The Effect of Opioid Receptor Blockade on the Neural Processing of Thermal Stimuli

The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore measured BOLD (blood oxygen level dependent) signal responses and intensity ratings to non-painful and painful thermal stimuli in a double-blind, cross-over design using the opioid receptor antagonist naloxone. On the behavioral level, we observed an increase in intensity ratings under naloxone due mainly to a difference in the non-painful stimuli. On the neural level, painful thermal stimulation was associated with a negative BOLD signal within the pregenual anterior cingulate cortex, and this deactivation was abolished by naloxone.     

Biological Markers of Auditory Gap Detection in Young,Middle-Aged,and Older Adults

The capability of processing rapid fluctuations in the temporal envelope of sound declines with age and this contributes to older adults'' difficulties in understanding speech. Although, changes in central auditory processing during aging have been proposed as cause for communication deficits, an open question remains which stage of processing is mostly affected by age related changes. We investigated auditory temporal resolution in young, middle-aged, and older listeners with neuromagnetic evoked responses to gap stimuli with different leading marker and gap durations. Signal components specific for processing the physical details of sound stimuli as well as the auditory objects as a whole were derived from the evoked activity and served as biological markers for temporal processing at different cortical levels. Early oscillatory 40-Hz responses were elicited by the onsets of leading and lagging markers and indicated central registration of the gap with similar amplitude in all three age groups. High-gamma responses were predominantly related to the duration of no-gap stimuli or to the duration of gaps when present, and decreased in amplitude and phase locking with increasing age. Correspondingly, low-frequency activity around 200 ms and later was reduced in middle aged and older participants. High-gamma band, and long-latency low-frequency responses were interpreted as reflecting higher order processes related to the grouping of sound items into auditory objects and updating of memory for these objects. The observed effects indicate that age-related changes in auditory acuity have more to do with higher-order brain functions than previously thought.     

Topography of alpha and theta oscillatory responses upon auditory and visual stimuli in humans

Brain resonance phenomena and induced rhythms in the brain recently gained importance in electroencephalographic, magnetoencephalographic and cellular studies (Ba\c sar and Bullock 1992). It was hypothesized that evoked potentials are superpositions of induced rhythms caused by resonance phenomena in neural populations (Ba\c sar et al. 1992). According to Ba\c sar (1972), such resonance phenomena are reflected in the main peaks of the amplitude frequency characteristics computed from EEG responses. The present study is based on a frequency domain approach for the evaluation of topography- and modality-dependent properties of oscillatory brain responses. EEG and evoked potentials were recorded from vertex, parietal and occipital scalp locations in 24 volunteers. Two combined methods were applied: (1) amplitude frequency characteristics were computed from the transient evoked responses, and (2) frequency components of the transient responses were obtained by adaptive digital filtering. Our main goal was to investigate theta (4--7 Hz) and alpha (8--15 Hz) response components. (1) Amplitude frequency characteristics. Auditory stimuli elicited theta-alpha compound responses in the 4--11 Hz frequency band (e.g. typical peaking frequency around 7 Hz for vertex recordings). Visual stimuli elicited alpha responses (e.g. typical peaking frequency for vertex recordings around 9--12 Hz). Frequency maxima for visual stimuli thus had main peaks at higher frequency values than frequency maxima for auditory stimuli. (2) Digital filtering confirmed these results: for vertex recordings, theta vs. alpha response amplitudes were 9 vs 6 for auditory stimuli and 5 vs 5 for visual stimuli, thus confirming a shift towards higher frequencies, i.e. a more prominent contribution of the alpha range, in the case of visual stimulation. We hypothesize that these properties might reflect site- and modality-specific features of stimulus encoding in the brain in which resonance properties of neuron populations are involved. Furthermore we emphasize the utility of the systems theory approach for a better understanding of brain function by means of EPs. Received: 25 February 1994 / Accepted in revised form: 5 August 1994     

Reaction times to painless and painful CO2 and argon laser stimulation

The introduction of lasers in pain research has made it possible to activate the nociceptive system without activating mechanosensitive afferents. In the present study the reaction times to painless and painful laser stimuli were studied to investigate if the reaction time to experimental pain is reproduceable. CO2 and argon lasers were used for stimulation, and the influence of stimulus (intensity and duration) and skin parameters (temperature, thickness, and reflectance) on reaction time were investigated. When these parameters were controlled the reaction times to painful CO2 and argon laser stimulation were within the same range (350-450 ms), and the intra-individual variability minimal (6.9%). The reaction time was used to estimate peripheral conduction velocity (10 m.s-1) for the activated fibre population when distinct pain was perceived. Determination of reaction times to non-painful and painful stimuli may be suitable ways to assess the functioning of thermal and nociceptive pathways.     

Dopamine Precursor Depletion Influences Pain Affect Rather than Pain Sensation

Pain is a multidimensional experience, which includes sensory, cognitive, and affective aspects. Converging lines of evidence indicate that dopaminergic neurotransmission plays an important role in human pain perception. However, the precise effects of dopamine on different aspects of pain perception remain to be elucidated. To address this question, we experimentally decreased dopaminergic neurotransmission in 22 healthy human subjects using Acute Phenylalanine and Tyrosine Depletion (APTD). During APTD and a control condition we applied brief painful laser stimuli to the hand, assessed different aspects of pain perception, and recorded electroencephalographic responses. APTD-induced decreases of cerebral dopaminergic activity did not influence sensory aspects of pain perception. In contrast, APTD yielded increases of pain unpleasantness. The increases of unpleasantness ratings positively correlated with effectiveness of APTD. Our finding of an influence of dopaminergic neurotransmission on affective but not sensory aspects of phasic pain suggests that analgesic effects of dopamine might be mediated by indirect effects on pain affect rather than by direct effects on ascending nociceptive signals. These findings contribute to our understanding of the complex relationship between dopamine and pain perception, which may play a role in various clinical pain states.     

Interactions between Chemical and Thermal Cutaneous Stimuli: Inhibition (Counterirritation) and Integration

Methyl salicylate, a commonly used chemical counterirritant, was applied topically to the forearm to determine whether a nonpainful chemical irritation could inhibit the perception of another (weaker) chemical irritation. In the first experiment, sensations of irritation (burning and stinging) produced by a 10% solution of methyl salicylate were significantly attenuated when a 15% solution of the same chemical was applied to the opposite forearm. In the second experiment, neither the perception of warmth nor the heat pain threshold was affected by application of 10% or 15% methyl salicylate to a site 10 cm from the thermal stimulus. Inhibition did, however, occur in the opposite direction: Chemical irritation was reduced after the thermal stimulus reached a painful level. In the third experiment, a 15% solution of methyl salicylate was applied immediately adjacent to the thermal stimulus, with the result that ratings of warmth intensity increased rather than decreased, and perceived irritation was again attenuated following a painful heat stimulus. Overall, the results indicate that (1) chemical counterirritation can occur at nonpainful levels; (2) the resulting inhibition is confined to the nociceptive system; and (3) when the nociceptive and warmth systems are activated together, the tendency is toward integration rather than inhibition.     

Interactions between chemical and thermal cutaneous stimuli: inhibition (counterirritation) and integration.

Methyl salicylate, a commonly used chemical counterirritant, was applied topically to the forearm to determine whether a nonpainful chemical irritation could inhibit the perception of another (weaker) chemical irritation. In the first experiment, sensations of irritation (burning and stinging) produced by a 10% solution of methyl salicylate were significantly attenuated when a 15% solution of the same chemical was applied to the opposite forearm. In the second experiment, neither the perception of warmth nor the heat pain threshold was affected by application of 10% or 15% methyl salicylate to a site 10 cm from the thermal stimulus. Inhibition did, however, occur in the opposite direction: Chemical irritation was reduced after the thermal stimulus reached a painful level. In the third experiment, a 15% solution of methyl salicylate was applied immediately adjacent to the thermal stimulus, with the result that ratings of warmth intensity increased rather than decreased, and perceived irritation was again attenuated following a painful heat stimulus. Overall, the results indicate that (1) chemical counterirritation can occur at nonpainful levels; (2) the resulting inhibition is confined to the nociceptive system; and (3) when the nociceptive and warmth system are activated together, the tendency is toward integration rather than inhibition.     

An fMRI Study Exploring the Overlap and Differences between Neural Representations of Physical and Recalled Pain

Implementing a recall paradigm without hypnosis, we use functional MRI (fMRI) to explore and compare nociceptive and centrally-driven pain experiences. We posit that a trace of a recent nociceptive event can be used to create sensory-re-experiencing of pain that can be qualified in terms of intensity and vividness. Fifteen healthy volunteers received three levels of thermal stimuli (warm, low pain and high pain) and subsequently were asked to recall and then rate this experience. Neuroimaging results reveal that recalling a previous sensory experience activates an extensive network of classical pain processing structures except the contralateral posterior insular cortex. Nociceptive-specific activation of this structure and the rated intensity difference between physical and recalled pain events allow us to investigate the link between the quality of the original nociceptive stimulus and the mental trace, as well as the differences between the accompanying neural responses. Additionally, by incorporating the behavioural ratings, we explored which brain regions were separately responsible for generating either an accurate or vivid recall of the physical experience. Together, these observations further our understanding of centrally-mediated pain experiences and pain memory as well as the potential relevance of these factors in the maintenance of chronic pain.     

Pain Perception Is Increased in Congenital but Not Late Onset Blindness

There is now ample evidence that blind individuals outperform sighted individuals in various tasks involving the non-visual senses. In line with these results, we recently showed that visual deprivation from birth leads to an increased sensitivity to pain. As many studies have shown that congenitally and late blind individuals show differences in their degree of compensatory plasticity, we here address the question whether late blind individuals also show hypersensitivity to nociceptive stimulation. We therefore compared pain thresholds and responses to supra-threshold nociceptive stimuli in congenitally blind, late blind and normally sighted volunteers. Participants also filled in questionnaires measuring attention and anxiety towards pain in everyday life. Results show that late blind participants have pain thresholds and ratings of supra-threshold heat nociceptive stimuli similar to the normally sighted, whereas congenitally blind participants are hypersensitive to nociceptive thermal stimuli. Furthermore, results of the pain questionnaires did not allow to discriminate late blind from normal sighted participants, whereas congenitally blind individuals had a different pattern of responses. Taken together, these results suggest that enhanced sensitivity to pain following visual deprivation is likely due to neuroplastic changes related to the early loss of vision.     

Thermosensory intensity and affect throughout the perceptible range

The thermosensory system was evaluated psychophysically in 12 healthy volunteers, spanning the full range of tolerable temperatures. Subjects provided ratings of (1) perceived thermal intensity, (2) perceived pleasantness or unpleasantness, and (3) perceived pain intensity after placing either one hand or foot in a temperature controlled water bath. Of particular interest were the interrelationships among the three perceptual measures, and differences between heat and cold. The relationship between perceived intensity and (un)pleasantness was different for hot vs cold stimuli. Specifically, for a given perceived thermal intensity, cold stimuli were rated as less pleasant or more unpleasant than hot stimuli. Similarly, for a given pain intensity, cold stimuli were rated as more unpleasant than hot stimuli. As warm temperatures increased and as cold temperatures decreased, stimuli were perceived as being unpleasant before they were perceived as being painful. The difference in transition temperatures for unpleasantness vs pain for heat averaged 1.4 degrees C, while the same difference for cold averaged 5.6 degrees C. Thus, there was a fourfold difference in the range of unpleasant but non-painful cold vs hot temperatures. Pain intensity and unpleasantness ratings were significantly higher for heat stimuli applied to the foot vs hand. In contrast, there was no significant body site difference for pain intensity or unpleasantness ratings of cold stimuli. All of these results reveal important differences in the processing of cold vs hot stimuli. These differences could be exploited to differentiate processing relevant to discriminative vs affective components of somesthetic perception, in both the innocuous and noxious ranges.     

Sex differences in nociceptive withdrawal reflex and pain perception

Experimentally induced pain often reveals sex differences, with higher pain sensitivity in females. The degree of differences has been shown to depend on the stimulation and assessment methods. Since sex differences in pain develop anywhere along the physiological and psychological components of the nociceptive system, we intended to compare the nociceptive flexion reflex (NFR) as a more physiological (spinal) aspect of pain procession to the verbal pain report of intensity and unpleasantness as the more psychological (cortical) aspect. Twenty female and twenty male healthy university students were investigated by use of nociceptive flexion reflex threshold (staircase method) after electrical stimulation of the N. suralis. Furthermore, we assessed supra-threshold reflex responses (latency, amplitude and area) by applying 10 stimuli 5 mA above reflex threshold. Following each stimulation, the subjects provided pain ratings of intensity and unpleasantness on a visual analogue scale. Females exhibited marked lower nociceptive flexion reflex thresholds than males, while the supra-threshold reflex response tailored to the individual reflex threshold did not show any significant differences. The verbal pain ratings, corrected for NFR threshold, were not found to differ significantly. The large sex differences in nociception that were present in NFR threshold but not in the pain ratings corroborate the hypothesis that spinal processes contribute substantially to sex differences in pain procession.     

Nociceptive Local Field Potentials Recorded from the Human Insula Are Not Specific for Nociception

The insula, particularly its posterior portion, is often regarded as a primary cortex for pain. However, this interpretation is largely based on reverse inference, and a specific involvement of the insula in pain has never been demonstrated. Taking advantage of the high spatiotemporal resolution of direct intracerebral recordings, we investigated whether the human insula exhibits local field potentials (LFPs) specific for pain. Forty-seven insular sites were investigated. Participants received brief stimuli belonging to four different modalities (nociceptive, vibrotactile, auditory, and visual). Both nociceptive stimuli and non-nociceptive vibrotactile, auditory, and visual stimuli elicited consistent LFPs in the posterior and anterior insula, with matching spatial distributions. Furthermore, a blind source separation procedure showed that nociceptive LFPs are largely explained by multimodal neural activity also contributing to non-nociceptive LFPs. By revealing that LFPs elicited by nociceptive stimuli reflect activity unrelated to nociception and pain, our results confute the widespread assumption that these brain responses are a signature for pain perception and its modulation.     

Stimulus-dependent oscillations and evoked potentials in chinchilla auditory cortex

Besides the intensity and frequency of an auditory stimulus, the length of time that precedes the stimulation is an important factor that determines the magnitude of early evoked neural responses in the auditory cortex. Here we used chinchillas to demonstrate that the length of the silent period before the presentation of an auditory stimulus is a critical factor that modifies late oscillatory responses in the auditory cortex. We used tetrodes to record local-field potential (LFP) signals from the left auditory cortex of ten animals while they were stimulated with clicks, tones or noise bursts delivered at different rates and intensity levels. We found that the incidence of oscillatory activity in the auditory cortex of anesthetized chinchillas is dependent on the period of silence before stimulation and on the intensity of the auditory stimulus. In 62.5% of the recordings sites we found stimulus-related oscillations at around 8-20 Hz. Stimulus-induced oscillations were largest and consistent when stimuli were preceded by 5 s of silence and they were absent when preceded by less than 500 ms of silence. These results demonstrate that the period of silence preceding the stimulus presentation and the stimulus intensity are critical factors for the presence of these oscillations.     

Smell-induced gamma oscillations in human olfactory cortex are required for accurate perception of odor identity

Studies of neuronal oscillations have contributed substantial insight into the mechanisms of visual, auditory, and somatosensory perception. However, progress in such research in the human olfactory system has lagged behind. As a result, the electrophysiological properties of the human olfactory system are poorly understood, and, in particular, whether stimulus-driven high-frequency oscillations play a role in odor processing is unknown. Here, we used direct intracranial recordings from human piriform cortex during an odor identification task to show that 3 key oscillatory rhythms are an integral part of the human olfactory cortical response to smell: Odor induces theta, beta, and gamma rhythms in human piriform cortex. We further show that these rhythms have distinct relationships with perceptual behavior. Odor-elicited gamma oscillations occur only during trials in which the odor is accurately perceived, and features of gamma oscillations predict odor identification accuracy, suggesting that they are critical for odor identity perception in humans. We also found that the amplitude of high-frequency oscillations is organized by the phase of low-frequency signals shortly following sniff onset, only when odor is present. Our findings reinforce previous work on theta oscillations, suggest that gamma oscillations in human piriform cortex are important for perception of odor identity, and constitute a robust identification of the characteristic electrophysiological response to smell in the human brain. Future work will determine whether the distinct oscillations we identified reflect distinct perceptual features of odor stimuli.

Intracranial recordings from human olfactory cortex reveal a characteristic spectrotemporal response to odors, including theta, beta and gamma oscillations, and show that high-frequency responses are critical for accurate perception of odors.     

Emotional stimulation alters olfactory sensitivity and odor judgment

Emotions have a strong influence on the perception of visual and auditory stimuli. Only little is known about the relation between emotional stimulation and olfactory functions. The present study investigated the relationship between the presentation of affective pictures, olfactory functions, and sex. Olfactory performance was assessed in 32 subjects (16 male). Olfactory sensitivity was significantly reduced following unpleasant picture presentation for all subjects and following pleasant picture presentation for male subjects only. Pleasantness and intensity ratings of a neutral suprathreshold odor were related to the valence of the pictures: After unpleasant picture presentation, the odor was rated as less pleasant and more intense, whereas viewing positive pictures induced a significant increase in reported odor pleasantness. We conclude that inducing a negative emotional state reduces olfactory sensitivity. A relation to functional deviations within the primary olfactory cortices is discussed.     

Effects of upper airway pressure on abdominal muscle activity in conscious dogs.

We have examined arousal and abdominal muscle electromyogram (EMGabd) responses to upper airway pressure stimuli during physiological sleep in four dogs with permanent side-hole tracheal stomata. The dogs were trained to sleep with a tightly fitting snout mask, hermetically sealed in place, while breathing through a cuffed endotracheal tube inserted through the tracheostomy. Sleep stage was determined by behavioral and electroencephalographic criteria. EMGabd activity was measured using bipolar fine-wire electrodes inserted into the abdominal muscle layers. Static increases or decreases in upper airway pressure (+/- 6 cmH2O), when applied at the snout mask or larynx (upper trachea), caused an immediate decrease in EMGabd on the first two to three breaths; EMGabd usually returned to control levels within the 1-min test interval. In contrast, oscillatory pressure waves at 30 Hz and +/- 3 cmH2O amplitude (or -2 to -8 cmH2O amplitude) produced an immediate and sustained reduction in IMGabd in all sleep states. Inhibition of EMGabd could be maintained over many minutes when the oscillatory pressure stimulus was pulsed by using a cycle of 0.5 s on and 0.5 s off. Oscillatory upper airway pressures were also found to be powerful arousal-promoting stimuli, producing arousal in 94% of tests in drowsiness and 66% of tests in slowwave sleep. The results demonstrate the presence of breath-by-breath upper airway control of abdominal muscle activity.     

Auditory affective norms for German: testing the influence of depression and anxiety on valence and arousal ratings

Background

The study of emotional speech perception and emotional prosody necessitates stimuli with reliable affective norms. However, ratings may be affected by the participants'' current emotional state as increased anxiety and depression have been shown to yield altered neural responding to emotional stimuli. Therefore, the present study had two aims, first to provide a database of emotional speech stimuli and second to probe the influence of depression and anxiety on the affective ratings.

Methodology/Principal Findings

We selected 120 words from the Leipzig Affective Norms for German database (LANG), which includes visual ratings of positive, negative, and neutral word stimuli. These words were spoken by a male and a female native speaker of German with the respective emotional prosody, creating a total set of 240 auditory emotional stimuli. The recordings were rated again by an independent sample of subjects for valence and arousal, yielding groups of highly arousing negative or positive stimuli and neutral stimuli low in arousal. These ratings were correlated with participants'' emotional state measured with the Depression Anxiety Stress Scales (DASS). Higher depression scores were related to more negative valence of negative and positive, but not neutral words. Anxiety scores correlated with increased arousal and more negative valence of negative words.

Conclusions/Significance

These results underscore the importance of representatively distributed depression and anxiety scores in participants of affective rating studies. The LANG-audition database, which provides well-controlled, short-duration auditory word stimuli for the experimental investigation of emotional speech is available in Supporting Information S1.     

Neural mechanisms of infant learning: differences in frontal theta activity during object exploration modulate subsequent object recognition

Investigating learning mechanisms in infancy relies largely on behavioural measures like visual attention, which often fail to predict whether stimuli would be encoded successfully. This study explored EEG activity in the theta frequency band, previously shown to predict successful learning in adults, to directly study infants'' cognitive engagement, beyond visual attention. We tested 11-month-old infants (N = 23) and demonstrated that differences in frontal theta-band oscillations, recorded during infants'' object exploration, predicted differential subsequent recognition of these objects in a preferential-looking test. Given that theta activity is modulated by motivation to learn in adults, these findings set the ground for future investigation into the drivers of infant learning.     

Endogenous cortical rhythms determine cerebral specialization for speech perception and production

Across multiple timescales, acoustic regularities of speech match rhythmic properties of both the auditory and motor systems. Syllabic rate corresponds to natural jaw-associated oscillatory rhythms, and phonemic length could reflect endogenous oscillatory auditory cortical properties. Hemispheric lateralization for speech could result from an asymmetry of cortical tuning, with left and right auditory areas differentially sensitive to spectro-temporal features of speech. Using simultaneous electroencephalographic (EEG) and functional magnetic resonance imaging (fMRI) recordings from humans, we show that spontaneous EEG power variations within the gamma range (phonemic rate) correlate best with left auditory cortical synaptic activity, while fluctuations within the theta range correlate best with that in the right. Power fluctuations in both ranges correlate with activity in the mouth premotor region, indicating coupling between temporal properties of speech perception and production. These data show that endogenous cortical rhythms provide temporal and spatial constraints on the neuronal mechanisms underlying speech perception and production.     

Source Space Estimation of Oscillatory Power and Brain Connectivity in Tinnitus

Tinnitus is the perception of an internally generated sound that is postulated to emerge as a result of structural and functional changes in the brain. However, the precise pathophysiology of tinnitus remains unknown. Llinas’ thalamocortical dysrhythmia model suggests that neural deafferentation due to hearing loss causes a dysregulation of coherent activity between thalamus and auditory cortex. This leads to a pathological coupling of theta and gamma oscillatory activity in the resting state, localised to the auditory cortex where normally alpha oscillations should occur. Numerous studies also suggest that tinnitus perception relies on the interplay between auditory and non-auditory brain areas. According to the Global Brain Model, a network of global fronto—parietal—cingulate areas is important in the generation and maintenance of the conscious perception of tinnitus. Thus, the distress experienced by many individuals with tinnitus is related to the top—down influence of this global network on auditory areas. In this magnetoencephalographic study, we compare resting-state oscillatory activity of tinnitus participants and normal-hearing controls to examine effects on spectral power as well as functional and effective connectivity. The analysis is based on beamformer source projection and an atlas-based region-of-interest approach. We find increased functional connectivity within the auditory cortices in the alpha band. A significant increase is also found for the effective connectivity from a global brain network to the auditory cortices in the alpha and beta bands. We do not find evidence of effects on spectral power. Overall, our results provide only limited support for the thalamocortical dysrhythmia and Global Brain models of tinnitus.