A connectionist modeling study of the neural mechanisms underlying pain's ability to reorient attention.

Connectionist modeling was used to investigate the brain mechanisms responsible for pain's ability to shift attention away from another stimulus modality and toward itself. Different connectionist model architectures were used to simulate the different possible brain mechanisms underlying this attentional bias, where nodes in the model simulated the brain areas thought to mediate the attentional bias, and the connections between the nodes simulated the interactions between the brain areas. Mathematical optimization techniques were used to find the model parameters, such as connection strengths, that produced the best quantitative fits of reaction time and event-related potential data obtained in our previous work.

Neural mechanisms underlying pain's ability to reorient attention: evidence for sensitization of somatic threat detectors.

Pain typically signals damage to the body, and as such can be perceived as threatening and can elicit a strong emotional response. This ecological significance undoubtedly underlies pain's well-known ability to demand attention. However, the neural mechanisms underlying this ability are poorly understood.

The role of somatic threat feature detectors in the attentional bias toward pain: effects of spatial attention.

Our previous work suggests that somatic threat feature detectors indexed by a pain-evoked midlatency negative scalp potential play an important role in the attentional bias toward pain. In these studies the somatic threat feature detectors facilitated the shift in attention to a somatic threat when attention was focused on another stimulus modality but not when it was focused on another spatial location. This experiment used the Posner cuing paradigm to investigate possible explanations for this discrepancy.

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.

An artificial neural network model of orienting attention toward threatening somatosensory stimuli.

An artificial neural network model was designed to test the threat detection hypothesis developed in our experimental studies, where threat detector activity in the somatosensory association areas is monitored by the medial prefrontal cortex, which signals the lateral prefrontal cortex to redirect attention to the threat. As in our experimental studies, simulated threat-evoked activations of all three brain areas were larger when the somatosensory target stimulus was unattended than attended, and the increase in behavioral reaction times when the target stimulus was unattended was smaller for threatening than nonthreatening stimuli. The model also generated a number of novel predictions, for example, the effect of threat on reaction time only occurs when the target stimulus is unattended, and the P3a indexes prefrontal cortex activity involved in redirecting attention toward response processes on that trial and sensory processes on subsequent trials.

Neural mechanisms of detecting and orienting attention toward unattended threatening somatosensory target stimuli. II. Intensity effects.

Negative potentials evoked by painful electrical stimulation of the sural nerve that occur at 100-180 ms poststimulus over the contralateral temporal scalp (CTN100-180) and at 130-200 ms over the fronto-central scalp (FCN130-200) exhibit unusual attention effects. That is, their amplitudes are larger when the painful evoking stimulus is unattended than when it is attended. In this experiment, I show that attention has no effect on the CTN100-180 evoked by a weak, nonthreatening sural nerve electrical stimulus.

Neural mechanisms of detecting and orienting attention toward unattended threatening somatosensory targets. I. Intermodal effects.

Our previous work has identified four components of the somatosensory-evoked potential elicited by painful electrical stimulation of the sural nerve that might index an involuntary process that detects and orients attention toward threatening somatosensory stimuli. These components include a negativity over the central scalp at 70-110 ms poststimulus (CN70-110), a contralateral temporal negativity at 100-180 ms (CTN100-180), a frontocentral negativity at 130-200 ms, and a positive potential at 270-340 ms (the pain-related P2). The results of the endogenous cuing experiment used here suggest that the CN70-110 and CTN100-180 index somatosensory cortex activity that detects a threatening somatosensory stimulus when the subject's attention is focused on another stimulus modality but not another location.

Human intracranially-recorded cortical responses evoked by painful electrical stimulation of the sural nerve.

Intracranial recordings were obtained from 5 epilepsy patients to help identify the generators of the scalp somatosensory evoked potential (SEP) components that appear to be involved in orienting attention towards a potentially threatening, painful sural nerve electrical stimulus. The intracranial recording data support, for the most part, the generators suggested by our scalp SEP studies. The generators of the central negativity at 70-110 ms post-stimulus and the contralateral temporal negativity at 100-180 ms are located in the somatosensory association areas in the medial wall of the parietal cortex and in the parietal operculum and insula, respectively.

Effects of response conflict on pain-evoked medial prefrontal cortex activity.

Experimental studies of pain may introduce a response conflict, where the subject must inhibit an escape response and make a pain-rating response. Several lines of evidence have shown that the medial prefrontal cortex is activated by painful stimuli and by response conflict. It is not clear, however, to what extent pain-evoked medial prefrontal cortex activation reflects response conflict.

The pain-evoked P2 is not a P3a event-related potential.

The topographic pattern and latency of the P2 component of the somatosensory evoked potential elicited by painful electrical stimulation of the sural nerve was compared to the P3a event-related potential evoked by an infrequent task-irrelevant (deviant) innocuous sural nerve stimulus presented as part of the deviant-odd ball paradigm. Conditions typically used to record the sural nerve pain-evoked P2 (multiple stimulus levels, short fixed inter-stimulus intervals, and the subjects engaged in a pain rating task) did not elicit a P3a. The P3a was elicited when the painful stimuli were presented at a long and variable inter-stimulus interval.

The role of the pain-evoked negative difference potential in dual-task response conflict.

The possible role of the generators of the sural nerve pain-evoked negative difference potential (NDP), the anterior cingulate cortex and supplementary somatosensory area, in monitoring response conflict was investigated in 19 healthy adults. Each trial consisted of a visual arrow stimulus and a painful electrical stimulus applied to the sural nerve. The subjects determined whether their left or right sural nerve had been stimulated and whether the arrow was pointing to the left or to the right.

Electrophysiological indices of orienting attention toward pain.

This study examined the effects of orienting on two pain-related components of the sural nerve-evoked somatosensory evoked potential: the NDP (80-230 ms), which is generated in part by the anterior cingulate cortex (ACCc), and SP6 (280-340 ms). NDP and SP6 amplitudes were larger when subjects oriented their attention away from an invalidly cued location and toward the sural nerve pain than when their attention remained focused on the pain. These results and our earlier studies suggest that the ACCc activity generating the NDP is involved in detecting transient painful stimuli.

Distraction produces an increase in pain-evoked anterior cingulate activity.

This study examined the effects of distraction on pain-evoked activity in the anterior cingulate cortex (ACC). Twenty-eight healthy adults were given painful electrical stimulation of the sural nerve during an attend condition, where they rated the subjective magnitude of each electrical stimulus, and during a distraction condition, where they performed an arithmetic distraction task. The magnitude of the pain-evoked ACC activity was estimated from the dipole source localization analysis of the somatosensory evoked potential.

Topographic analysis of painful laser and sural nerve electrical evoked potentials.

A quantitative scalp topographic pattern analysis was used to compare evoked potentials elicited by painful laser (LEP) and electrical stimulation of the sural nerve (snSEP) in 22 healthy adults. The snSEP and LEP were separated into stable periods (consecutive time points having the same topographic pattern). The topographic pattern is dependent upon the number, location, orientation and relative magnitudes of the brain areas active at that time (source configuration).

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.

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.

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.

Innocuous-related sural nerve-evoked and finger-evoked potentials generated in the primary somatosensory and supplementary motor cortices.

Objective: Our earlier work revealed two components of the somatosensory evoked potential, which we have labeled SP1 and SP4a, that appear to be generated by neurons involved in the innocuous aspects of somatosensation. The objective of the present study was to examine a hypothesis developed in our earlier work, namely that SP1 and SP4a are generated in the primary somatosensory cortex.

Methods: The dipole source localization method was applied to SP1 and SP4a evoked by electrical stimulation of the fingers and of the sural nerve in 20 subjects.

The pain-related negative difference potential: a direct measure of central pain pathway activity or of interactions between the innocuous somatosensory and pain pathways?

Negative difference potential (NDP) is a sural nerve-evoked scalp potential derived by subtracting potentials elicited at the pain threshold level from those elicited at supra-pain threshold levels. Our recent work examined the possibility that the NDP reflects a pain-related inhibition of neurons in the innocuous somatosensory pathways. Although failing to find any evidence for this inhibition, these studies do present the possibility that the NDP reflects an attention- and/or task-related decrease in the innocuous somatosensory activity that is elicited by the noxious electrical stimulus.

Laser pain fails to inhibit innocuous-related activity in the central somatosensory pathways.

Our recent work suggests that innocuous somatosensory activity elicited by a brief electrical stimulus is inhibited by pain evoked by the same electrical stimulus but not by pain evoked by continuous heat. These results led to the hypothesis, tested in the present experiment, namely that pain only inhibits innocuous somatosensation when the painful and innocuous stimuli have short durations and close temporal and spatial overlap. A painful 200-ms laser pulse did not produce a decrease in the perceived magnitude of the innocuous electrical stimulus or in the amplitude of a scalp potential that earlier work suggested is generated by neurons involved in innocuous somatosensation.

Interstimulus interval has no effect on a mid-latency scalp potential generated by innocuous-related activity in the primary somatosensory cortex.

The sural nerve-evoked somatosensory evoked potential (SEP) scalp topography was separated into stable periods, where a stable period refers to consecutive time points with the same topographic pattern. The stimulus intensity-amplitude function, conduction velocity measurements, and a dipole source localization analysis of one of these stable periods, SP1 (60-90 ms post-stimulus), strongly suggests that it is generated by the response of neurons in the primary somatosensory cortex (SI) to inputs arising from the innocuous A beta peripheral afferents. Interstimulus intervals (ISI) ranging between 2.

Negative difference potential isolates scalp potentials generated by activity in supraspinal nociceptive pathways.

A negative difference potential (75-240 ms poststimulus) was computed by subtracting the sural nerve-evoked somatosensory evoked potential (SEP) elicited at the pain threshold level from SEPs elicited at noxious levels. The effects of stimulus intensity and interstimulus interval on the negative difference potential amplitude plus conduction velocity measurements and a dipole source localization analysis all suggest that the negative difference potential reflects the response of neurons in the primary somatosensory cortex to inputs that arise from the nociceptive A delta peripheral afferents. Furthermore, a comparison of these results with our earlier sural nerve-evoked SEP studies suggests that these pain-related inputs to the primary somatosensory cortex are largely inhibitory.

Effects of interstimulus interval on scalp topographies evoked by noxious sural nerve stimulation.

The amplitude of the late pain-related negative-positive peak complex, which we have labeled SP3 (134-150 ms) and SP6 (277-331 ms), respectively, increased with increasing interstimulus interval (ISI). This contrasts with the nociceptive spinal withdrawal reflex and subjective pain rating data, which implied that nociceptive somatosensory processes were unaffected by ISI at stimulus levels that were well within the pain range. A scalp topographic analysis strongly suggested that none of the brain areas responsible for SP3 or SP6 are involved exclusively in nociception.

Effects of operantly conditioning the amplitude of the P200 peak of the SEP on pain sensitivity and the spinal nociceptive withdrawal reflex in humans.

This study attempted to replicate and extend earlier work that reported that the amplitude of the P200 peak of the human somatosensory evoked potential (SEP) can be increased and decreased when reward is made contingent upon change and that these changes are accompanied by alterations in pain sensitivity. Twenty-one subjects were able to make the amplitude of the P200 peak evoked by sural nerve stimulation larger during increased training (up-training) than during decreased training (down-training). There were no differences in the sural nerve compound action potential between up-training and down-training.

Heat pain increases the perceived magnitude of an innocuous electrical stimulus: evidence for a peripheral mechanism.

Painful heat produced an increase in the perceived magnitude of an innocuous electrical stimulus applied either to the sural nerve or to the skin of the dorsum of the foot. The increased sensitivity was observed when the painful heat was spatially coincident with the electrical stimulus, and when it was not coincident but adjacent within the same dermatome. Painful heat had no effect when it was applied to the contralateral foot, which makes it unlikely that attention or arousal played any role in the increased electrical sensitivity produced by ipsilateral heat.