutral probe. There was no difference between a single 49°C stimulus and combined 49 and 35°C stimuli. Thus the presence of a thermal neutral probe did not increase pain intensity.

Fig. 7.

Hypothetical data from CNS neurons demonstrating the conceptual mechanism of filling-in and SSP. A: pairs of stimuli delivered in close proximity activate a very similar population of neurons. There are increases in the discharge of single neurons that are stimulated in the central areas of their receptive field (RF; black bars) and their activation (∼2.3) is beyond the localization threshold (1.0). Thus these cells contribute to the spatial location of stimuli (dashed line). Since there is no valley between these 2 peaks, the spatial percept is of one contiguous area of pain. Neurons that receive stimulation at intermediary RF zones (blue bars) (∼1.3) are also able to reach the localization threshold, but contribute to the percept that pain radiates from the stimulated area. Other neurons that are stimulated in more peripheral RF zones (green bars) are not able to contribute to spatial location of the stimulated area (∼0.8), but contribute to the total population output and perceived pain intensity. At distant areas, neurons are not activated (red bars). The total output (7.2) from all of this activation gives an afferent signal that is used to process intensity-related information downstream in the system. B: filling-in during population recruitment. When stimuli are separated at an optimal distance, 2 overlapping neuronal populations are recruited. Some neurons (orange bar) that before were not able to reach the localization threshold level are now recruited because they receive low-level input from both stimuli and, accordingly, contribute to filling-in. The neurons that are stimulated in the center of their RFs (black bars) receive afferent input from only one probe and their activation is somewhat diminished (1.7), compared with A, where those neurons are activated by both stimuli. However, in consequence of the greater number of neurons recruited, the total population output is greater (9.4) than when 2 stimuli are placed side by side (A) or placed at greater distances apart (C). Thus SSP is more pronounced. C: when stimuli are located at greater separation distances, each stimulus activates independent populations of neurons that interact minimally with each other. As a result there is no perception of spatial connection between stimuli (filling-in) and SSP is less pronounced than when more neurons are recruited (B). In fact, there is no difference in the population output between A and C (∼7.2). However, the mechanisms that produce spatial summation in both situations are different. In A spatial summation is driven mainly by increased activation of single neurons and in B spatial summation is produced by the increase in the number of neurons recruited. This is in agreement with the present psychophysical data in which SSP was not different in 0-, 20-, and 40-cm separation distances, but was more pronounced at 5- and 10-cm separation distances.

Fig. 8.

Individual differences in sensitivity and the perception of filling-in. Here a hypothetical representation of the activity of populations of CNS nociceptive neurons during pairs of stimuli at an “optimal separation distance” is shown in 4 different situations in which subjects have perception of connectivity independently of their pain sensitivity. The perception of connectivity is due to the overlapping of the population activity between the 2 sites. A: neuronal population distribution of activity for a highly sensitive subject with high connectivity. During pairs of simultaneously noxious stimuli, this subject would perceive a continuous area of pain (gray horizontal bar under the graphic). B: neuronal population distribution of activity for a low-sensitivity subject with high connectivity. During pairs of simultaneously noxious stimuli, similarly to A, this subject would perceive a continuous area of pain (gray horizontal bar under the graphic). C: neuronal population distribution of activity for a highly sensitive subject with low connectivity. During pairs of simultaneously noxious stimuli, this subject would perceive 2 separated areas of pain (2 gray horizontal bars under the graphic). D: neuronal population distribution of activity for a low-sensitivity subject with low connectivity. During pairs of simultaneously noxious stimuli, this subject would perceive 2 separated areas of pain (2 gray horizontal bars under the graphic).