Multichannel magnetoencephalographical recordings: separation of cortical responses to different chemical stimulation in man.
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Adult↗
Biomedical subjects
G Kobal
Publications and source records attributed to G Kobal.
Tonic versus phasic pain: dose-related effects of ketoprofen.
Only recently has a new experimental technique been developed which combines tonic and phasic painful stimulation. By means of this technique the non-steroidal anti-inflammatory drug (NSAID) ibuprofen has been shown to produce a dose-related decrease in heterotopically applied phasic and tonic pain. The present study aimed to investigate the dose-related effects of the NSAID ketoprofen (50, 100, and 150 mg i.v.) when tonic and phasic stimuli were applied homotopically. Eighteen healthy volunteers participated in the double-blind, randomized, placebo-controlled study. After an initial training session subjects took part in four experiments, each of which was divided into three sessions (before, 30, and 120 min after drug administration). During each session 45 painful phasic CO2 stimuli of three concentrations were presented to the left nostril in randomized order (duration 200 ms; interval 40 s; 45%, 52%, and 59% v/v CO2). The left nostril was additionally stimulated with a constant stream of dry air, which produced a tonic painful sensation described as dull and burning. Subjects rated the intensity of the painful stimuli by means of visual analogue scales. Chemosomatosensory event-related potentials (CSSERPs) were recorded in response to phasic painful CO2 stimuli. Ketoprofen reduced the subjects' estimates of tonic pain in a dose-related manner. In contrast, given the special conditions of homotopic application of tonic and phasic painful stimuli, estimates of phasic pain increased significantly, corresponding to a significant increase in CSSERP amplitudes. An explanation of this inverse effect of the drug on responses to tonic and phasic pain may be a lateralized interaction between both C-fiber and A delta-fiber systems at a spinal or peripheral level.
Adult↗
Responses recorded from the frog olfactory epithelium after stimulation with R(+)- and S(-)-nicotine.
The aim of this study was to determine whether the olfactory system is responsible for the discriminability of the stereoisomers of nicotine. The EOG was recorded after stimulation with different concentrations of undistilled S(-)-, distilled S(-)- and distilled R(-)-nicotine separately in three groups of frogs (Xenopus laevis). The responses to all types of nicotine used in the experiments increased with increasing stimulus concentration. The responses to undistilled S(-)-nicotine were significantly lower compared to responses to distilled S(-)- and R(+)-nicotine, whereas no significant differences could be found when the purified stereoisomers of nicotine [distilled S(-)-nicotine, distilled R(+)-nicotine] were compared. Control measurements of time course and peak concentration employing a UV-detection method demonstrated that the differences between distilled and undistilled S(-)-nicotine could not be explained by different nicotine concentrations. The fact that no differences between the pure nicotine stereoisomers could be found for all concentrations used in our experiments and that experiments in humans revealed similar detection thresholds for both stereoisomers points to a similar receptor affinity of R(+)- and S(-)-nicotine within the olfactory system. At this point, it cannot be determined whether the observed differences in the perception of nicotine enantiomers in humans are due to differences in quality coding by stereospecific receptors on the olfactory sensory cells or by specific receptors on the trigeminal nerve endings.
Animals↗
Effects of flurbiprofen enantiomers on pain-related chemo-somatosensory evoked potentials in human subjects.
1. The aim of the study was to investigate the analgesic effects of flurbiprofen enantiomers using an experimental pain model based on both chemo-somatosensory event-related potentials (CSSERP) and subjective pain ratings. 2. Healthy female volunteers (n = 16, age 23-36 years) participated in a placebo-controlled, randomised, double-blind, four-way crossover study. Single doses of (S)-flurbiprofen (50 mg), (R)-flurbiprofen (50 and 100 mg) and placebo were administered orally. Measurements were taken before and 2 h after administration of the medications. During each measurement, 32 painful stimuli of gaseous carbon dioxide (200 ms duration, interval approximately 30 s) of two concentrations (60 and 65% CO2 v/v) were applied to the right nostril. EEG was recorded from five positions and CSSERP were obtained in response to the painful CO2- stimuli. Additionally, subjects rated the perceived intensity of the painful stimuli by means of a visual analogue scale (VAS). 3. The CSSERP-amplitude P2, a measure of analgesic effect, decreased after administration of both (R)- and (S)-flurbiprofen, while it increased after placebo. This was statistically significant at recording positions C4 (P < 0.01) and Fz (P < 0.05). The analgesia-related decreases in evoked potential produced by (R)-flurbiprofen were dose-dependent. Comparing similar doses of (R)- and (S)-flurbiprofen, the decrease in CSSERP-amplitudes produced by the (S)-enantiomer was somewhat more pronounced, indicating a higher analgesic potency. 4. The present data indicate that both enantiomers of flurbiprofen produce analgesic effects. Since (R)-flurbiprofen caused only little toxicity in rats as compared with the (S)-enantiomer or the racemic compound, a reduction of the quantitatively most important side effects in the gastrointestinal tract might be achieved by employing (R)-flurbiprofen in pain therapy.
Adult↗
Effects of azapropazone on pain-related brain activity in human subjects.
1. The dose-related effects of azapropazone on (i) event-related and spontaneous EEG-activity and (ii) the subjects' pain ratings were investigated using an experimental human pain model based on both chemo-somatosensory event-related potentials (CSSERP) and subjects' pain ratings. 2. Healthy subjects (n = 20) participated in a placebo-controlled, randomized, double-blind, four-way cross-over study. Single doses of azapropazone (300 mg, 600 mg and 1200 mg) and placebo were administered intravenously. Each experiment consisted of five sessions (before and 1, 2, 4 and 8 h after administration of the medication). Each session lasted for approximately 40 min. In the first 20 min, pain was induced by short CO2-stimuli presented to the right nostril (phasic pain; interstimulus interval 30 s) and EEG was recorded from five positions. CSSERPs were obtained in response to painful CO2-stimuli. In the following 20 min period, tonic pain was induced by a constant stream of dry air introduced in the left nostril. Subjects rated the intensity of both phasic and tonic pain by means of a visual analogue scale. Additionally, a frequency analysis of the spontaneous EEG was performed. 3. Azapropazone reduced the pain-related CSSERP-amplitudes at frontal and parietal recording positions. This topographical pattern was observed in previous studies with opioids, while NSAIDs such as flurbiprofen and ketoprofen exerted effects at frontal and central positions. In contrast to other NSAIDs, administration of azapropazone resulted in a reduction of the frequency bands alpha 1, delta and theta of the spontaneous EEG. At the subjective level, analgesic effects of azapropazone were observed in the ratings of tonic pain. 4. Analgesic properties of azapropazone were demonstrated in man. The topographical pattern of the changes in the CSSERPs and the effects on EEG background activity suggest a central component of the analgesic action of azapropazone.
Adult↗
Chemosensory event-related potentials in patients with temporal lobe epilepsy.
We investigated chemosensory functions in patients with temporal lobe epilepsy (TLE) to discover whether olfactory and trigeminal stimuli applied either ipsilaterally or contralaterally to the epileptic focus are processed differently. Twenty-two patients were investigated, 12 of whom had epilepsy with a focus located in left temporal lobe (LTL). The remaining 10 patients had a right temporal lobe (RTL) focus. Input from the trigeminal system was examined by use of CO2; input from the olfactory system was evaluated with vanillin and hydrogen sulfide as stimuli. Chemosensory function was assessed by evaluation of chemosensory event-related potentials (CSERP) and the patients' verbal reports in an odor identification test. In both groups of patients, prolonged CSERP latencies were noted after stimulation of the left nostril with CO2 as compared with stimulation of the right nostril. In contrast, a different pattern emerged for olfactory stimuli. After right-sided olfactory stimulation, latencies were prolonged in patients with right-sided epileptical foci. Similarly, when the left nostril was stimulated in patients with a left-sided focus, CSERP latencies were prolonged. Thus, neocortical processing of olfactory, but not trigeminally mediated information evidently is affected by functional lesions of the temporal lobe. After olfactory stimulation in patients with a right-sided focus, the distribution of amplitudes was different from normal. Moreover, analyses showed nonoverlapping 95% confidence intervals (CI) for latency N1 when vanillin was applied to the right nostril. These results indicate that RTL may play a different role in processing of olfactory information as compared with LTL.
Adult↗
Analgesic effects of dihydrocodeine and tramadol when administered either in the morning or evening.
The aim of the study was to investigate the analgesic effects of two opioids [dihydrocodeine (DHC) and tramadol] when administered either in the morning or evening. The experimental technique used is based on chemosomatosensory event-related potentials (CSSERPs) in response to painful chemical stimuli that are applied to the nasal mucosa. Eighteen healthy volunteers participated in the experiments. The study followed a controlled, randomized, double-blind, sixfold, cross-over design. Thus, each of the three medications (90 mg DHC, 50 mg tramadol, or placebo) was perorally administered to all subjects on different days at 08:00 or 20:00 h. Measurements were performed before and 60, 120, 240, and 360 min after administration of the medication. In addition to the assessment of CSSERP, subjects rated the intensity of the stimuli. Moreover, unspecific drug effects were monitored by means of acoustical event-related potentials and the subjects' performance in a video game. The results indicated that the painful intensity of the chemical stimuli strongly increased during evening sessions. In addition, both DHC and tramadol exerted stronger analgesic effects when administered in the evening. Thus, an inflexible scheme of prescription might produce either an increase of pain in the morning due to insufficient analgesia or the unnecessary overdosing of analgesics in the evening.
Acoustic Stimulation↗
[Diagnostic methods in the assessment of anosmia in neurologic diseases].
Several important neurological diseases can impair the sense of smell. In the past the substances generally used for testing were not well defined, and the testing procedures did not follow the rules of psychophysical test procedures. Therefore, in this paper standardized new methods of testing the olfactory system are presented. Based on published data, the University of Pennsylvania Smell Identification Test is the most suitable test for screening purposes. More detailed information can be obtained when using the Connecticut Chemosensory Clinical Research Center's Odor Identification Test that includes the possibility of determining the olfactory threshold. Additionally, a new method that combines the testing of olfactory threshold, odor discrimination and odor identification with the recording of specific olfactory-evoked potentials is described. The latter test is especially useful when objective neurophysiological data are requested.
Cerebral Cortex↗
Chemo-somatosensory event-related potentials in response to repetitive painful chemical stimulation of the nasal mucosa.
The aim of the study was to investigate how chemo-somatosensory event-related potentials (CSSERPs) and pain ratings are modified by repetitive painful stimulation of the nasal mucosa (58% v/v CO2, 200 msec duration). Twenty-two subjects performed 3 experiments during which trains of stimuli were applied. The interstimulus interval (ISI) between stimuli was constant for each experiment, but varied between experiments (8, 4, and 2 sec). CSSERPs were obtained from 5 positions (Fz, C3, Cz, C4, and Pz). The subjects not only rated the overall perceived intensities but also reported the quality of the stimuli. At an ISI of 8 sec estimates decreased and only stinging sensations were reported. In contrast, at an interval of 2 sec estimates increased being accompanied by the buildup of burning pain. This phenomenon was interpreted in terms of the superposition of first (sharp and stinging pain: A delta fibers) and second pain (dull and burning pain: C fibers), respectively. However, given the special circumstances of short ISIs CSSERP amplitudes decreased the more the shorter the ISI was. In line with previous investigations it is hypothesised that CSSERPs predominantly reflect nociceptive information transmitted via A delta fibers.
Adult↗
A comparison of the antinociceptive effects of imipramine, tramadol and anpirtoline.
The pain relieving properties of imipramine (100 mg orally), tramadol (150 mg orally), and anpirtoline (60 mg orally) were compared in 16 healthy subjects in a cross-over, double-blind, randomized, and placebo-controlled study. Anpirtoline exhibits analgesia which is possibly mediated via serotoninergic pathways, whereas tramadol exerts its effects at opioid receptors. The pain-relieving effect of the tricyclic antidepressant imipramine may involve both serotoninergic and opioid mechanisms. Chemo-somatosensory event-related potentials (CSSERP) were recorded after painful stimulation of the nasal mucosa with carbon dioxide. Subjects rated the perceived intensity of the stimuli by means of a visual analogue scale. In addition, acoustically evoked responses were recorded, the spontaneous EEG was analyzed in the frequency domain, the subjects' vigilance was assessed in a tracking task, and side effects of the drugs were monitored. Anpirtoline and tramadol produced a decrease of both CSSERP amplitudes and subjective estimates of pain, the effects of the former compound being greater. In contrast, after administration of imipramine no change of CSSERP amplitudes could be detected, whereas the subjective estimate of pain intensity decreased significantly. This was accompanied by a significant decrease of arousal indicating that pain relief produced by acute administration of imipramine was primarily related to its sedation action. The analgesic properties of anpirtoline were demonstrated in man. Tramadol was characterized as a week opioid analgesic. In contrast, imipramine appeared to produce its pain-relieving effects predominantly by non-specific actions. It is hypothesized that different analgesics may change ERP sources in a drug-specific manner.
Administration, Oral↗
Stereoselective disposition of flurbiprofen in healthy subjects following administration of the single enantiomers.
Plasma concentrations of the enantiomers of flurbiprofen were measured following oral administration of (S)-flurbiprofen 50 mg and (R)-flurbiprofen 50 mg and 100 mg to sixteen healthy subjects. Chiral inversion did not occur to a measurable extent. Significantly higher values of AUC (55.2 +/- 17.0 vs 44.6 +/- 11.2 micrograms ml-1h) elimination half-life (5.6 +/- 1.4 vs 4.0 +/- 1.0 h) and mean residence time (7.5 +/- 1.6 vs 5.7 +/- 1.2 h) were observed after 50 mg (S)-flurbiprofen as compared with 50 mg (R)-flurbiprofen. With the exception of Cmax and AUC values pharmacokinetic data for the 50 mg and the 100 mg dose of (R)-flurbiprofen did not differ significantly. The data are of clinical relevance if (R)-flurbiprofen also has analgesic activity in humans and is to be developed as an analgesic.
Administration, Oral↗
Different sensitivity of pain-related chemosensory potentials evoked by stimulation with CO2, tooth pulp event-related potentials, and acoustic event-related potentials to the tranquilizer diazepam.
1. The aim of this study was to investigate the sensitivity of pain-related potentials used in experimental pain models to the non-specific effects of the tranquilizer diazepam. Pain-related potentials were recorded after painful stimulation of the nasal mucosa with CO2 and after painful stimulation of the tooth pulp. Acoustically evoked potentials were measured in order to compare their sensitivity to the tranquilizer diazepam with the sensitivity of the pain-related potentials. 2. Twenty volunteers participated in this randomised, double-blind, three-fold crossover study. Measurements were obtained before and 20 min after the administration of the drug. Event-related potentials were recorded after painful stimulation of the nasal mucosa with CO2 (two stimulus intensities: 60% v/v and 70% v/v CO2), after painful stimulation of the tooth pulp (two stimulus intensities: 2.2 x and 3.3 x detection threshold), and after non-painful acoustical stimulation of the right ear. The subjects rated the perceived intensity of the painful stimuli by means of a visual analogue scale. In addition the spontaneous EEG was analysed in the frequency domain and the vigilance of the subjects was assessed in a tracking task. 3. Diazepam reduced significantly the amplitudes of the event-related potentials after painful stimulation of the tooth pulp and after acoustical stimulation. In contrast only a small, statistically non-significant reduction could be found after painful stimulation with CO2. The pain ratings of the painful stimuli were not affected by diazepam. Diazepam reduced the performance of the tracking task. A decrease of arousal could be found in the alpha 2-range, whereas in the beta 2 and the theta-range the power density increased under diazepam. 4. We demonstrated that event-related potentials after painful stimulation of the nasal mucosa with CO2 are less affected by the nonspecific effects of the tranquilizer diazepam than event-related potentials after painful stimulation of the tooth pulp. The effects of diazepam on the tracking task, the spontaneous EEG and the event-related potentials clearly confirm its sedative properties. Diazepam had no analgesic effect measurable by pain intensity estimates.
Acoustic Stimulation↗
Dose-related effects of ibuprofen on pain-related potentials.
1. The aim of this study was to investigate the dose-related effects of ibuprofen (placebo, 400 and 800 mg rac-ibuprofen [Aktren], administered orally) on experimentally-induced tonic and phasic pain. 2. Eighteen volunteers participated in this randomized, double-blind, three-fold cross-over study. Measurements were obtained before and 90 min after administration of the drugs. Phasic pain was produced by CO2 pulses of two concentrations applied to the right nostril. The left nostril was stimulated with a constant stream of dry air which produced a tonic painful sensation described as dull and burning. Subjects rated the intensity of the painful stimuli by means of visual analogue scales. In addition, chemo-somatosensory event-related potentials (CSSERP) were also recorded in response to phasic painful CO2 stimuli. 3. While mean intensity estimates of both tonic and phasic painful stimuli showed a non-significant dose-related decrease, a statistically significant dose-related decrease was observed for CSSERP amplitudes. 4. In conclusion, in order to investigate analgesic drug effects, CSSERP appear to be a more sensitive measure compared with psychophysically obtained responses.
Adult↗
[Algesimetry by pain-related evoked potentials].
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Analgesia↗
Nociceptive and reflexive responses recorded from the human nasal mucosa.
Slow electrical responses after painful stimulation with carbon dioxide, which is known to specifically activate nociceptors, were recorded from the nasal respiratory epithelium in human volunteers. The negative component of these potentials (negative mucosal potential NMP) has been hypothesized to be a summated receptor potential. The aim of the present study was to characterize the stimulus-response relationship and to demonstrate that the NMP is restricted to the site of stimulation, i.e., to the area of activated nociceptors. Eight healthy volunteers participated in the experiments. The NMP was recorded from the nasal septum and intensity ratings were obtained for each of the applied stimuli. To control for autonomic reflexes, blood flow changes were additionally recorded using a laser Doppler flow meter. Both increasing stimulus duration and increasing concentration produced a significant increase in the subjects' intensity estimates, in the NMP's amplitudes and areas under the curve, but did not change the local blood flow in a dose-related manner. The odorant hydrogen sulphide, which was used as a non-painful control stimulus, did not elicit mucosal potentials or produce blood flow changes. By recording both ipsi- and contralaterally it was also demonstrated that the NMP could only be obtained at the stimulated site, thus supporting the hypothesis that the NMP is a specific peripheral nociceptive correlate.
Adult↗
Perception of olfactory and intranasal trigeminal stimuli following cutaneous electrical stimulation.
Based on previous research it may be hypothesized that the perception of odorants is modified by an axon reflex emanating from trigeminal afferents activated via the skin and/or the intranasal respiratory epithelium. The present experiment investigated the effects of trigeminal cutaneous stimulation on intensity estimates of intranasal chemical stimuli. While the left nostril was stimulated chemically with olfactory and trigeminal stimulants, four regions of the face were stimulated electrically. Intensity estimates of the chemical stimuli tended to increase after cutaneous electrical stimulation which may be interpreted in terms of response priming. The effect of electrical stimulation did not differ at the 4 stimulation sites. The results argue against the hypothesis that the processing of intranasal chemical stimuli is modified peripherally by cutaneous trigeminal excitation.
Adolescent↗
Olfactory event-related potentials in psychosis-prone subjects.
Previous studies in schizophrenic patients have suggested that there are changes in olfactory sensitivity. In order to externally validate a psychometrical assessment of the psychosis-risk indicated by schizotypic factors, this study was carried out to determine whether changes in olfactory perception could be determined even for persons merely at risk of developing schizophrenia. These 'psychosis-prone' subjects consistently scored high in either the scale for 'physical anhedonia' (PA) or the scale for 'perceptual aberration' (PAB). Thus, three groups were investigated (control, n = 11; PA, n = 12; PAB, n = 12). Each subject participated in one testing session where the two odorants, vanillin (pleasant) and hydrogen sulphide (unpleasant), were applied by means of a specially designed delivery apparatus. Subjects rated both the intensity and the hedonic quality of the stimuli. In addition, olfactory event-related potentials (OERP) were recorded after dichotomous stimulation. In general, there were only few significant differences between the three groups investigated. Contrary to expectations, ratings for pleasantness of vanillin were highest in PA subjects compared to PAB subjects and controls (p < 0.05). Correspondingly, OERP amplitudes in response to vanillin were largest within the PA group (p < 0.05). For hydrogen sulphide, PAB subjects showed the smallest OERP amplitudes (p < 0.05). In addition, it was observed that female subjects had significantly larger OERP amplitudes when compared to male subjects (p < 0.05), which possibly indicates gender differences in olfactory sensitivity.
Adult↗
Psychophysiology of experimentally induced pain.
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Animals↗