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.
Touch is a fundamental, but complex, element of everyday interaction that impacts one’s sensory and affective experience via interoceptive processing. The insular cortex is an integral component of the neural processes involved in interoception, i.e. the generation of an “emotional moment in time” through the sensing of the internal body state (Craig, 2002). Here, we examine the contribution of different parts of the insular cortex in the representation of both affective and sensory aspects of touch. To that end, subjects were administered a cued application of touch during functional MRI. We find that stimulus-related activation occurs in the mid-to-posterior insula, whereas anticipatory related activation is seen mostly in anterior insula. Moreover, the degree of activation in anterior insula during anticipation is correlated with the degree of activation in the posterior insula and caudate during stimulus processing. Finally, the degree of activation in the anterior insula during anticipation is also correlated with experienced intensity of the touch. Taken together, these results are consistent with the hypothesis that the anterior insula is preparing for the sensory and affective impact of touch. This preparatory function has important implications for the understanding of both anxiety and addictive disorders because dysfunctions in anticipatory processing are a fundamental part of the psychopathology.
Both fear and pain processing are altered in post-traumatic stress disorder (PTSD), as evidenced by functional neuroimaging studies showing increased amygdala responses to threats, and increased insula, putamen and caudate activity in response to heat pain. Using psychophysiology and functional magnetic resonance imaging, we studied conditioned and unconditioned autonomic and neuronal responses in subjects with PTSD versus trauma-exposed non-PTSD control (TENC) subjects. A design using an electric shock selected by subjects to be 'highly annoying but not painful' as an unconditioned stimulus (US) with partially reinforced cues allowed us to partly disentangle the expectancy- and prediction-error components from sensory components of the unconditioned response.
Whereas responses to the conditioned stimulus (CS) were similar in PTSD and TENC, the former displayed higher putamen, insula, caudate and amygdala responses to the US. Reactivity to the US in the anterior insula correlated with PTSD symptom severity. Functional connectivity analyses using the putamen as a seed region indicated that TENC subjects had increased amygdala-putamen connectivity during US delivery; this connection was disengaged in PTSD.
Our results indicate that although neural processing of fear learning in people with PTSD seems to be comparable with controls, neural responses to unconditioned aversive stimuli in PTSD seem to be increased.
Transcranial direct current stimulation (tDCS) has been shown to modulate cortical excitability. A small number of studies suggested that tDCS modulates the response to experimental pain paradigms. No trials have been conducted to evaluate the response of patients already suffering from pain, to an additional experimental pain before and after tDCS. The present study investigated the effect of a single session of anodal, cathodal and sham stimulation (15 mins/1 mA) over the primary motor cortex on the perceived intensity of repeated noxious thermal and electrical stimuli and on elements of quantitative sensory testing (thermal pain and perception thresholds) applied to the right hand in 15 patients with chronic low back pain. The study was conducted in a double-blind sham-controlled and cross-over design. No significant alterations of pain ratings were found. Modalities of quantitative sensory testing remained equally unchanged. It is therefore hypothesized that a single 15 mins session of tDCS at 1 mA may not be sufficient to alter the perception of experimental pain and in patients with chronic pain. Further studies applying repetitive tDCS to patients with chronic pain are required to fully answer the question whether experimental pain perception may be influenced by tDCS over the motor cortex.
Subjective sensory experiences are constructed by the integration of afferent sensory information with information about the uniquely personal internal cognitive state. The insular cortex is anatomically positioned to serve as one potential interface between afferent processing mechanisms and more cognitively-oriented modulatory systems. However, the role of the insular cortex in such modulatory processes remain poorly understood. Two individuals with extensive lesions to the insula were examined to better understand the contribution of this brain region to the generation of subjective sensory experiences. Despite substantial differences in the extent of the damage to the insular cortex, three findings were common to both individuals. First, both subjects had substantially higher pain intensity ratings of acute experimental noxious stimuli than age-matched control subjects. Second, when pain-related activation of the primary somatosensory cortex was examined during left and right-sided stimulation, both individuals exhibited dramatically elevated activity of the primary somatosensory cortex ipsilateral to the lesioned insula in relation to healthy control subjects. Finally, both individuals retained the ability to evaluate pain despite substantial insular damage and no evidence of detectible insular activity. Taken together, these results indicate that the insula may be importantly involved in tuning cortical regions to appropriately utilize prior cognitive information during afferent processing. Finally, these data suggest that a subjectively available experience of pain can be instantiated by brain mechanisms that do not require the insular cortex.
Pain Asymbolia; Anterior Cingulate Cortex; Dorsolateral Prefrontal Cortex; Somatosensory; Hyperalgesia; Stroke
We use fMRI to examine brain activity for pain elicited by palpating joints in a single patient suffering from psoriatic arthritis. Changes in these responses are documented when the patient ingested a single dose of a selective cyclooxygenase-2 inhibitor (COX-2i). We show that mechanical stimulation of the painful joints exhibited a cortical activity pattern similar to that reported for acute pain, with activity primarily localized to the thalamus, insular, primary and secondary somatosensory cortices and the mid anterior cingulum. COX-2i resulted in significant decreased in reported pain intensity and in brain activity after 1 hour of administration. The anterior insula and SII correlated with pain intensity, however no central activation site for the drug was detected. We demonstrate the similarity of the activation pattern for palpating painful joints to brain activity in normal subjects in response to thermal painful stimuli, by performing a spatial conjunction analysis between these maps, where overlap is observed in the insula, thalamus, secondary somatosensory cortex, and anterior cingulate. The results demonstrate that one can study effects of pharmacological manipulations in a single subject where the brain activity for a clinical condition is delineated and its modulation by COX-2i demonstrated. This approach may have diagnostic and prognostic utility.
The experience of pain can be described using two dimensions – sensory and affective-motivational – of which the affective-motivational component is strongly modulated by context and the cognitive appraisal of pain. In pain research, the sensory component is commonly represented by ratings of pain intensity, while the affective component is represented by ratings of pain unpleasantness. However, there is evidence to suggest that test subjects tend to judge pain intensity different from unpleasantness whenever separate scales for both dimensions are presented concurrently. This study used a startle reflex as an objective measure of affective response to stimuli of varying intensities to determine whether the affective component can be abolished when predictable stimulation paradigms are applied.
Experimental pain research has shown that the affective component of pain is influenced strongly by situational characteristics; affective pain processing appears to be particularly pronounced in situations that provoke a feeling of uncertainty and uncontrollability.
To determine whether the affective component of pain can be completely abolished if a ‘safe’, particularly predictable stimulation paradigm is applied.
Forty healthy volunteers recruited at the University of Bamberg (Bamberg, Germany) were assessed in two experiments. Tonic contact heat stimuli staged in three intensities (warmth, heat and pain) relative to the individual pain threshold was applied; these were predictable with regard to intensity and course, and the subjects had easy access to control. The startle reflex was assessed as an objective measure of affective response. In addition, the subjects provided unpleasantness ratings. To compare these results to a gold standard for affective response, affective pictures taken from the International Affective Picture System were presented during temperature stimulation in the second experiment.
Both experiments showed no potentiation of the startle reflex under painful heat stimulation compared with the two nonpainful stimulus intensities (heat and warmth), although the painful stimulation was clearly rated as more unpleasant.
Results suggest that it is possible to develop a ‘safe’ noxious stimulus, which is rated as clearly unpleasant, but lacks physiological indication of negative affect. This divergence might be explained by subjective ratings being influenced by the instructions. The possibility of reducing the pain affect by suggesting ‘safety’ may be of therapeutic interest.
Affective pain processing; Affective pictures; Startle; Thermal pain
One approach to the study of disordered spatial attention is to carry out tests of extinction, in which stimuli are detected on the left when they are presented on the left alone, but not when both sides are stimulated simultaneously in a dual simultaneous stimulation (DSS) protocol. Extinction has been documented for multiple sensory modalities, but not for thermal pain stimuli, to our knowledge. We now test the hypothesis that subjects with visual spatial neglect (hemi-neglect) will have alterations in thermal pain sensation which are related to abnormal spatial attention. The results demonstrate that thermal pain extinction of hot and cold pain stimuli occurs in a proportion of subjects with hemi-neglect. In the subjects with visual spatial hemi-neglect but without thermal pain extinction, the sensation of the thermal pain stimulus on the affected (left) side was not extinguished but was often localized to the unaffected (right) side, and the submodality of the stimulus (cold or hot) was often misidentified. Ratios indicating the magnitude of extinction, mislocalization and misidentification were significantly larger on the left side of subjects with visual spatial neglect than in healthy controls or in controls with stroke but without hemineglect. The proportion of subjects with thermal pain extinction, mislocalization, or misidentification was significantly higher in subjects with hemi-neglect than those in either control group. These results demonstrate that disordered attention exerts a powerful effect upon the perception of both the location and the quality of thermal pain stimuli.
Neglect; Attention; Human; Thermal pain; Mislocalization; Misidentification
The objective of this appraisal is to shed light on the various approaches to screen sensory information in the human gut. Understanding and characterization of sensory symptoms in gastrointestinal disorders is poor. Experimental methods allowing the investigator to control stimulus intensity and modality, as well as using validated methods for assessing sensory response have contributed to the understanding of pain mechanisms. Mechanical stimulation based on impedance planimetry allows direct recordings of luminal cross-sectional areas, and combined with ultrasound and magnetic resonance imaging, the contribution of different gut layers can be estimated. Electrical stimulation depolarizes free nerve endings non-selectively. Consequently, the stimulation paradigm (single, train, tetanic) influences the involved sensory nerves. Visual controlled electrical stimulation combines the probes with an endoscopic approach, which allows the investigator to inspect and obtain small biopsies from the stimulation site. Thermal stimulation (cold or warm) activates selectively mucosal receptors, and chemical substances such as acid and capsaicin (either alone or in combination) are used to evoke pain and sensitization. The possibility of multimodal (e.g. mechanical, electrical, thermal and chemical) stimulation in different gut segments has developed visceral pain research. The major advantage is involvement of distinctive receptors, various sensory nerves and different pain pathways mimicking clinical pain that favors investigation of central pain mechanisms involved in allodynia, hyperalgesia and referred pain. As impairment of descending control mechanisms partly underlies the pathogenesis in chronic pain, a cold pressor test that indirectly stimulates such control mechanisms can be added. Hence, the methods undoubtedly represent a major step forward in the future characterization and treatment of patients with various diseases of the gut, which provides knowledge to clinicians about the underlying symptoms and treatment of these patients.
Endoscopy; Intestine; Experimental; Neurophysiology; Pain
Mechanisms of pain relief induced by vibration and movement were investigated. A CO2 laser beam, which is useful for pure nociceptive stimulation, was used for recording pain-related somatosensory evoked potentials (pain SEPs) and for measuring pain threshold and reaction time (RT). Concurrently applied vibratory stimuli to and active movements of the fingers significantly reduced and prolonged pain SEPs, increased pain threshold, and prolonged RT, indicating that an increase in the inhibitory mechanisms of painful feeling was induced by the concurrently adopted sensory inputs mediated by large myelinated fibres. In contrast, continuous cooling enhanced pain SEPs and decreased pain threshold, probably due to the spatial summation of two kinds of nociceptive impulses mediated by the same pathways. The results of this investigation throw light on the mechanisms of the alleviation of pain by vibration and movement.
Pain contains both sensory and affective dimensions. Using a rodent visceral pain assay that combines the colorectal distension (CRD) model with the conditioned place avoidance (CPA) paradigms, we measured a learned behavior that directly reflects the affective component of visceral pain, and showed that perigenual anterior cingulate cortex (pACC) activation is critical for memory processing involved in long-term visceral affective state and prediction of aversive stimuli by contextual cue. Progress has been made and suggested that activation of vagal afferents plays a role in the behavioral control nociception and memory storage processes.
In human patients, electrical vagus nerve stimulation enhanced retention of verbal learning performance. Cholecystokinin-octapeptide (CCK), which is a gastrointestinal hormone released during feeding, has been shown to enhance memory retention. Mice access to food immediately after training session enhanced memory retention. It has been well demonstrated that CCK acting on vagal afferent fibers mediates various physiological functions. We hypothesize that CCK activation of vagal afferent enhances visceral pain-related affective memory.
In the presented study, infusion of CCK-8 at physiological concentration combining with conditional training significantly increased the CRD-induced CPA scores, and enhanced the pain affective memory retention. In contrast, CCK had no effect on CPA induced by non-nociceptive aversive stimulus (U69,593). The physiological implications were further strengthened by the similar effects observed in the rats with duodenal infusion of 5% peptone, which has been shown to induce increases in plasma CCK levels. CCK-8 receptor antagonist CR-1409 or perivagal application of capsaicin abolished the effect of CCK on aversive visceral pain memory, which was consistent with the notion that vagal afferent modulates affective aspects of visceral pain. CCK does not change the nociceptive response (visceral pain sensitivity) and anterior cingulate cortex neuronal responses to CRD.
CCK activating vagal afferent C fibers enhances memory consolidation and retention involved in long-term visceral negative affective state. Thus, in a number of gastrointestinal disorders, such as irritable bowel syndrome, nutrient content may contribute to painful visceral perception by enhancing visceral aversive memory via acts on vagal afferent pathway.
Cholecystokinin; Conditioned place avoidance; Visceral pain; Visceral aversive memory; Anterior cingulate cortex; Vagal afferent pathway
Background and aims
Independent component analysis (ICA) of the electroencephalogram (EEG) overcomes many of the classical problems in EEG analysis. We used ICA to determine the brain responses to painful stimulation of the oesophagus.
Twelve subjects with a median age of 41 years were included. With a nasal endoscope, two series of 35 electrical stimuli at the pain threshold were given to the distal oesophagus and the EEG was subjected to ICA. The sessions were separated by 30 minutes. For each component head models, event related images, spectral perturbation, coherence analysis, and dipoles were extracted. The most valid components were found according to time/frequency information and reliability in both experiments.
Reliable components with the most valid dipoles were found in the thalamus, insula, cingulate gyrus, and sensory cortex. Time locked activities were consistent with upstream activation of these areas, and cross coherence analysis of the sources demonstrated dynamic links in the β(14–25 Hz) and γ(25–50 Hz) bands between the suggested networks of neurones. The thalamic components were time and phase locked intermittently, starting around 50 ms. In the cingulate gyrus, the posterior areas were always firstly activated, followed by the middle and anterior regions. Components with dipoles in the sensory cortex were localised in several regions of the somatosensory area.
The method gives new information relating to the localisation and dynamics between neuronal networks in the brain to pain evoked from the human oesophagus, and should be used to increase our understanding of clinical pain.
oesophagus; experimental pain; electroencephalography; signal analysis; independent component analysis
The attribution of personal relevance, i.e. relating internal and external stimuli to establish a sense of belonging, is a common phenomenon in daily life. Although previous research demonstrated a relationship between reward and personal relevance, their exact neuronal relationship including the impact of personality traits remains unclear.
Using functional magnetic resonance imaging, we applied an experimental paradigm that allowed us to explore the neural response evoked by reward and the attribution of personal relevance separately. We observed different brain regions previously reported to be active during reward and personal relevance, including the bilateral caudate nucleus and the pregenual anterior cingulate cortex (PACC). Additional analysis revealed activations in the right and left insula specific for the attribution of personal relevance. Furthermore, our results demonstrate a negative correlation between signal changes in both the PACC and the left anterior insula during the attribution of low personal relevance and the personality dimension novelty seeking.
While a set of subcortical and cortical regions including the PACC is commonly involved in reward and personal relevance, other regions like the bilateral anterior insula were recruited specifically during personal relevance. Based on our correlation between novelty seeking and signal changes in both regions during personal relevance, we assume that the neuronal response to personally relevant stimuli is dependent on the personality trait novelty seeking.
Increasing evidence about the central nervous representation of pain in the brain suggests that the operculo-insular cortex is a crucial part of the pain matrix. The pain-specificity of a brain region may be tested by administering nociceptive stimuli while controlling for unspecific activations by administering non-nociceptive stimuli. We applied this paradigm to nasal chemosensation, delivering trigeminal or olfactory stimuli, to verify the pain-specificity of the operculo-insular cortex. In detail, brain activations due to intranasal stimulation induced by non-nociceptive olfactory stimuli of hydrogen sulfide (5 ppm) or vanillin (0.8 ppm) were used to mask brain activations due to somatosensory, clearly nociceptive trigeminal stimulations with gaseous carbon dioxide (75% v/v). Functional magnetic resonance (fMRI) images were recorded from 12 healthy volunteers in a 3T head scanner during stimulus administration using an event-related design. We found that significantly more activations following nociceptive than non-nociceptive stimuli were localized bilaterally in two restricted clusters in the brain containing the primary and secondary somatosensory areas and the insular cortices consistent with the operculo-insular cortex. However, these activations completely disappeared when eliminating activations associated with the administration of olfactory stimuli, which were small but measurable. While the present experiments verify that the operculo-insular cortex plays a role in the processing of nociceptive input, they also show that it is not a pain-exclusive brain region and allow, in the experimental context, for the interpretation that the operculo-insular cortex splay a major role in the detection of and responding to salient events, whether or not these events are nociceptive or painful.
Processing stimuli in one sensory modality is known to result in suppression of other sensory-specific cortices. Additionally, behavioral experiments suggest that the primary consequence of paying attention to a specific sensory modality is poorer task performance in the unattended sensory modality. This study was designed to determine how focusing attention on the auditory or visual modality impacts neural activity in cortical regions responsible for processing stimuli in the unattended modality.
Functional MRI data were collected in 15 participants who completed a cued detection paradigm. This task allowed us to assess the effects of modality-specific attention both during the presence and the absence of targets in the attended modality.
The results of this experiment demonstrate that attention to a single sensory modality can result in decreased activity in cortical regions that process information from an unattended sensory modality (cross-modal deactivations). The effects of attention are likely additive with stimulus-driven effects with the largest deactivations being observed during modality-specific selective attention, in the presence of a stimulus in that modality.
Modality-specific selective attention results in behavioral decrements in unattended sensory modalities. The imaging results presented here provide a neural signature (cross-modal deactivation) for modality-specific selective attention.
Math can be difficult, and for those with high levels of mathematics-anxiety (HMAs), math is associated with tension, apprehension, and fear. But what underlies the feelings of dread effected by math anxiety? Are HMAs’ feelings about math merely psychological epiphenomena, or is their anxiety grounded in simulation of a concrete, visceral sensation – such as pain – about which they have every right to feel anxious? We show that, when anticipating an upcoming math-task, the higher one’s math anxiety, the more one increases activity in regions associated with visceral threat detection, and often the experience of pain itself (bilateral dorso-posterior insula). Interestingly, this relation was not seen during math performance, suggesting that it is not that math itself hurts; rather, the anticipation of math is painful. Our data suggest that pain network activation underlies the intuition that simply anticipating a dreaded event can feel painful. These results may also provide a potential neural mechanism to explain why HMAs tend to avoid math and math-related situations, which in turn can bias HMAs away from taking math classes or even entire math-related career paths.
We have performed a noninvasive bilateral optical imaging study of the hemodynamic evoked response to unilateral finger opposition task, finger tactile, and electrical median nerve stimulation in the human sensorimotor cortex. This optical study shows the hemoglobin-evoked response to voluntary and nonvoluntary stimuli. We performed measurements on 10 healthy volunteers using block paradigms for motor, sensory, and electrical stimulations of the right and left hands separately. We analyzed the spatial/temporal features and the amplitude of the optical signal induced by cerebral activation during these three paradigms. We consistently found an increase (decrease) in the cerebral concentration of oxy-hemoglobin (deoxy-hemoglobin) at the cortical side contralateral to the stimulated side. We observed an optical response to activation that was larger in size and amplitude during voluntary motor task compared to the other two stimulations. The ipsilateral response was consistently smaller than the contralateral response, and even reversed (i.e., a decrease in oxy-hemoglobin, and an increase in deoxy-hemoglobin) in the case of the electrical stimulation. We observed a systemic contribution to the optical signal from the increase in the heart rate increase during stimulation, and we made a first attempt to subtract it from the evoked hemoglobin signal. Our findings based on optical imaging are in agreement with results in the literature obtained with positron emission tomography and functional magnetic resonance imaging.
Diffuse optical imaging; Hemodynamic evoked response; Sensorimotor cortex
Pain has a distinct sensory and affective (i.e., unpleasantness) component. BreEStim, during which electrical stimulation is delivered during voluntary breathing, has been shown to selectively reduce the affective component of post-amputation phantom pain. The objective was to examine whether BreEStim increases pain threshold such that subjects could have improved tolerance of sensation of painful stimuli.
Eleven pain-free healthy subjects (7 males, 4 females) participated in the study. All subjects received BreEStim (100 stimuli) and conventional electrical stimulation (EStim, 100 stimuli) to two acupuncture points (Neiguan and Weiguan) of the dominant hand in a random order. The two different treatments were provided at least three days apart. Painful, but tolerable electrical stimuli were delivered randomly during EStim, but were triggered by effortful inhalation during BreEStim. Measurements of tactile sensation threshold, electrical sensation and electrical pain thresholds, thermal (cold sensation, warm sensation, cold pain and heat pain) thresholds were recorded from the thenar eminence of both hands. These measurements were taken pre-intervention and 10−min post-intervention.
There was no difference in the pre-intervention baseline measurement of all thresholds between BreEStim and EStim. The electrical pain threshold significantly increased after BreEStim (27.5±6.7% for the dominant hand and 28.5±10.8% for the non-dominant hand, respectively). The electrical pain threshold significantly decreased after EStim (9.1±2.8% for the dominant hand and 10.2±4.6% for the non–dominant hand, respectively) (F[1, 10] = 30.992, p = .00024). There was no statistically significant change in other thresholds after BreEStim and EStim. The intensity of electrical stimuli was progressively increased, but no difference was found between BreEStim and EStim.
Voluntary breathing controlled electrical stimulation selectively increases electrical pain threshold, while conventional electrical stimulation selectively decreases electrical pain threshold. This may translate into improved pain control.
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.
Chronic pain is mainly a result of two processes: peripheral and central sensitization, which can result in neuroplastic changes. Previous psychophysical studies suggested a decrease of the so-called pain-inhibiting-pain effect (DNIC) in chronic pain patients. We aimed to study the DNIC effect on the neuronal level using magnetoencephalography and electroencephalography in 12 patients suffering from advanced unilateral knee osteoarthritis (OA). DNIC was induced in patients by provoking the typical OA pain by a slightly hyperextended joint position, while they received short electrical pain stimuli. Although the patients did not report a reduction of electrical pain perception, the cingulate gyrus showed a decrease of activation during provoked OA pain, while activity in the secondary somatosensory cortex did not change. Based on much stronger DNIC induction at comparable intensities of an acute counterirritant pain in healthy subjects this result suggests a deficit of DNIC in OA patients. We suggest that the strength of DNIC is subject to neuronal plasticity of descending inhibitory pain systems and diminishes during the development of a chronic pain condition.
counterirritation; DNIC; osteoarthritis; chronic pain; EEG; MEG
Human experimental pain models are essential in understanding the pain mechanisms and appear to be ideally suited to test analgesic compounds. The challenge that confronts both the clinician and the scientist is to match specific treatments to different pain-generating mechanisms and hence reach a pain treatment tailored to each individual patient. Experimental pain models offer the possibility to explore the pain system under controlled settings. Standardized stimuli of different modalities (i.e., mechanical, thermal, electrical, or chemical) can be applied to the skin, muscles, and viscera for a differentiated and comprehensive assessment of various pain pathways and mechanisms. Using a multimodel-multistructure testing, the nociception arising from different body structures can be explored and modulation of specific biomarkers by new and existing analgesic drugs can be profiled. The value of human experimental pain models is to link animal and clinical pain studies, providing new possibilities for designing successful clinical trials. Spontaneous pain, the main compliant of the neuropathic patients, but currently there is no human model available that would mimic chronic pain. Therefore, current human pain models cannot replace patient studies for studying efficacy of analgesic compounds, although being helpful for proof-of-concept studies and dose finding.
Analgesics; multimodel-multitissue; pain models; proof-of-concept; spontaneous pain
Although individual differences in fear and anxiety modulate the pain response and may even cause more suffering than the initiating physical stimulus, little is known about the neural systems mediating this relationship. The present study provided the first examination of the neural correlates of individual differences in the tendency to (1) feel anxious about the potentially negative implications of physical sensations, as measured by the anxiety sensitivity index (ASI), and (2) fear various types of physical pain, as indexed by the fear of pain questionnaire (FPQ). In separate sessions, participants completed these questionnaires and experienced alternating blocks of noxious thermal stimulation (45–50 °C) and neutral thermal stimulation (38 °C) during the collection of whole-brain fMRI data. Regression analyses demonstrated that during the experience of pain, ASI scores predicted activation of a medial prefrontal region associated with self-focused attention, whereas FPQ scores predicted activation of a ventral lateral frontal region associated with response regulation and anterior and posterior cingulate regions associated with monitoring and evaluation of affective responses. These functional relationships cannot be wholly explained by generalized anxiety (indexed by STAI-T scores), which did not significantly correlate with activation of any regions. The present findings may help clarify both the impact of individual differences in emotion on the neural correlates of pain, and the roles in anxiety, fear, and pain processing played by medial and orbitofrontal systems.
Anxiety sensitivity; Fear of pain; Pain; Medial prefrontal cortex; Orbitofrontal cortex; Anxiety; Brain imaging; Fear; Pain behavior
Intense stress and fear have long been known to give rise to a suppression of pain termed “stress-induced analgesia,” mediated by brainstem pain-modulating circuitry, including pain-inhibiting neurons of the rostral ventromedial medulla. However, stress does not invariably suppress pain, and indeed, may exacerbate it. Although there is a growing support for the idea of “stress-induced hyperalgesia,” the neurobiological basis for this effect remains almost entirely unknown. Using simultaneous single-cell recording and functional analysis, we show here that stimulation of the dorsomedial nucleus of the hypothalamus, known to be a critical component of central mechanisms mediating neuroendocrine, cardiovascular and thermogenic responses to mild or “emotional” stressors such as air puff, also triggers thermal hyperalgesia by recruiting pain-facilitating neurons, “ON-cells”, in the rostral ventromedial medulla.
Activity of identified RVM ON-cells, OFF-cells and NEUTRAL cells, nociceptive withdrawal thresholds, rectal temperature, and heart rate were recorded in lightly anesthetized rats. In addition to expected increases in body temperature and heart rate, disinhibition of the DMH induced a robust activation of ON-cells, suppression of OFF-cell firing and behavioral hyperalgesia. Blocking ON-cell activation prevented hyperalgesia, but did not interfere with DMH-induced thermogenesis or tachycardia, pointing to differentiation of neural substrates for autonomic and nociceptive modulation within the RVM.
These data demonstrate top-down activation of brainstem pain-facilitating neurons, and suggest a possible neural circuit for stress-induced hyperalgesia.
hyperalgesia; pain-modulation; rostral ventromedial medulla; brainstem; ON cells; OFF cells
Although it has been accepted that depression and pain are common comorbidities, their interaction is not fully understood. The present study was aimed to investigate the effects of depression on both evoked pain behavior (thermal induced nociception and hyperalgesia) and spontaneous pain behavior (formalin pain) in rats. An unpredictable chronic mild stress (UCMS) paradigm was employed to develop a classical depression. The emotional behaviors were assessed by sucrose preference test, open field test, and elevated plus-maze test. The results showed that the depressed rats always exhibited stronger tolerance to noxious thermal stimulation under both normal and complete Freund’s adjuvant (CFA)-induced chronic pain conditions, when compared to non-depressed animals. Interestingly, the spontaneous nociceptive behaviors induced by formalin injection were significantly enhanced in rats exposed to UCMS in comparison to those without UCMS. Systemic administration of antidepressant fluoxetine significantly restored the nociceptive behaviors to normal level in depressed animals. An additional finding was that the inflammatory rats tended to display depressive-like behaviors without being exposed to UCMS. These results demonstrated that depression can have different effects on stimulus-evoked pain and spontaneous pain, with alleviation in the former while aggravation in the latter.
Perspective: The present study provides evidence that depression can have divergent effects on stimulus-evoked and spontaneous pain by confirming that rats exposed to chronic mild stress tend to exhibit decreased pain sensitivity to experimental stimuli but increased intensity of ongoing pain. This may contribute to further understanding of the perplexing relationship between clinical depression and chronic pain.
depression; fluoxetine; pain; thermal hyperalgesia; unpredictable chronic mild stress
Uncontrollable aversive events are associated with feelings of helplessness and cortisol elevation and are suitable as a model of depression. The high comorbidity of depression and pain symptoms and the importance of controllability in both conditions are clinically well-known but empirical studies are scarce. The study investigated the relationship of pain experience, helplessness, and cortisol secretion after controllable vs. uncontrollable electric skin stimulation in healthy male individuals.
Sixty-four male volunteers were randomly assigned to receive 30 controllable (self-administered) or uncontrollable (experimenter-administered) painful electric skin stimuli. Perceived pain intensity (PPI), subjective helplessness ratings, and salivary cortisol concentrations were assessed. PPI was assessed after stress exposure. For salivary cortisol concentrations and subjective helplessness ratings, areas under the response curve (AUC) were calculated.
After uncontrollable vs. controllable stress exposure significantly higher PPI ratings (P = 0.023), higher subjective helplessness AUC (P < 0.0005) and higher salivary cortisol AUC (P = 0.004, t-tests) were found. Correlation analyses revealed a significant correlation between subjective helplessness AUC and PPI (r = 0.500, P < 0.0005), subjective helplessness AUC and salivary cortisol AUC (r = 0.304, P = 0.015) and between PPI and salivary cortisol AUC (r = 0.298, P = 0.017).
The results confirm the impact of uncontrollability on stress responses in humans; the relationship of PPI with subjective helplessness and salivary cortisol suggests a cognitive-affective sensitization of pain perception, particularly under uncontrollable conditions.