The perception of painful and nonpainful stimuli during voluntary motor activity in man

Previous studies have shown that voluntary movement diminishes the transmission of cutaneous afferent input through the dorsal column-medial lemniscal system, and also raises the threshold for detecting nonpainful, cutaneous stimuli (electrical shocks). Although there is some evidence that pain elicited by electrical stimulation is diminished during movement, no studies have tested the effect of movement on the perception of pain produced by natural stimulation. For this reason, we tested the effects of voluntary motor activity on the perception of noxious thermal stimuli in human volunteers. We first developed a motor paradigm in which the thermal stimulation could be applied to the immobile limb (isometric elbow flexion-extension). Both isometric and isotonic muscle contractions about the elbow increased the threshold for detecting weak cutaneous stimuli (electrical shocks) applied to the forearm, and to a lesser extent the detection of stimuli applied to the dorsum of the hand. Afterwards, noxious and innocuous heat stimuli were applied to the forearm during isometric contractions and at rest. Magnitude estimates for the intensity of the pain, as well as latency measures of the onset of pain, were recorded. We found no evidence that isometric motor activity diminished either the threshold for pain or the subjective intensity of the noxious and innocuous thermal stimuli. Thus, motor activity decreases the ability to detect weak low-threshold cutaneous inputs, but has no effect on the perception of warmth and heat pain.     

The molecular basis of individual differences in phenylthiocarbamide and propylthiouracil bitterness perception

Individual differences in perception are ubiquitous within the chemical senses: taste, smell, and chemical somesthesis . A hypothesis of this fact states that polymorphisms in human sensory receptor genes could alter perception by coding for functionally distinct receptor types . We have previously reported evidence that sequence variants in a presumptive bitter receptor gene (hTAS2R38) correlate with differences in bitterness recognition of phenylthiocarbamide (PTC) . Here, we map individual psychogenomic pathways for bitter taste by testing people with a variety of psychophysical tasks and linking their individual perceptions of the compounds PTC and propylthiouracil (PROP) to the in vitro responses of their TAS2R38 receptor variants. Functional expression studies demonstrate that five different haplotypes from the hTAS2R38 gene code for operatively distinct receptors. The responses of the three haplotypes we also tested in vivo correlate strongly with individuals' psychophysical bitter sensitivities to a family of compounds. These data provide a direct molecular link between heritable variability in bitter taste perception to functional variations of a single G protein coupled receptor that responds to compounds such as PTC and PROP that contain the N-C=S moiety. The molecular mechanisms of perceived bitterness variability have therapeutic implications, such as helping patients to consume beneficial bitter-tasting compounds-for example, pharmaceuticals and selected phytochemicals.     

Predictive Dynamics of Human Pain Perception

While the static magnitude of thermal pain perception has been shown to follow a power-law function of the temperature, its dynamical features have been largely overlooked. Due to the slow temporal experience of pain, multiple studies now show that the time evolution of its magnitude can be captured with continuous online ratings. Here we use such ratings to model quantitatively the temporal dynamics of thermal pain perception. We show that a differential equation captures the details of the temporal evolution in pain ratings in individual subjects for different stimulus pattern complexities, and also demonstrates strong predictive power to infer pain ratings, including readouts based only on brain functional images.     

Sex differences in thermal detection and thermal pain threshold and the thermal grill illusion: a psychophysical study in young volunteers

Background

Sex-related differences in human thermal and pain sensitivity are the subject of controversial discussion. The goal of this study in a large number of subjects was to investigate sex differences in thermal and thermal pain perception and the thermal grill illusion (TGI) as a phenomenon reflecting crosstalk between the thermoreceptive and nociceptive systems. The thermal grill illusion is a sensation of strong, but not necessarily painful, heat often preceded by transient cold upon skin contact with spatially interlaced innocuous warm and cool stimuli.

Methods

The TGI was studied in a group of 78 female and 58 male undergraduate students and was evoked by placing the palm of the right hand on the thermal grill (20/40 °C interleaved stimulus). Sex-related thermal perception was investigated by a retrospective analysis of thermal detection and thermal pain threshold data that had been measured in student laboratory courses over 5 years (776 female and 476 male undergraduate students) using the method of quantitative sensory testing (QST). To analyse correlations between thermal pain sensitivity and the TGI, thermal pain threshold and the TGI were determined in a group of 20 female and 20 male undergraduate students.

Results

The TGI was more pronounced in females than males. Females were more sensitive with respect to thermal detection and thermal pain thresholds. Independent of sex, thermal detection thresholds were dependent on the baseline temperature with a specific progression of an optimum curve for cold detection threshold versus baseline temperature. The distribution of cold pain thresholds was multi-modal and sex-dependent. The more pronounced TGI in females correlated with higher cold sensitivity and cold pain sensitivity in females than in males.

Conclusions

Our finding that thermal detection threshold not only differs between the sexes but is also dependent on the baseline temperature reveals a complex processing of “cold” and “warm” inputs in thermal perception. The results of the TGI experiment support the assumption that sex differences in cold-related thermoreception are responsible for sex differences in the TGI.

     

Functional neuroanatomy of the hypnotic state

The neural mechanisms underlying hypnosis and especially the modulation of pain perception by hypnosis remain obscure. Using PET we first described the distribution of regional cerebral blood flow during the hypnotic state. Hypnosis relied on revivification of pleasant autobiographical memories and was compared to imaging autobiographical material in "normal alertness". The hypnotic state was related to the activation of a widespread set of cortical areas involving occipital, parietal, precentral, premotor, and ventrolateral prefrontal and anterior cingulate cortices. This pattern of activation shares some similarities with mental imagery, from which it mainly differs by the relative deactivation of precuneus. Second, we looked at the anti-nociceptive effects of hypnosis. Compared to the resting state, hypnosis reduced pain perception by approximately 50%. The hypnosis-induced reduction of affective and sensory responses to noxious thermal stimulation were modulated by the activity in the midcingulate cortex (area 24a'). Finally, we assessed changes in cerebral functional connectivity related to hypnosis. Compared to normal alertness (i.e., rest and mental imagery), the hypnotic state, significantly enhanced the functional modulation between midcingulate cortex and a large neural network involved in sensory, affective, cognitive and behavioral aspects of nociception. These findings show that not only pharmacological but also psychological strategies for pain control can modulate the cerebral network involved in noxious perception.     

Temperature and the two-point threshold

Studies dating back to 1834 have shown that the temperature of objects contacting the skin can substantially intensify their apparent pressure on the skin. Later research demonstrated qualitatively that object temperature can also sharpen the spatial acuity of the skin as revealed by gap perception (two-point and two-edge thresholds). Pressure intensification and sharpening probably relate intimately. The present experiments sought to provide several more accurate and parametric extensions of thermal sharpening: (1) sharpening can improve tactile spatial acuity by as much as 60%, but the degree of sharpening is graded as a function of deviation of stimulator temperature from normal (neutral) skin temperature; (2) thermal sharpening seems to characterize the body surface since it takes place freely in forearm, forehead, and palm; local differences do, however, become apparent; (3) large thermal sharpening can even occur when one tip of the stimulator is warm, the other cold; and (4) thermal sharpening is easily captured by experiment and is basically the same in magnitude whether assessed by modern forced-choice procedure (controlled criterion) or by the more traditional procedures (uncontrolled criterion) used for more than a century before the advent of signal detection theory. Various arguments are put forth here and elsewhere to suggest that both thermal intensification of pressure sensation and thermal sharpening of gap perception result from direct thermal stimulation of mechanoreceptors and/or polymodal nociceptor networks; neither phenomenon yeilds readily to a "cognitive" interpretation.     

An integrated study of heart pain and behavior in freely moving rats (using fos as a marker for neuronal activation)

The awareness in specific brain centers of angina pectoris most often results from ischemic episodes in the heart. These ischemic episodes induce the release of a collage of chemicals that activate chemosensitive and mechanoreceptive receptors in the heart, which in turn excite receptors of the sympathetic afferent pathways. Ascending pain signals from these fibers result in the activation of the brain centers which are involved in the perception and integration of cardiac pain. Cytochemical studies of the nervous system provide the opportunity to identify these areas at the cellular level. In the present investigation, cardiac nociception was studied in the brains and the spinal cords of rats, using Fos protein as a marker of neuronal activation, following the application of pain-inducing chemicals to the heart. Induction of myocardial pain in conscious rats was achieved by infusion of bradykinin (0.5 microg) or capsaicin (5 microg) into the pericardial sac. During pain stimulation, the rats demonstrated pain behavior, in conjunction with alterations in heart rate and blood pressure. The cerebral Fos expression pattern was studied 2 h after pain stimulation. In contrast to the control group, increased Fos expression was found following the use of both capsaicin and bradykinin in a variety of areas of the brain. Bradykinin, but not capsaicin, induced Fos expression in the upper thoracic and upper cervical spinal cord; these segments are the sites where cardiac sympathetic fibers terminate. This finding suggests that these two chemicals use two different pathways, and provides extra evidence for the role of the vagus nerve in the transmission of cardiac nociception. Different cerebral areas showed an increase in the c-fos activity following pericardial application of pain-inducing chemicals. The role of these cerebral areas in the integration of cardiac pain is discussed in relation to the identified pathways which transmit cardiac pain.     

Effects of Acupuncture on Sensory Perception: A Systematic Review and Meta-Analysis

Background

The effect of acupuncture on sensory perception has never been systematically reviewed; although, studies on acupuncture mechanisms are frequently based on the idea that changes in sensory thresholds reflect its effect on the nervous system.

Methods

Pubmed, EMBASE and Scopus were screened for studies investigating the effect of acupuncture on thermal or mechanical detection or pain thresholds in humans published in English or German. A meta-analysis of high quality studies was performed.

Results

Out of 3007 identified articles 85 were included. Sixty five studies showed that acupuncture affects at least one sensory threshold. Most studies assessed the pressure pain threshold of which 80% reported an increase after acupuncture. Significant short- and long-term effects on the pressure pain threshold in pain patients were revealed by two meta-analyses including four and two high quality studies, respectively. In over 60% of studies, acupuncture reduced sensitivity to noxious thermal stimuli, but measuring methods might influence results. Few but consistent data indicate that acupuncture reduces pin-prick like pain but not mechanical detection. Results on thermal detection are heterogeneous. Sensory threshold changes were equally frequent reported after manual acupuncture as after electroacupuncture. Among 48 sham-controlled studies, 25 showed stronger effects on sensory thresholds through verum than through sham acupuncture, but in 9 studies significant threshold changes were also observed after sham acupuncture. Overall, there is a lack of high quality acupuncture studies applying comprehensive assessments of sensory perception.

Conclusions

Our findings indicate that acupuncture affects sensory perception. Results are most compelling for the pressure pain threshold, especially in pain conditions associated with tenderness. Sham acupuncture can also cause such effects. Future studies should incorporate comprehensive, standardized assessments of sensory profiles in order to fully characterize its effect on sensory perception and to explore the predictive value of sensory profiles for the effectiveness of acupuncture.     

Skin thermal pain modeling—A holistic method

Pain sensation has been studied extensively, over a range of scales, from the molecular level to the entire human neural system. Thermal stimulation of pain has been widely used in the study of pain sensation. Skin thermal pain is induced through both direct (an increase/decrease in temperature) and indirect (thermomechanical and thermochemical) ways, and is governed by complicated thermomechanical–chemical–neurophysiologic responses. This paper is focused on the theoretical modeling of the underlying mechanisms in the process of skin thermal pain. A holistic model has been developed, which is composed of three sub-models, namely, transduction, transmission, and modulation and perception. The model can contribute to the understanding of thermally related pain phenomena in skin tissue and to improvements in a range of thermal therapeutic methods.     

Fluid mechanics in dentinal microtubules provides mechanistic insights into the difference between hot and cold dental pain

Dental thermal pain is a significant health problem in daily life and dentistry. There is a long-standing question regarding the phenomenon that cold stimulation evokes sharper and more shooting pain sensations than hot stimulation. This phenomenon, however, outlives the well-known hydrodynamic theory used to explain dental thermal pain mechanism. Here, we present a mathematical model based on the hypothesis that hot or cold stimulation-induced different directions of dentinal fluid flow and the corresponding odontoblast movements in dentinal microtubules contribute to different dental pain responses. We coupled a computational fluid dynamics model, describing the fluid mechanics in dentinal microtubules, with a modified Hodgkin-Huxley model, describing the discharge behavior of intradental neuron. The simulated results agreed well with existing experimental measurements. We thence demonstrated theoretically that intradental mechano-sensitive nociceptors are not "equally sensitive" to inward (into the pulp) and outward (away from the pulp) fluid flows, providing mechanistic insights into the difference between hot and cold dental pain. The model developed here could enable better diagnosis in endodontics which requires an understanding of pulpal histology, neurology and physiology, as well as their dynamic response to the thermal stimulation used in dental practices.     

Human perceptual and metacognitive decision-making rely on distinct brain networks

Perceptual decisions depend on the ability to exploit available sensory information in order to select the most adaptive option from a set of alternatives. Such decisions depend on the perceptual sensitivity of the organism, which is generally accompanied by a corresponding level of certainty about the choice made. Here, by use of corticocortical paired associative transcranial magnetic stimulation protocol (ccPAS) aimed at inducing plastic changes, we shaped perceptual sensitivity and metacognitive ability in a motion discrimination task depending on the targeted network, demonstrating their functional dissociation. Neurostimulation aimed at boosting V5/MT+-to-V1/V2 back-projections enhanced motion sensitivity without impacting metacognition, whereas boosting IPS/LIP-to-V1/V2 back-projections increased metacognitive efficiency without impacting motion sensitivity. This double-dissociation provides causal evidence of distinct networks for perceptual sensitivity and metacognitive ability in humans.

Transcranial magnetic stimulation targeting cortico-cortical connections reveals a functional dissociation between temporo-visual and parieto-visual re-entrant pathways in humans, controlling perceptual sensitivity and metacognitive abilities respectively, during a visual motion perception task.     

Attention modulates spinal cord responses to pain

Reduced pain perception while being distracted from pain is an everyday example of how cognitive processes can interfere with pain perception. Previous neuroimaging studies showed distraction-related modulations of pain-driven activations in various cortical and subcortical brain regions, but the precise neuronal mechanism underlying this phenomenon is unclear. Using high-resolution functional magnetic resonance imaging of the human cervical spinal cord in combination with thermal pain stimulation and a well-established working memory task, we demonstrate that this phenomenon relies on an inhibition of incoming pain signals in the spinal cord. Neuronal responses to painful stimulation in the dorsal horn of the corresponding spinal segment were significantly reduced under high working memory load compared to low working memory load. At the individual level, reductions of neuronal responses in the spinal cord predicted behavioral pain reductions. In a subsequent behavioral experiment, using the opioid antagonist naloxone in a double-blind crossover design with the same paradigm, we demonstrate a substantial contribution of endogenous opioids to this mechanism. Taken together, our results show that the reduced pain experience during mental distraction is related to a spinal process and involves opioid neurotransmission.     

Visceral nociception: peripheral and central aspects of visceral nociceptive systems

Discomfort and pain are the sensations most commonly evoked from viscera. Most nociceptive signals that originate from visceral organs reach the central nervous system (c.n.s.) via afferent fibres in sympathetic nerves, whereas parasympathetic nerves contain mainly those visceral afferent fibres concerned with the non-sensory aspects of visceral afferent function. Noxious stimulation of viscera activates a variety of specific and non-specific receptors, the vast majority of which are connected to unmyelinated afferent fibres. Studies on the mechanisms of visceral sensation can thus provide information on the more general functions of unmyelinated afferent fibres. Specific visceral nociceptors have been found in the heart, lungs, testes and biliary system, whereas noxious stimulation of the gastro-intestinal tract appears to be detected mainly by non-specific visceral receptors that use an intensity-encoding mechanism. Visceral nociceptive messages are conveyed to the spinal cord by relatively few visceral afferent fibres which activate many central neurons by extensive functional divergence through polysynaptic pathways. Impulses in visceral afferent fibres excite spinal cord neurons also driven by somatic inputs from the corresponding dermatome (viscero-somatic neurons). Noxious intensities of visceral stimulation are needed to activate viscero-somatic neurons, most of which can also be excited by noxious stimulation of their somatic receptive fields. The visceral input to some viscero-somatic neurons in the spinal cord can be mediated via long supraspinal loops. Pathways of projection of viscero-somatic neurons include the spino-reticular and spino-thalamic tracts. All these findings give experimental support to the 'convergence-projection' theory of referred visceral pain. Visceral pain is the consequence of the diffuse activation of somato-sensory nociceptive systems in a manner that prevents accurate spatial discrimination or localization of the stimuli. Noxious stimulation of visceral receptors triggers general reactions of alertness and arousal and evokes unpleasant and poorly localized sensory experiences. This type of response may be a feature of sensory systems dominated by unmyelinated afferent inputs.     

Tactile motion and pattern processing assessed with high-field FMRI

Processing of motion and pattern has been extensively studied in the visual domain, but much less in the somatosensory system. Here, we used ultra-high-field functional magnetic resonance imaging (fMRI) at 7 Tesla to investigate the neuronal correlates of tactile motion and pattern processing in humans under tightly controlled stimulation conditions. Different types of dynamic stimuli created the sensation of moving or stationary bar patterns during passive touch. Activity in somatosensory cortex was increased during both motion and pattern processing and modulated by motion directionality in primary and secondary somatosensory cortices (SI and SII) as well as by pattern orientation in the anterior intraparietal sulcus. Furthermore, tactile motion and pattern processing induced activity in the middle temporal cortex (hMT+/V5) and in the inferior parietal cortex (IPC), involving parts of the supramarginal und angular gyri. These responses covaried with subjects' individual perceptual performance, suggesting that hMT+/V5 and IPC contribute to conscious perception of specific tactile stimulus features. In addition, an analysis of effective connectivity using psychophysiological interactions (PPI) revealed increased functional coupling between SI and hMT+/V5 during motion processing, as well as between SI and IPC during pattern processing. This connectivity pattern provides evidence for the direct engagement of these specialized cortical areas in tactile processing during somesthesis.     

Characterization of VR1 within the BMBF-Leitproject: 'Molecular Pain Research'

Agents that activate cannabinoid CB1 receptors for marijuana's active principal, THC, or vanilloid VR1 receptors for red chilli peppers' pungent ingredient, capsaicin, modulate pain perception. Stimulation of presynaptic CB1 leads to inhibition of glutamate release in the spinal cord, whereas VR1 stimulation causes release of substance P and CGRP from DRG neurons. VR1 undergoes rapid desensitization by its agonists, which makes VR1-expressing neurons insensitive to subsequent stimulation and results in analgesia. Thus, both CB1 and VR1, which are coexpressed in several spinal and DRG neurons, are targets for analgesic drug development. CB1 and VR1 also share endogenous agonists, namely anandamide, NADA and some of their analogs, and may be regarded as metabotropic and ionotropic receptors for the same family of mediators, with opposing roles in pain perception. The development of 'hybrid' CB1/VR1 agonists as potent analgesics and the functional relationships between CB1 and VR1 in sensory neurons will be discussed.     

Caloric Vestibular Stimulation Reduces Pain and Somatoparaphrenia in a Severe Chronic Central Post-Stroke Pain Patient: A Case Study

Central post-stroke pain is a neuropathic syndrome characterized by intolerable contralesional pain and, in rare cases, somatic delusions. To date, there is limited evidence for the effective treatments of this disease. Here we used caloric vestibular stimulation to reduce pain and somatoparaphrenia in a 57-year-old woman suffering from central post-stroke pain. Resting-state functional magnetic resonance imaging was used to assess the neurological effects of this treatment. Following vestibular stimulation we observed impressive improvements in motor skills, pain, and somatic delusions. In the functional connectivity study before the vestibular stimulation, we observed differences in the patient’s left thalamus functional connectivity, with respect to the thalamus connectivity of a control group (N = 20), in the bilateral cingulate cortex and left insula. After the caloric stimulation, the left thalamus functional connectivity with these regions, which are known to be involved in the cortical response to pain, disappeared as in the control group. The beneficial use of vestibular stimulation in the reduction of pain and somatic delusion in a CPSP patient is now documented by behavioral and imaging data. This evidence can be applied to theoretical models of pain and body delusions.     

Cannabinoid–vanilloid receptor interactions in pain signaling

Agents that activate cannabinoid CB1 receptors for marijuana's active principal, THC, or vanilloid VR1 receptors for red chilli peppers' pungent ingredient, capsaicin, modulate pain perception. Stimulation of presynaptic CB1 leads to inhibition of glutamate release in the spinal cord, whereas VR1 stimulation causes release of substance P and CGRP from DRG neurons. VR1 undergoes rapid desensitization by its agonists, which makes VR1‐expressing neurons insensitive to subsequent stimulation and results in analgesia. Thus, both CB1 and VR1, which are coexpressed in several spinal and DRG neurons, are targets for analgesic drug development. CB1 and VR1 also share endogenous agonists, namely anandamide, NADA and some of their analogs, and may be regarded as metabotropic and ionotropic receptors for the same family of mediators, with opposing roles in pain perception. The development of ‘hybrid’ CB1/VR1 agonists as potent analgesics and the functional relationships between CB1 and VR1 in sensory neurons will be discussed.     

Modeling of nociceptor transduction in skin thermal pain sensation

All biological bodies live in a thermal environment with the human body as no exception, where skin is the interface with protecting function. When the temperature moves out of normal physiological range, skin fails to protect and pain sensation is evocated. Skin thermal pain is one of the most common problems for humans in everyday life as well as in thermal therapeutic treatments. Nocicetors (special receptor for pain) in skin play an important role in this process, converting the energy from external noxious thermal stimulus into electrical energy via nerve impulses. However, the underlying mechanisms of nociceptors are poorly understood and there have been limited efforts to model the transduction process. In this paper, a model of nociceptor transduction in skin thermal pain is developed in order to build direct relationship between stimuli and neural response, which incorporates a skin thermomechanical model for the calculation of temperature, damage and thermal stress at the location of nociceptor and a revised Hodgkin-Huxley form model for frequency modulation. The model qualitatively reproduces measured relationship between spike rate and temperature. With the addition of chemical and mechanical components, the model can reproduce the continuing perception of pain after temperature has returned to normal. The model can also predict differences in nociceptor activity as a function of nociceptor depth in skin tissue.     

'Thermal taste' predicts higher responsiveness to chemical taste and flavor

Individual differences in taste perception have been explained in part by variations in peripheral innervation associated with the genetic ability to taste the bitter substances PTC and PROP. In the present study we report evidence of another source of individual differences that is independent of taste stimulus, taste quality, or gustatory nerve. Individuals who perceived taste from thermal stimulation alone (thermal taste) gave significantly higher taste ratings to chemical stimuli--often by a factor of >2:1--than did individuals who perceived no taste from thermal stimulation. This was true for all taste stimuli tested (sucrose, saccharin, sodium chloride, citric acid, quinine sulfate, MSG and PROP), for all three gustatory areas of the mouth (anterior tongue, posterior tongue and soft palate) and for whole-mouth stimulation. Moreover, the same individuals reported stronger sensations from the olfactory stimulus vanillin, particularly when it was sensed retronasally. The generality of the thermal-taster advantage and its extension to an olfactory stimulus suggests that it arises from individual differences in CNS processes that are involved in perception of both taste and flavor.     

Temperature and the Two-Point Threshold

Studies dating back to 1834 have shown that the temperature of objects contacting the skin can substantially intensify their apparent pressure on the skin. Later research demonstrated qualitatively that object temperature can also sharpen the spatial acuity of the skin as revealed by gap perception (two-point and two-edge thresholds). Pressure intensification and sharpening probably relate intimately. The present experiments sought to provide several more accurate and parametric extensions of thermal sharpening: (1) sharpening can improve tactile spatial acuity by as much as 60%, but the degree of sharpening is graded as a function of deviation of stimulator temperature from normal (neutral) skin temperature; (2) thermal sharpening seems to characterize the body surface since it takes place freely in forearm, forehead, and palm; local differences do, however, become apparent; (3) large thermal sharpening can even occur when one tip of the stimulator is warm, the other cold; and (4) thermal sharpening is easily captured by experiment and is basically the same in magnitude whether assessed by modern forced-choice procedure (controlled criterion) or by the more traditional procedures (uncontrolled criterion) used for more than a century before the advent of signal detection theory. Various arguments are put forth here and elsewhere to suggest that both thermal intensification of pressure sensation and thermal sharpening of gap perception result from direct thermal stimulation of mechanoreceptors and/or polymodal nociceptor networks; neither phenomenon yields readily to a “cognitive” interpretation.