Robert Dowman

Spinal and supraspinal correlates of nociception in man.

&NA; The objective of this work was to simultaneously measure pain‐related spinal and supraspinal physiological responses in humans. The sural nerve compound action potential (CAP), the spinal withdrawal reflex (RIII), the somatosensory evoked potential (SEP) and subjective magnitude ratings were elicited by electrical stimulation of the sural nerve in 10 healthy subjects. The sural nerve CAP was used to normalize the evoking stimulus current and to help identify the peripheral nerve afferent types contributing to the physiological and psychophysical responses. Normalizing stimulus current to a proportion of that which elicited a just maximal sural nerve CAP significantly reduced individual variability in magnitude ratings, the RIII and the SEP. Pain and RIII responses only occurred at stimulus levels that were greater than or equal to 1.5 × that which produced a just maximal sural nerve CAP and both responses were positively related to stimulus intensity above that level. Activity in the large diameter A&bgr; fibers will be saturated at stimulus levels near that which produced a just maximal CAP, which implies that both the pain and RIII responses can be attributed to recruitment of the smaller diameter A&dgr; fibers. Although the amplitudes of the P200 and P300 peaks of the SEP were significantly related to stimulation at noxious levels, both were also affected by stimulation at innocuous levels. This result implies that these peaks receive contributions from both noxious and innocuous somatosensory processes. Clearly, the non‐pain‐related components of these SEP peaks must be identified and isolated before their potential in measuring supraspinal nociceptive processes can be fully realized.

Possible startle response contamination of the spinal nociceptive withdrawal reflex.

&NA; The objective of this study was to examine the possibility that the spinal nociceptive withdrawal reflex, otherwise known as the RIII reflex, is contaminated by the startle response, which is a non‐pain‐related supraspinal response. Startle response contamination of the RIII reflex would seriously compromise the RIIIs ability to measure spinal nociceptive processes in man, since a change in the startle response affecting EMG amplitude in the RIII latency range would be erroneously interpreted as a change in a spinal nociceptive process. EMG responses evoked by electrical stimulation of the sural nerve were recorded from the orbicularis oculi, neck, biceps, and biceps femoris muscles in 31 healthy human volunteers. The startle response was elicited under conditions often used to record the RIII reflex. Procedures are described that will completely eliminate the startle response. Comparisons between subjects that did and did not elicit a startle response revealed that the startle does not appear to significantly contaminate the biceps femoris RIII reflex, at least when performing group comparisons. There are, however, situations not dealt with in this study in which the startle might significantly contaminate the RIII reflex, such as patients with pre‐existing negative emotional states, experimental procedures that induce fear and/or anxiety, and single case studies. It is important, therefore, that investigators using the RIII reflex be cognizant of the startle response and take appropriate precautions to monitor and if necessary eliminate the startle before attributing a change in the RIII reflex to a spinal nociceptive process.

Attentional set effects on spinal and supraspinal responses to pain.

The effects of attentional set on subjective magnitude ratings, spinal reflexes, and somatosensory evoked potentials (SEP) elicited by innocuous and painful sural nerve stimulation were investigated in 24 subjects. Cuing stimuli informed subjects as to whether a visual identification or a somatosensory rating task would follow. Twenty percent of the trials were invalidly cued, where the subjects were expecting a visual stimulus but were given a sural nerve stimulus and vice versa. Subjective magnitude ratings were lower in the invalidly cued condition than the validly cued condition. Attentional set had no effect on innocuous-related spinal or early cortical responses, nor on the spinal nociceptive withdrawal reflex. The pain-related negative difference potential (NDP) and P2 component of the SEP were largest in the invalidly cued condition. These results provide further support for our hypothesis that the NDP is generated in part by the anterior cingulate, and suggest that the anterior cingulate response to pain reflects non-pain-specific cognitive processes (e.g., orienting attention towards important stimuli in the environment and/or response competition) and not some aspect of the pain experience. The effects of attentional set on the pain-related P2 suggests that it might correspond to the P3a event-related potential. If this is the case, the pain-related P2 could serve as a useful index of neural processes involved in the cognitive-evaluative aspect of pain.

SEP topographies elicited by innocuous and noxious sural nerve stimulation. I. Identification of stable periods and individual differences

Scalp potential topographies evoked by innocuous and noxious sural nerve stimulation were obtained from 15 human subjects. The SEP scalp topography could be separated into 6 different stable periods (SP), that is, consecutive time points where there were no major changes in the topographic pattern. SP1 (occurring 58-90 msec post stimulus) was characterized by a contralateral frontal positivity and a central negativity oriented ipsilateral to the evoking stimulus; SP2 (92-120 msec) by a bilateral frontal positivity and a symmetrical central negativity; SP3 (135-158 msec) by a widespread negativity with a minimum at the contralateral temporo-frontal region; and SP4 (178-222 msec), SP5 (223-277 msec) and SP6 (282-339 msec) by a widespread positivity with a maximum located along the centro-parietal midline. SP4, SP5, and SP6 could be distinguished by changes in the orientation of the isovoltage contour lines and/or by changes in the location of the maximum. The stable periods had similar onset and offset latencies and the same major features across subjects. However, the topographic patterns were not identical across subjects. These individual differences are likely due to the expected variability in the orientation of the equivalent regional dipole sources generating these potentials.

SEP topographies elicited by innocuous and noxious sural nerve stimulation. III. Dipole source localization analysis

The dipole source localization method was used to determine which of the brain areas known to be involved in somatosensation are the best candidate generators of the somatosensory evoked potential evoked by sural nerve stimulation. The ipsilateral central negativity and contralateral frontal positivity which occurred between 58 and 90 msec post stimulus (stable period 1) were best represented by a single source located in the primary somatosensory cortex (SI). The symmetrical central negativity and bilateral frontal positivity which occurred between 92 and 120 msec post stimulus (stable period 2) was best represented by 3 sources. One of these sources was located in SI and the other 2 were located bilaterally in either the frontal operculum or near the second somatosensory cortex (SII). The widespread negativity whose minimum was located in the contralateral fronto-temporal region and which occurred between 135 and 157 msec post stimulus (stable period 3) was also best represented by 3 sources. Two of these sources may be located bilaterally in the hippocampus. We cannot, however, eliminate the possibility that multiple sources in the cortex overlying the hippocampus (e.g., SII and frontal cortex) are responsible for these potentials. At innocuous stimulus levels the third source for stable period 3 was located near the vertex, possibly involving the supplementary motor cortex, whereas at noxious levels this source appears to be located in the cingulate cortex. We were unable to achieve any convincing source localization for the widespread positivity which occurred between 178 and 339 msec post stimulus (stable periods 4-6). Available evidence suggests that more sources were active during this interval than the three we could reliably test under these conditions.

SEP topographies elicited by innocuous and noxious sural nerve stimulation. II. Effects of stimulus intensity on topographic pattern and amplitude

The effects of innocuous and noxious sural nerve stimulation on the SEP scalp topography were examined in 15 human subjects. This analysis focused on the 6 stable periods (i.e., consecutive time points where the topography did not change) that were identified in the companion paper (Dowman 1994). Stable period 1 (SP1: 58-90 msec post stimulus), SP4 (178-222 msec) and SP5 (223-277 msec) showed amplitude-stimulus intensity relationships that are similar to those of neurons involved in the sensory-discriminative aspects of innocuous somatosensation. The SP1 topographic pattern showed little or no change across the innocuous and noxious stimulus levels, which together with the amplitude data suggests that SP1 is largely generated by neurons involved in innocuous somatosensation. The SP4 topographic pattern did not change appreciably across the innocuous and noxious stimulus levels, but its amplitude decreased with increasing noxious stimulation. These data suggest that SP4 is generated by neurons involved in innocuous somatosensation and that noxious inputs inhibit these cells. There were differences in the SP5 topographic patterns evoked at the innocuous and the noxious stimulus levels, which suggest SP5 also receives a contribution from neurons involved in noxious somatosensation. SP3 (135-157 msec) and SP6 (282-339 msec) are probably generated by neurons involved in noxious somatosensation. The topographic patterns of both were different at innocuous and noxious levels. SP3s amplitude-stimulus intensity function suggests that it is generated by neurons that respond to noxious inputs in a non-graded fashion. The amplitude and offset latency of SP6 increased with increasing noxious stimulation, which suggests that SP6 is generated by neurons that respond to noxious inputs in a graded fashion.

EEG INDICES OF TONIC PAIN-RELATED ACTIVITY IN THE SOMATOSENSORY CORTICES

OBJECTIVE To identify EEG features that index pain-related cortical activity, and to identify factors that can mask the pain-related EEG features and/or produce features that can be misinterpreted as pain-specific. METHODS The EEG was recorded during three conditions presented in counterbalanced order: a tonic cold pain condition, and pain anticipation and arithmetic control conditions. The EEG was also recorded while the subjects made a wincing facial expression to estimate the contribution of scalp EMG artifacts to the pain-related EEG features. RESULTS Alpha amplitudes decreased over the contralateral temporal scalp and increased over the posterior scalp during the cold pain condition. There was an increase in gamma band activity during the cold pain condition at most electrode locations that was due to EMG artifacts. CONCLUSIONS The decrease in alpha over the contralateral temporal scalp during cold pain is consistent with pain-related activity in the primary somatosensory cortex and/or the somatosensory association areas located in the parietal operculum and/or insula. This study also identified factors that might mask the pain-related EEG features and/or generate EEG features that could be misinterpreted as being pain-specific. These include (but are not limited to) an increase in alpha generated in the visual cortex that results from attention being drawn towards the pain; the widespread increase in gamma band activity that results from scalp EMG generated by the facial expressions that often accompany pain; and the possibility that non-specific changes in the EEG over time mask the pain-related EEG features when the pain and control conditions are given in the same order across subjects. SIGNIFICANCE This study identified several factors that need to be controlled and/or isolated in order to successfully record EEG features that index pain-related activity in the somatosensory cortices.

A noninvasive strategy for identifying and quantifying innocuous and nociceptive peripheral afferent activity evoked by nerve stimulation

This study evaluated the utility of the compound nerve action potential (CAP) and spinal nociceptive withdrawal (R3) reflex in identifying and quantifying peripheral afferent activity evoked by sural nerve stimulation in humans. The results of this work demonstrate that currents less than or equal to that which elicits a just-maximal CAP can be considered purely innocuous; provide further evidence that the R3 is an objective means of identifying noxious stimulus levels; and suggest that current provides the best noninvasive quantitative estimate of afferent activity throughout the innocuous and noxious range. This work also demonstrates that some of the individual variability in the psychophysical function can be attributed to peripheral factors that affect the amount of current reaching the nerve. It is important, therefore, that these peripheral factors be considered when studying individual differences in the psychophysical function generated by electrical stimulation.

Pain-evoked anterior cingulate activity generating the negative difference potential may reflect response selection processes

The effects of a heterotopic cold pain stimulus applied to the hand on the scalp-recorded negative difference potential (NDP) and subjective pain ratings elicited by electrical stimulation of the sural nerve were examined in 24 participants. Our previous work strongly suggests that the NDP is generated in part by the cognitive division of the anterior cingulate cortex (ACCcd). The latency and magnitude of the ACCcd activity were estimated from the NDP and from the dipole source localization analysis of the NDP. As expected, the sural nerve pain ratings were smaller in the cold pain condition than in the control condition. The ACCcd activity underlying the 125-ms peak of the NDP did not change across conditions, whereas the ACCcd activity underlying the 210-ms NDP peak was largest in the cold pain condition. The dissociation between pain-evoked ACCcd activity and pain ratings observed here and elsewhere suggest that not all of the nociresponsive neurons in the ACCcd are involved in pain sensation. Rather, differences in the cognitive demands of the control and cold pain conditions suggest that the pain-evoked 210-ms ACCcd activity reflects response selection processes, perhaps response competition monitoring.

Evidence that the anterior cingulate and supplementary somatosensory cortices generate the pain-related negative difference potential

OBJECTIVE The pain-related negative difference potential (NDP) is derived by subtracting sural nerve-evoked somatosensory evoked potentials elicited at the pain threshold level from those elicited at supra-pain threshold levels. This experiment evaluated a hypothesis derived from our earlier work, namely that the NDP is generated by pain-related activity in the primary somatosensory (SI) cortex. METHODS The dipole source localization method was applied to NDPs evoked by electrical stimulation of the finger and of the sural nerve in 20 subjects. RESULTS Comparison of several one-, two- and three-source configurations demonstrated that both the finger-evoked NDP and the sural nerve-evoked NDP are best-fit by two sources, with one located in or near the anterior cingulate cortex and the other in or near the supplementary somatosensory area. CONCLUSIONS Both the anterior cingulate cortex and the supplementary somatosensory area receive afferent projections from medial thalamic nuclei that receive nociceptive inputs, and both have been shown to respond to noxious stimulation. Hence, although the results of this experiment did not confirm our hypothesis that the NDP is generated in SI, they are consistent with the hypothesis that the NDP is generated in the supraspinal pain pathways.