Pain and related suffering reduce attention toward others.

BACKGROUND: It has been proposed that the expression of pain-related suffering may lead to an enhanced focus on oneself and reduced attention toward the external world. This study aimed at investigating whether experimentally induced painrelated suffering may lead persons to withdraw into themselves, causing a reduced focus on external stimuli as reflected by impaired performance in a facial recognition task and heightened perception of internal stimuli measured by interoceptive awareness. METHODS: Thirty-two participants had to recognize different emotional facial expressions (neutral, sad, angry, happy), or neutral geometrical figures under conditions of no pain, low, and high prolonged pain intensities. Interoceptive accuracy was measured using a heartbeat-detection task prior to and following the pain protocol. RESULTS: Males but not females were slower to recognize facial expressions under the condition of high painful stimulation compared to the condition of no pain. In both, male and female participants, the difficulty in recognizing another person's emotions from a facial expression was directly related to the level of suffering and unpleasantness experienced during pain. Interoceptive accuracy was higher after the pain experiment. However, neither the initial interoceptive accuracy nor the change were significantly related to the pain ratings. CONCLUSIONS: Our results suggest that long-lasting and intense painful stimuli, which induce suffering, lead to attentional shifts leading to withdrawal from others. These findings contribute to a better understanding of the social dynamics of pain and pain-related suffering.

Stress-induced hyperalgesia instead of analgesia in patients with chronic musculoskeletal pain.

Many individuals with chronic musculoskeletal pain (CMP) show impairments in their pain-modulatory capacity. Although stress plays an important role in chronic pain, it is not known if stress-induced analgesia (SIA) is affected in patients with CMP. We investigated SIA in 22 patients with CMP and 18 pain-free participants. Pain thresholds, pain tolerance and suprathreshold pain ratings were examined before and after a cognitive stressor that typically induces pain reduction (SIA). Whereas the controls displayed a significant increase in pain threshold in response to the stressor, the patients with CMP showed no analgesia. In addition, increased pain intensity ratings after the stressor indicated hyperalgesia (SIH) in the patients with CMP compared to controls. An exploratory analysis showed no significant association of SIA or SIH with spatial pain extent. We did not observe significant changes in pain tolerance or pain unpleasantness ratings after the stressor in patients with CMP or controls. Our data suggest that altered stress-induced pain modulation is an important mechanism involved in CMP. Future studies need to clarify the psychobiological mechanisms of these stress-induced alterations in pain processing and determine the role of contributing factors such as early childhood trauma, catastrophizing, comorbidity with mental disorders and genetic predisposition.

Psychological, cognitive factors and contextual influences in pain and pain-related suffering as revealed by a combined qualitative and quantitative assessment approach.

Previous psychophysiological research suggests that pain measurement needs to go beyond the assessment of Pain Intensity and Unpleasantness by adding the evaluation of Pain-Related Suffering. Based on this three-dimensional approach, we attempted to elucidate who is more likely to suffer by identifying reasons that may lead individuals to report Pain and Pain-Related Suffering more than others. A sample of 24 healthy participants (age range 18-33) underwent four different sessions involving the evaluation of experimentally induced phasic and tonic pain. We applied two decision tree models to identify variables (selected from psychological questionnaires regarding pain and descriptors from post-session interviews) that provided a qualitative characterization of the degrees of Pain Intensity, Unpleasantness and Suffering and assessed the respective impact of contextual influences. The overall classification accuracy of the decision trees was 75% for Intensity, 77% for Unpleasantness and 78% for Pain-Related Suffering. The reporting of suffering was predominantly associated with fear of pain and active cognitive coping strategies, pain intensity with bodily competence conveying strength and resistance and unpleasantness with the degree of fear of pain and catastrophizing. These results indicate that the appraisal of the three pain dimensions was largely determined by stable psychological constructs. They also suggest that individuals manifesting higher active coping strategies may suffer less despite enhanced pain and those who fear pain may suffer even under low pain. The second decision tree model revealed that suffering did not depend on pain alone, but that the complex rating-related decision making can be shifted by situational factors (context, emotional and cognitive). The impact of coping and fear of pain on individual Pain-Related Suffering may highlight the importance of improving cognitive coping strategies in clinical settings.

Probing the endocannabinoid system in healthy volunteers: Cannabidiol alters fronto-striatal resting-state connectivity.

Tetrahydrocannabinol (THC) and Cannabidiol (CBD) are two substances from cannabis sativa that have beenimplicated in the treatment of mental and neurological disorders. We concentrated on a previously validated neuroimaging phenotype, fronto-striatal connectivity across different striatal seeds, because of this loop's relevance to executive functioning, decision making, salience generation and motivation and its link to various neuropsychiatric conditions. Therefore, we studied the effect of THC and CBD on fronto-striatal circuitry by a seed-voxel connectivity approach using seeds from the caudate and the putamen. We conducted a cross-over pharmaco-fMRI study in 16 healthy male volunteers with placebo, 10 mg oral THC and 600 mg oral CBD. Resting state was measured in a 3 T scanner. CBD lead to an increase of fronto-striatal connectivity in comparison to placebo. In contrast to our expectation that THC and CBD show opposing effects, THC versus placebo did not show any significant effects, probably due to insufficient concentration of THC during scanning. The effect of CBD on enhancing fronto-striatal connectivity is of interest because it might be a neural correlate of its anti-psychotic effect in patients.

Impact of controllability on pain and suffering.

INTRODUCTION: Chronic pain and pain-related suffering are major health problems. The lack of controllability of experienced pain seems to greatly contribute to the extent of suffering. This study examined how controllability affects the perception of pain and pain-related suffering, and the modulation of this effect by beliefs and emotions such as locus of control of reinforcement, pain catastrophizing, and fear of pain. METHODS: Twenty-six healthy subjects received painful electric stimulation in both controllable and uncontrollable conditions. Visual analogue scales and the "Pictorial Representation of Illness and Self Measure" were used to assess pain intensity, unpleasantness, pain-related suffering, and the level of perceived control. We also investigated nonverbal indicators of pain and suffering such as heart rate, skin conductance, and corrugator electromyogram. RESULTS: Controllability selectively reduced the experience of pain-related suffering, but did not affect pain intensity or pain unpleasantness. This effect was modulated by chance locus of control but was unrelated to fear of pain or catastrophizing. Physiological responses were not affected by controllability. In a second sample of 25 participants, we varied the instruction. The effect of controllability on pain-related suffering was only present when instructions focused on the person being able to stop the pain. DISCUSSION: Our data suggest that the additional measure of pain-related suffering may be important in the assessment of pain and may be more susceptible to the effects of perceived control than pain intensity and unpleasantness. We also show that this effect depends on personal involvement.

Placebo effects of a sham opioid solution: a randomized controlled study in patients with chronic low back pain.

This study tested the experimental placebo effect in a group of chronic pain patients. Forty-eight patients having chronic back pain participated in a randomized clinical trial that tested the efficacy of a sham opioid solution (NaCl) compared with an alleged neutral, completely inactive solution (NaCl). We shaped the placebo effect by 2 interventions: verbal instruction and conditioning. The patients were either told that the "solution reduces pain and improves physical capacity" or the "solution is neutral, a placebo." Half of each group was additionally conditioned (coupling solution with reduced experimental pain), yielding 4 subgroups with 12 participants each. Outcome measures were as follows: the patients' clinical back pain ratings and acute pain ratings (both examined by numerical rating scale 0-10) and self-rated functional capacity (0%-100%; time required for the exercise). Expected pain relief before and after solution intake was also assessed. The inactive solution (NaCl), when presented as an effective treatment (sham "opioid" solution), induced placebo analgesia as evident in lower ratings of the patients' clinical back pain (F(3.12,144.21) = 25.05, P < 0.001), acute pain ratings (F(1.99,87.40) = 18.12, P < 0.01), and time needed to complete a series of daily activities exercises (F(1,44) = 8.51, P < 0.01) as well as increased functional capacity (F(1,44.00) = 19.42, P < 0.001). The 2 manipulations (instruction and conditioning) changed pain expectations, and they were maintained in both sham opioid groups. The results suggest that it may be clinically useful to explicitly integrate placebo analgesia responses into pain management.

The role of cognitive reappraisal in placebo analgesia: an fMRI study.

Placebo analgesia (PA) depends crucially on the prefrontal cortex (PFC), which is assumed to be responsible for initiating the analgesic response. Surprisingly little research has focused on the psychological mechanisms mediated by the PFC and underlying PA. One increasingly accepted theory is that cognitive reappraisal-the reinterpretation of the meaning of adverse events-plays an important role, but no study has yet addressed the possible functional relationship with PA. We studied the influence of individual differences in reappraisal ability on PA and its prefrontal mediation. Participants completed a cognitive reappraisal ability task, which compared negative affect evoked by pictures in a reappraise versus a control condition. In a subsequent fMRI session, PA was induced using thermal noxious stimuli and an inert skin cream. We found a region in the left dorsolateral PFC, which showed a positive correlation between placebo-induced activation and (i) the reduction in participants' pain intensity ratings; and (ii) cognitive reappraisal ability scores. Moreover, this region showed increased placebo-induced functional connectivity with the periaqueductal grey, indicating its involvement in descending nociceptive control. These initial findings thus suggest that cognitive reappraisal mechanisms mediated by the dorsolateral PFC may play a role in initiating pain inhibition in PA.

Impact of patient information leaflets on pain medication intake behavior: a pilot study.

INTRODUCTION: Patient information leaflets on pain medication primarily list side effects while positive effects and action mechanisms remain underrepresented. Nocebo research has shown that negative instructions can lower analgesic effects. OBJECTIVES: Research on information leaflets and their influence on mood, memory of side effects, and intake behavior of healthy participants is needed. METHODS: To determine the ratio of positive to negative phrases, 18 information leaflets of common, over-the-market analgesics were examined of which 1 was selected. In a randomized, controlled study design, 18 healthy participants read this leaflet while 18 control group participants read a matched, neutral leaflet of an electrical device. Collected data concerned the recall of positive and negative contents, mood, anxiety, and the willingness to buy and take the drug. RESULTS: All examined leaflets listed significantly more side effects than positive effects (t17 = 5.82, P < 0.01). After reading the analgesic leaflet, participants showed a trend towards more negative mood (F1,34 = 3.78, P = 0.06, ηp2 = 0.1), a lower intention to buy [χ2 (1, n = 36) = 12.5, P < 0.01], a higher unwillingness to take the medication [χ2 (1, n = 36) = 7.2, P < 0.01], and even a greater recall for side effects than positive effects (t17 = 7.47, P < 0.01). CONCLUSION: Reading the patient information leaflets can increase fear and lower the intention to buy and the willingness to take a pain medication.

Controllability and hippocampal activation during pain expectation in fibromyalgia syndrome.

To examine the role of perceived control in pain perception, fibromyalgia patients and healthy controls participated in a reaction time experiment under different conditions of pain controllability. No significant differences between groups were found in pain intensity and unpleasantness ratings. However, during the expectation of uncontrollable pain, patients compared to controls showed higher hippocampal activation. In addition, hippocampal activity during the pain expectation period predicted activation of the posterior cingulate cortex (PCC), precuneus and hippocampus during pain stimulation in fibromyalgia patients. The increased activation of the hippocampus during pain expectation and subsequent activation of the PCC/precuneus during the lack of control phase points towards an influence of pain perception through heightening of alertness and anxiety responses to pain in fibromyalgia patients.

Contextual modulation of pain in masochists: involvement of the parietal operculum and insula.

Pain can be modulated by contextual stimuli, such as emotions, social factors, or specific bodily perceptions. We presented painful laser stimuli together with body-related masochistic visual stimuli to persons with and without preferred masochistic sexual behavior and used neutral, positive, and negative pictures with and without painful stimuli as control. Masochists reported substantially reduced pain intensity and unpleasantness in the masochistic context compared with controls but had unaltered pain perception in the other conditions. Functional magnetic resonance imaging revealed that masochists activated brain areas involved in sensory-discriminative processing rather than affective pain processing when they received painful stimuli on a masochistic background. The masochists compared with the controls displayed attenuated functional connectivity of the parietal operculum with the left and right insulae, the central operculum, and the supramarginal gyrus. Masochists additionally showed negative correlations between the duration of interest in masochistic activities and activation of areas involved in motor activity and affective processing. We propose that the parietal operculum serves as an important relay station that attenuates the affective-motivational aspects of pain in masochists. This novel mechanism of pain modulation might be related to multisensory integration and has important implications for the assessment and treatment of pain.

Illusion-related brain activations: a new virtual reality mirror box system for use during functional magnetic resonance imaging.

Extended viewing of movements of one's intact limb in a mirror as well as motor imagery have been shown to decrease pain in persons with phantom limb pain or complex regional pain syndrome and to increase the movement ability in hemiparesis following stroke. In addition, mirrored movements differentially activate sensorimotor cortex in amputees with and without phantom limb pain. However, using a so-called mirror box has technical limitations, some of which can be overcome by virtual reality applications. We developed a virtual reality mirror box application and evaluated its comparability to a classical mirror box setup. We applied both paradigms to 20 healthy controls and analyzed vividness and authenticity of the illusion as well as brain activation patterns. In both conditions, subjects reported similar intensities for the sensation that movements of the virtual left hand felt as if they were executed by their own left hand. We found activation in the primary sensorimotor cortex contralateral to the actual movement, with stronger activation for the virtual reality 'mirror box' compared to the classical mirror box condition, as well as activation in the primary sensorimotor cortex contralateral to the mirrored/virtual movement. We conclude that a virtual reality application of the mirror box is viable and that it might be useful for future research.

The importance of synchrony and temporal order of visual and tactile input for illusory limb ownership experiences - an FMRI study applying virtual reality.

In the so-called rubber hand illusion, synchronous visuotactile stimulation of a visible rubber hand together with one's own hidden hand elicits ownership experiences for the artificial limb. Recently, advanced virtual reality setups were developed to induce a virtual hand illusion (VHI). Here, we present functional imaging data from a sample of 25 healthy participants using a new device to induce the VHI in the environment of a magnetic resonance imaging (MRI) system. In order to evaluate the neuronal robustness of the illusion, we varied the degree of synchrony between visual and tactile events in five steps: in two conditions, the tactile stimulation was applied prior to visual stimulation (asynchrony of -300 ms or -600 ms), whereas in another two conditions, the tactile stimulation was applied after visual stimulation (asynchrony of +300 ms or +600 ms). In the fifth condition, tactile and visual stimulation was applied synchronously. On a subjective level, the VHI was successfully induced by synchronous visuotactile stimulation. Asynchronies between visual and tactile input of ±300 ms did not significantly diminish the vividness of illusion, whereas asynchronies of ±600 ms did. The temporal order of visual and tactile stimulation had no effect on VHI vividness. Conjunction analyses of functional MRI data across all conditions revealed significant activation in bilateral ventral premotor cortex (PMv). Further characteristic activation patterns included bilateral activity in the motion-sensitive medial superior temporal area as well as in the bilateral Rolandic operculum, suggesting their involvement in the processing of bodily awareness through the integration of visual and tactile events. A comparison of the VHI-inducing conditions with asynchronous control conditions of ±600 ms yielded significant PMv activity only contralateral to the stimulation site. These results underline the temporal limits of the induction of limb ownership related to multisensory body-related input.

An augmented reality home-training system based on the mirror training and imagery approach.

Mirror training and movement imagery have been demonstrated to be effective in treating several clinical conditions, such as phantom limb pain, stroke-induced hemiparesis, and complex regional pain syndrome. This article presents an augmented reality home-training system based on the mirror and imagery treatment approaches for hand training. A head-mounted display equipped with cameras captures one hand held in front of the body, mirrors this hand, and displays it in real time in a set of four different training tasks: (1) flexing fingers in a predefined sequence, (2) moving the hand into a posture fitting into a silhouette template, (3) driving a "Snake" video game with the index finger, and (4) grasping and moving a virtual ball. The system records task performance and transfers these data to a central server via the Internet, allowing monitoring of training progress. We evaluated the system by having 7 healthy participants train with it over the course of ten sessions of 15-min duration. No technical problems emerged during this time. Performance indicators showed that the system achieves a good balance between relatively easy and more challenging tasks and that participants improved significantly over the training sessions. This suggests that the system is well suited to maintain motivation in patients, especially when it is used for a prolonged period of time.

Cortico-subcortical activation patterns for itch and pain imagery.

The imagery of itch and pain evokes emotional responses and covert motor responses (scratching to itch and withdrawal to pain). This suggests some similarity in cerebral mechanisms. However, itch is more socially contagious than pain, as evidenced by the fact that scratching behaviors can be easily initiated by watching itch-inducing situations, whereas withdrawal is less easily initiated by watching painful situations. Thus, we assumed that the cerebral mechanisms of itch imagery partly differ from those of pain imagery in particular with respect to motor regions. We addressed this issue in 18 healthy subjects using functional magnetic resonance imaging. The subjects were instructed to imagine itch and pain sensations in their own bodies while viewing pictures depicting stimuli associated with these sensations. Itch and pain imagery activated the anterior insular cortex (aIC) and motor-related regions such as supplementary motor area, basal ganglia, thalamus, and cerebellum. Activity in these regions was not significantly different between itch and pain imagery. However, functional connectivity between motor-related regions and the aIC showed marked differences between itch and pain imagery. Connectivity with the aIC was stronger in the primary motor and premotor cortices during pain imagery and stronger in the globus pallidus during itch imagery. These findings indicate that brain regions associated with imagery of itch are the same as those involved in imagery of pain, but their functional networks differ. These differences in brain networks may explain why motor responses to itch are more socially contagious than those related to pain.

Deficient modulation of pain by a positive emotional context in fibromyalgia patients.

This study aimed to investigate the modulating effects of emotional context on pain perception in 16 patients with fibromyalgia syndrome (FMS) and 16 healthy control (HC) subjects. An infrared laser was used to apply individually adapted painful stimuli to the dorsum of the left hand. The emotional background of the painful stimuli was modulated by concurrent presentations of negative, neutral, and positive picture stimuli selected from the International Affective Picture System. As control conditions, painful stimuli and the pictures were also presented by themselves. During each of the 5 laser-picture trials, subjects received 10 painful stimuli and were asked to rate the average intensity and unpleasantness of the experienced pain. Functional magnetic resonance images were obtained, using a T2(∗) sensitive echo planar sequence. HC subjects showed a linear increase in pain intensity and unpleasantness ratings when painful stimuli were presented during positive, neutral, and negative pictures. In contrast, FMS patients showed a quadratic trend for pain intensity ratings indicating a lack of pain reduction by the positive pictures. In addition, the FMS patients showed less activation in secondary somatosensory cortex, insula, orbitofrontal cortex, and anterior cingulate cortex during the positive picture pain trials. Our results suggest that fibromyalgia patients are less efficient in modulating pain by positive affect and may benefit less from appetitive events than healthy control subjects.

An MR-compatible device for automated and safe application of laser stimuli in experiments employing nociceptive stimulation.

In this paper the establishment of an automatic laser application device that reproducibly delivers laser stimuli in a safe, controlled, and reliable manner is presented. Nociceptive stimulation is widely used in functional magnetic resonance imaging (fMRI) experiments and a number of different methods are employed. One major advantage of laser stimulation as a method to administer painful stimuli is that it selectively activates nociceptors. To avoid damage to the subject's skin, which might occur if the same skin area were stimulated too often, the laser focal spot needs to be repositioned after each stimulus. Here, we describe the design of the mechanical set-up, the functionality, the computation of laser stimulus intensity, the materials used, the monitoring system, and the interface to the control software. Additionally, MR-compatibility and functionality of the device were evaluated and assessed in a 3T MR scanner. Finally, the reliability and validity of the device were tested and demonstrated. It permits easy and investigator-independent use of laser stimulation in the MR scanner.

Specific and nonspecific effects of transcranial magnetic stimulation on picture-word verification.

Repetitive transcranial magnetic stimulation (rTMS) can temporarily impair or improve performance, including language processing. It remains unclear, however, (i) which scalp sites are most appropriate to achieve the desired effects and (ii) which experimental setups produce facilitation or inhibition of language functions. We assessed the effects of TMS at different stimulation sites on picture-word verification in healthy volunteers. Twenty healthy volunteers with left language lateralization, as determined by functional transcranial Dopplersonography, performed picture-word verification prior to and after rTMS (1 Hz for 600 s at 110% of subjects' resting motor thresholds). Stimulation sites were the classical language areas (Broca's and Wernicke's), their homolog brain regions of the right hemisphere, and the occipital cortex. Additionally, sham stimulation over Broca's area was applied in a subsample of 11 subjects. As a control task, 10 volunteers performed a colour-tone matching task under the same experimental conditions. There was a general nonspecific arousal effect for both verum and sham TMS for both the picture-word verification and for the control task. However, superimposed there were opposite effects on picture-word verification for stimulation of Wernicke's area and Broca's area, namely a relative inhibition in the case of Wernicke's area and a relative facilitation in the case of Broca's area. These results demonstrate that low frequency rTMS has both general arousing effects and domain-specific effects.