Pain encoding in the human forebrain: binary and analog exteroceptive channels

Abstract

The neuronal system signaling pain has often been characterized as a labeled line consisting of neurons in the pain-signaling pathway to the brain [spinothalamic tract (STT)] that respond only to painful stimuli. It has been proposed recently that the STT contains a series of analog labeled lines, each signaling a different aspect of the internal state of the body (interoception) (e.g., visceral-cold-itch sensations). In this view, pain is the unpleasant emotion produced by disequilibrium of the internal state. We now show that stimulation of an STT receiving zone in awake humans (66 patients) produces two different responses. The first is a binary response signaling the presence of painful stimuli. The second is an analog response in which nonpainful and painful sensations are graded with intensity of the stimulus. Compared with the second pathway, the first was characterized by higher pain ratings and stimulus-evoked sensations covering more of the body surface (projected fields). Both painful responses to stimulation were described in terms usually applied to external stimuli (exteroception) rather than to internal or emotional phenomena, which were infrequently evoked by stimulation of either pathway. These results are consistent with those of functional imaging studies that have identified brain regions activated in a binary manner by the application of a specific, painful stimulus while increases in stimulus intensity do not produce increased activation. Such binary pain functions could be involved in pain-related alarm-alerting functions, which are independent of stimulus amplitude.

Figure 1.

Thalamic map of a single patient with parkinsonian tremor. A, Position of the trajectory, indicated by the oblique line, relative to the anterior commissure-posterior commissure line [horizontal line, posterior commissure indicated] and the region of the human thalamic principle sensory nucleus [Vc and subnucleus, Vc portae (VCpor)], thalamic termini of the STT (Lenz et al., 1993). PC, Posterior commissure; Vim, ventral intermediate (Hirai and Jones, 1989).B, Locations of the neurons and stimulation sites along a trajectory displayed relative to the anterior commissure-posterior commissure line. Stimulation sites are indicated by ticks to the left of the trajectory. Long ticks indicate that a somatic sensation is evoked by stimulation in a part of the body (PF), and the filled arrow is the site illustrated in Figure 2 A, left. Neuronal recordings are located by ticks to the right of the trajectory. Long ticks indicate neurons responding to stimuli over an area on the body (RF). The anteroposterior location of the last neuron with such an RF (site 82) defined the posterior border of Vc. C, Each tick is numbered with the same number in B and C. C shows the site number and illustrations for RFs and PFs (threshold below in microamperes). NR, No response.

Figure 2.

Pain+ and pain-/+ stimulation sites. Sensations evoked by threshold microstimulation were characterized by the PF, by descriptors from a validated questionnaire, and by a visual analog scale of intensity (Lenz et al., 1993, 1998; Lenz and Byl, 1999). A, Left, Site where stimulation at 300 Hz and 5 μA produced pain in the PF (shown in the illustration) and of the quality described. Pain identical to that evoked by 300 Hz was evoked at most sites with trains of ≥20 pulses and frequencies of ≥200 Hz (shaded rectangle; see Results). A, Right, Site where tightness was evoked in the first column at 10 Hz and then a tingle at 20, 38, and 100 Hz. At ≥200 Hz, warmth was evoked at each step in the staircase (except at 7 pulses of 10, 20, and 100 Hz) until 50 pulses, 38 Hz. At this step and further up the staircase, painful heat was evoked. B, Average VAS ratings across all pain+ and pain-/+ sites. Ratings were taken in response to pulse and frequency pairs ascending the staircase. The gray lines along the outside surfaces of the three-dimensional displays indicate the average VAS ratings across all sites by frequency and number of pulses.

Figure 3.

Location of pain+ and pain-/+ sites on sagittal planes through the thalamus. The location of pain+ and pain-/+ sites relative to the posterior (vertical line) and inferior (horizontal line) borders of Vc are identified by the most posterior and most inferior neuron with an RF (neuron 82 for both) (Fig. 1). The core of Vc is above this horizontal and anterior to this vertical. Sites in planes where the majority of cells have cranial and noncranial RFs are shown in A and B, respectively.

Figure 4.

Activity of neurons in the region of Vc responding to painful thermal stimuli. The response to nonpainful and painful heat-mechanical stimuli applied within the RF (Lenz et al., 1994a; Lee et al., 1999) is compared with the VAS evoked by the same stimulus. A, The response of a cell (WDR) to painful heat. B, VAS and firing rates for the response to painful stimuli are plotted for NS cells that respond only to painful stimuli and WDR neurons that respond in a graded manner to nonpainful and painful stimuli. VAS scores by decade to 20 Hz and by 30 Hz steps from 20 to 80 Hz were compared by Mann-Whitney U test.