Pain affect encoded in human anterior cingulate but not somatosensory cortex.

Recent evidence demonstrating multiple regions of human cerebral cortex activated by pain has prompted speculation about their individual contributions to this complex experience. To differentiate cortical areas involved in pain affect, hypnotic suggestions were used to alter selectively the unpleasantness of noxious stimuli, without changing the perceived intensity. Positron emission tomography revealed significant changes in pain-evoked activity within anterior cingulate cortex, consistent with the encoding of perceived unpleasantness, whereas primary somatosensory cortex activation was unaltered. These findings provide direct experimental evidence in humans linking frontal-lobe limbic activity with pain affect, as originally suggested by early clinical lesion studies.

Multiple representations of pain in human cerebral cortex.

The representation of pain in the cerebral cortex is less well understood than that of any other sensory system. However, with the use of magnetic resonance imaging and positron emission tomography in humans, it has now been demonstrated that painful heat causes significant activation of the contralateral anterior cingulate, secondary somatosensory, and primary somatosensory cortices. This contrasts with the predominant activation of primary somatosensory cortex caused by vibrotactile stimuli in similar experiments. Furthermore, the unilateral cingulate activation indicates that this forebrain area, thought to regulate emotions, contains an unexpectedly specific representation of pain.

The effects of dorsal column stimulation on measures of clinical and experimental pain in man.

Despite the extensive use of dorsal column stimulation (DCS) for the control of various chronic pain conditions, most clinicians report only modest success rates. Surprisingly, there has been little placebo-controlled investigation of its efficacy for altering either clinical or experimental pain perception. The current study compared the effects of DCS to placebo stimulation on clinical pain perception, perceived intensity of painful heat stimuli and visual stimuli, and the discrimination of small changes in noxious heat intensity and in light intensity. We found that DCS, but not placebo stimulation, significantly altered ratings of spontaneous clinical pain as well as those of painful cutaneous heat. In addition, heat discrimination thresholds were increased by DCS, but not placebo. On the other hand, DCS had no effect on ratings of visual stimulus intensity nor on visual discrimination, suggesting that the DCS modulation of pain perception was not due to a general change in attention. These data indicate that DCS significantly alters pain transmission in humans. Nevertheless, the relatively small reduction in clinical pain (less than 30%) must be weighed against the invasive nature of electrode implantation.

Representation of acute and persistent pain in the human CNS: potential implications for chemical intolerance.

The study of pain may be relevant to the study of chemical intolerance (CI) in many ways. Pain is often reported as a symptom of CI and it is defined as a subjective experience similar to many other symptoms of CI, making its objectification difficult. Furthermore, the CNS plastic changes that underlie the development of persistent pain states and abnormal pain responses may share some similarities with those involved in the sensitization to environmental chemicals. Functional brain imaging studies in humans demonstrate that acute pain evoked by nociceptive stimulation is accompanied by the activation of a widely distributed network of cerebral structures, including the thalamus and the somatosensory, insular, and anterior cingulate cortices. Abnormal activity within these regions has been associated with the experience of pain following damage to the peripheral or central nervous system (neuropathic pain) in a number of clinical populations. In normal individuals, activity within this network is correlated with subjective pain perception, is highly modifiable by cognitive interventions such as hypnosis and attention, and has been associated with emotions. Other cognitive mediators such as expectations can also produce robust changes in pain perception (e.g., in placebo analgesia). These effects likely depend on both higher-order cerebral structures and descending mechanisms modulating spinal nociceptive activity. These psychological processes can be solicited to reduce clinical pain and we speculate that they may further attenuate or promote central mechanisms involved in the transition from acute to persistent pain states. The investigation of central determinants of subjective experience is essential to assess the possibility that higher-order brain/psychological processes modulate and/or mediate the development of persistent pain states. These factors may contribute to the development of symptoms in CI.

Production of antiserum to a non-structural potyviral protein and its use to detect narcissus yellow stripe and other potyviruses.

A protein, of apparent molecular weight 72,000, was purified from experimentally infected narcissus plants with yellow stripe symptoms utilising SDS-polyacrylamide gel electrophoresis. This protein was excised from the gels and used to prepare antiserum, which reacted specifically with cytoplasmic cylindrical inclusions in ultra-thin sections of virus-infected cells and, in immunoblots, with the 72 kDa protein in preparations containing cytoplasmic inclusions. The antiserum reacted in ELISA with leaf extracts from yellow stripe diseased plants of four narcissus cultivars but not with extracts from comparable symptomless plants. In tests with extracts of plants infected with seven definitive potyviruses, reactions were obtained with bean yellow mosaic and iris mild mosaic viruses. Virus-specific reactions in dot-blot ELISA were dependent on the presence of Tween 20 in the extraction buffer. In contrast, an antiserum to the putative cytoplasmic inclusion protein of alstroemeria mosaic virus reacted only with SDS-treated leaf extracts of infected plants. In limited tests, the method of purifying cytoplasmic inclusion protein was successfully applied to four definitive potyviruses, suggesting that it may be generally applicable to potyviruses and of use for preparing antisera when purification of virus particles is difficult.

A primate model for the study of tonic pain, pain tolerance and diffuse noxious inhibitory controls.

A primate model of cold pressor pain is described in which the animal itself initiates all trials, may terminate painful stimuli at any time, and controls the duration of the experimental session, thus avoiding the inadvertent administration of intolerable pain stimuli. Pain tolerance time varies directly with stimulus intensity and is sensitive to motivational factors. This model will facilitate the study of endogenous pain-modulatory pathways and the assessment of analgesic treatments in animals.

Factors influencing capacity to judge direction of tactile stimulus movement on the face.

The influence of stimulus velocity and traverse length on a subject's ability to indicate direction of brush movement across perioral skin was determined using a forced-choice procedure. The data show that correct identification of brush direction increases with traverse length and is optimal for velocities between 3 and 25 cm/sec.

Preoperative flurbiprofen in oral surgery: a method of choice in controlling postoperative pain.

The analgesic efficacy of a single 50-mg preoperative dose of flurbiprofen was compared with ACC-30 (aspirin 375 mg, codeine 30 mg, caffeine 30 mg) and a placebo. Forty patients scheduled for the surgical removal of impacted maxillary third molars were enrolled in a double-blind, randomized study. Using a within-subject design we compared the analgesic efficacy of (1) preoperative flurbiprofen 50 mg with placebo in 20 patients, and (2) preoperative ACC-30 with placebo in 20 other patients. Using a between-group design, we then compared the analgesic efficacy of (3) each drug given preoperatively and postoperatively, and (4) each drug given postoperatively only. Patients rated 2 pain dimensions, intensity and unpleasantness, hourly for 8 hours after the presurgical dose. The results of this study indicate that better analgesia was obtained when flurbiprofen was given preoperatively compared to only after surgery. Conversely, preoperative administration of ACC-30 did not demonstrate any significant influence on postsurgical analgesia. When comparing the 2 drugs, flurbiprofen proved to be superior in providing pain relief only when it was given prior to surgery. There was no difference between them when given only after surgery. Side effects were moderate and not significantly different between patients receiving flurbiprofen and those receiving ACC-30.

Modulation of heat pain perception by high frequency transcutaneous electrical nerve stimulation (TENS).

Although many studies have indicated that high frequency nonpainful transcutaneous electrical nerve stimulation (TENS) reduces clinical pain, controlled studies of the modulation of experimental pain by TENS have produced conflicting results. This study evaluated the effect of high frequency nonpainful TENS on heat pain perception using a model that we have previously shown to be sensitive to other nonpharmacological analgesic treatments. We found that TENS significantly reduced subjects' ratings of painful and near painful heat stimuli (43-51 degrees C) (p = 0.01) and increased the pain threshold from 46.7 to 47.9 degrees C (p = 0.002). Placebo stimulation had no effect on the subjects' ratings or on their pain thresholds. Furthermore, TENS did not alter subjects' ratings of visual stimuli, indicating that the analgesic effect was not due to a nonspecific distraction. These data suggest that TENS alters the perception of experimentally produced natural pain stimuli. The TENS related modulation also appears to be comparable to that produced by other nonpharmacological analgesic manipulations such as counterirritation and changes in attention.

Aphid Acquisition and Cellular Transport of Potato leafroll virus-like Particles Lacking P5 Readthrough Protein.

ABSTRACT Lepidopteran cells (Spodoptera frugiperda) produced isometric virus-like particles (VLP) when infected with a recombinant baculovirus Ac61 that contained the Potato leafroll virus (PLRV) coat protein gene modified with an N-terminal histidine tag (P3-6H). Cells infected with AcFL, a recombinant baculovirus that expressed cDNA copies of the PLRV genome RNA, did not produce virus-like particles (VLP). In cell lines doubly infected with Ac61 and AcFL, VLP were formed that contained PLRV-RNA packaged in P3-6H coat protein (FL). Both the P3-6H and the FL particles were morphologically indistinguishable from particles of PLRV despite the fact that they lacked the P5 readthrough protein present in wild-type PLRV. When aphids (Myzus persicae) were fed on, or injected with, purified PLRV, or VLP of either type (FL or P3-6H) and examined by electron microscopy, no differences were observed among treatments for particle endocytosis, transcellular transport, or exocytosis at the aphid midgut or accessory salivary glands. Particles were observed in the salivary canals and in the salivary duct leading out of the aphid. These results suggest that P5 readthrough protein of PLRV may not be essential for cellular transport of virus through aphid vectors.

Self-regulation of acute experimental pain with and without biofeedback using spinal nociceptive responses.

Biofeedback training is an efficient means to gain control over a physiological function typically considered involuntary. Accordingly, learning to self-regulate nociceptive physiological activity may improve pain control by activating endogenous modulatory processes. The aim of the present study was to assess whether trial-by-trial visual feedback of nociceptive flexion reflex (RIII-reflex) responses (an index of spinal nociception) evoked by brief painful shocks applied to the sural nerve could be beneficial to guide participants in adopting strategies aiming at modulating pain perception. In order to determine specific changes induced by biofeedback, the modulation of RIII-reflex amplitude and pain ratings was compared following instructions to increase or decrease RIII-reflex amplitude in three groups, including a biofeedback group receiving a visual signal corresponding to the RIII-reflex amplitude (valid feedback), a sham biofeedback group (similar but invalid feedback), and a control group receiving no feedback. Results indicate that participants in all three groups could gain control over RIII-reflex (p<0.001), resulting in the modulation of pain intensity (p<0.001) and pain unpleasantness (p<0.001). The biofeedback group was not significantly superior to the sham and the control groups in the modulation of RIII-reflex amplitude, pain intensity or unpleasantness. These results are consistent with the notion that RIII-reflex amplitude and pain perception can be modulated voluntarily by various cognitive strategies. However, immediate retrospective visual feedback of acute nociceptive responses presented iteratively in successive trials may not improve the efficacy of these self-regulation processes.

Differential effects of cognitive demand on human cortical activation associated with vibrotactile stimulation.

This event-related functional MRI study examines the neural correlates of vibrotactile sensation within the context of different psychophysical demands. Nine subjects received vibrotactile stimuli on the right volar forearm during detection, localization, and passive tasks. In the detection task, subjects indicated the offset (end) of each stimulus by pressing a response key with their left hand. In the localization task, subjects identified the location of the stimulus ("distal?" or "proximal?") by pressing the appropriate response key 4 s after the end of the stimulus. In the passive task, subjects received the same vibrotactile stimuli, but no response was required. Analysis of stimulus-evoked activity compared with the resting baseline period revealed significant bilateral secondary somatosensory cortex activation for all three tasks. However, only in the offset-detection and localization tasks was stimulus-evoked activation observed in other expected areas of tactile processing, such as contralateral primary somatosensory cortex neighboring the posterior parietal cortex (SI/PPC) and in bilateral anterior insular cortex (aIC). During the localization task, we identified vibrotactile-evoked activation in the right aIC, which was maintained after the termination of the stimulus. Results suggest that vibrotactile-related activation within SI/PPC and aIC is enhanced by the increased levels of attention and cognitive demands required by the detection and localization tasks. Activation of aIC not only during vibrotactile stimulation, but also during the poststimulus delay in the localization trials, is consistent with the growing literature linking this area with the perception and short-term memory of tactile information.

Mechanical response properties of ventroposterior medial thalamic neurons in the alert monkey.

The properties of trigeminal cutaneous thalamic neurons were explored in alert cynomolgous monkeys to determine receptive field and response characteristics. Two monkeys received juice reward for sitting quietly while an investigator probed the monkey's face with mechanical stimuli. Extracellular single unit recordings were made from the ventroposterior medial thalamic nucleus (VPM), and mechanical response properties were evaluated for each cell having an extraoral cutaneous receptive field. Of 89 cells examined, 90% responded best to innocuous tactile stimulation, and were classified as low threshold. The other 10%, classified as wide dynamic range, showed a graded response to increasingly intense stimuli, with a maximum discharge to noxious pinch. Of the low threshold neurons, most exhibited excitatory responses, with about half being rapidly adapting and the others slowly adapting. The spontaneous activity of 11% of the low threshold neurons was inhibited by stimulation of the neuron's receptive field. There was no systematic difference in receptive field size for the various types of neurons, but the receptive fields of wide dynamic range cells were smaller than those previously observed in trigeminopthalamic neurons of the medullary dorsal horn. The wide dynamic range and inhibitory low threshold neurons were located primarily in the caudal third of VPM, while the excitatory low threshold neurons were located throughout. In summary, response characteristics of VPM neurons show more diversity in the alert monkey than has been reported in paralyzed and/or anesthetized animals.

Sensory and affective aspects of pain perception: is medial thalamus restricted to emotional issues?

Lateral and medial thalamus are traditionally thought to have separate roles in pain processing, with lateral lemniscal regions transmitting discriminative information about location and intensity, while medial nonspecific regions are involved in emotional responses. Contrary to this view, the present study shows that some single neurons in medial thalamus of alert monkey discriminate changes in the intensity of noxious stimuli that are equal to or below the monkey's own discrimination threshold. Since these neurons are also modulated by anesthesia and attentional factors, we suggest that parts of medial thalamus may participate in both discriminative and affective dimensions of pain.

Thalamic VPM nucleus in the behaving monkey. I. Multimodal and discriminative properties of thermosensitive neurons.

1. The role of the thalamic ventroposterior medial (VPM) nucleus in the discriminative aspects of nociception and thermoreception was evaluated in alert, trained rhesus monkeys. Single-unit responses were recorded from VPM while the monkeys performed a battery of tasks involving noxious heat, innocuous cool, and air-puff stimuli presented to the face. The discriminative ability of the monkey was compared directly with the responses of single neurons, to determine whether the neuronal response could subserve the monkey's discriminative behavior. 2. Most thermally sensitive neurons exhibited multimodal properties. Only 18% responded exclusively to heat (HT-Heat neurons), whereas 27% responded to innocuous mechanical, as well as noxious mechanical and heat stimuli (WDR-Heat). Twenty-three percent responded to innocuous mechanical stimuli and innocuous skin cooling (Mechano-Cool), and 32% responded to mechanical, innocuous cool, and noxious heat stimuli (WDR-Heat-Cool). 3. Almost all mechanical receptive fields were confined to one division of the trigeminal nerve. This was true for all of the above categories of VPM neurons, even those showing highly convergent properties (WDR-Heat-Cool). 4. Heat-activated neurons produced graded responses to noxious skin heating in the 46 to 49 degrees C range. Stimulus-response functions of neurons that responded to both heat and cool did not differ from those of neurons that responded exclusively to skin heating. 5. When the monkeys were detecting small changes in the intensity of a noxious heat stimulus (e.g., from 47 to 47.1-47.8 degrees C), heat-activated neurons responded to the smallest temperature changes that could be detected by the monkeys. Further, there was a high correlation between the monkey's success in detecting the stimulus changes and the magnitude of the neuronal responses to those changes. 6. Although the responsiveness of VPM cool-activated neurons was not compared with the monkeys' threshold for detecting cooling changes, larger stimulus changes (2 degrees C) that the monkey reliably detected produced significant neuronal responses. Further studies are needed to determine whether VPM neurons respond to the smallest detectable changes in skin cooling. 7. Several thermally sensitive VPM neurons were tested under two attentional conditions: 1) while the monkey was required to attend to a visual stimulus, and 2) while it was required to attend to the thermal stimulus to obtain reward. None showed a significant difference in heat- or cool-evoked activity in the two attentional states.(ABSTRACT TRUNCATED AT 400 WORDS)

Thalamic VPM nucleus in the behaving monkey. II. Response to air-puff stimulation during discrimination and attention tasks.

1. Single-unit activity was recorded in the ventral posterior medial (VPM) thalamic nucleus of awake monkeys while they performed detection and discrimination tasks involving tactile air-puff stimuli presented to the face. Neuronal responsiveness was compared directly with the monkey's discriminative performance. In addition, neuronal activity was compared when the monkey's attention was directed to the air-puff stimulus and when it was directed to a concurrent visual stimulus. 2. Neurons responding to the air-puff stimuli were classified as slowly adapting (SA), rapidly adapting (RA), inhibitory (IN), or multimodal (MM), according to their responses to manual and thermal stimulation, as well as their adaption rates to the air puff. Of 47 neurons responsive to air-puff stimulation and studied extensively in the behavioral task, 14 were classified as RA, 15 as SA, 6 as IN, and 12 as MM. The 12 MM neurons were so classified because, in addition to air puff, they responded to noxious heat, innocuous cooling, or noxious pinch. 3. Neurons from each class had restricted contralateral receptive fields localized within one division of the trigeminal nerve. There was no systematic difference in receptive-field size among groups. 4. A prominent difference in tactile responsiveness of MM neurons was response latency. Although the mean latency for RA, SA, and IN neurons was not significantly different (6.1, 9.1, and 12.2 ms, respectively), the mean latency for MM neurons was significantly longer than that for each of the other neuronal categories (28.8 ms; Ps < 0.001). These data suggest that the excitatory tactile afferent input to MM neurons is different from that to low-threshold neurons. 5. For RA, SA, and MM neurons the frequency of the neuronal discharge evoked by the air-puff stimulation was proportional to the intensity of the air puff. Thus responses of each neuronal class coded air-puff stimulus intensity. 6. The monkeys' ability to detect air-puff stimuli of various intensities was compared with the frequency of neuronal responses to those stimuli. Both the percent success in detecting differences in air-puff intensity and the detection latency were highly correlated with neuronal response frequency. The responses of all three excitatory neuronal categories corresponded well with the monkey's performance. Thus any or all of RA, SA, and MM neurons could play a role in the discrimination of air-puff intensities.(ABSTRACT TRUNCATED AT 400 WORDS)

A method for quantitative histological evaluation of neural cell populations.

In an attempt to facilitate quantitative analysis of neural perikarya, an inexpensive system of gridded coverslips has been developed to permanently map sections of tissue on microscopic slides. Utilizing common photographic copying techniques with Kodalith film, a mylar coverslip is produced which is imprinted with a grid of known dimensions. The exact scale of the grid can be varied precisely for compatibility with a particular field of magnification. The versatility and economy of this technique make it useful in many microscopic studies requiring superimposition of discrete landmarks.