[Placebo effects in pain therapy]. / Placeboeffekte in der Schmerztherapie.

In the past few decades, research on pain and placebo analgesia has gained importance both scientifically and clinically. In this article, the current findings and focus of research as well as the significance of placebo research for assessing the effectiveness of pain medication are illustrated. The underlying mechanisms of placebo analgesia not only have implications for theoretical models but also offer clinically relevant guidelines for everyday interventions in pain treatment. However, many placebo phenomena are not fully understood and have to be investigated further in order to exploit the full potential of placebo effects. Interindividual differences and their inclusion in treatment will play a major role in this aspect.

The differential effect of trigeminal vs. peripheral pain stimulation on visual processing and memory encoding is influenced by pain-related fear.

Compared to peripheral pain, trigeminal pain elicits higher levels of fear, which is assumed to enhance the interruptive effects of pain on concomitant cognitive processes. In this fMRI study we examined the behavioral and neural effects of trigeminal (forehead) and peripheral (hand) pain on visual processing and memory encoding. Cerebral activity was measured in 23 healthy subjects performing a visual categorization task that was immediately followed by a surprise recognition task. During the categorization task subjects received concomitant noxious electrical stimulation on the forehead or hand. Our data show that fear ratings were significantly higher for trigeminal pain. Categorization and recognition performance did not differ between pictures that were presented with trigeminal and peripheral pain. However, object categorization in the presence of trigeminal pain was associated with stronger activity in task-relevant visual areas (lateral occipital complex, LOC), memory encoding areas (hippocampus and parahippocampus) and areas implicated in emotional processing (amygdala) compared to peripheral pain. Further, individual differences in neural activation between the trigeminal and the peripheral condition were positively related to differences in fear ratings between both conditions. Functional connectivity between amygdala and LOC was increased during trigeminal compared to peripheral painful stimulation. Fear-driven compensatory resource activation seems to be enhanced for trigeminal stimuli, presumably due to their exceptional biological relevance.

[Imaging techniques and pain]. / Bildgebung und Schmerz.

Over the last 15 years, functional brain imaging techniques have provided critical insights into cortical, subcortical and even spinal mechanisms involved in pain perception and pain modulation in humans. The pivotal contribution of brain imaging studies conducted in Germany have thereby been internationally acknowledged. One of the key challenges for the next decade is to shift the focus from studies in healthy volunteers to different clinical populations suffering from chronic pain to characterize CNS mechanisms, as well as neurobiological predictors and resilience factors of pain chronification. Ultimately, the knowledge gained by this work may help identify individual or syndrome-specific CNS changes as biomarkers to make therapeutic decisions.

A new trigemino-nociceptive stimulation model for event-related fMRI.

Functional imaging of human trigemino-nociceptive processing provides meaningful insights into altered pain processing in head and face pain diseases. Although functional magnetic resonance imaging (fMRI) offers high temporal and spatial resolution, most studies available were done with radioligand-positron emission tomography, as fMRI requires non-magnetic stimulus equipment and fast on-off conditions. We developed a new approach for painful stimulation of the trigeminal nerve that can be implemented within an event-related design using fMRI and aimed to detect increased blood-oxygen-level-dependent (BOLD) signals as surrogate markers of trigeminal pain processing. Using an olfactometer, 20 healthy volunteers received intranasally standardized trigeminal nociceptive stimuli (ammonia gas) as well as olfactory (rose odour) and odorless control stimuli (air puffs). Imaging revealed robust BOLD responses to the trigeminal nociceptive stimulation in cortical and subcortical brain areas known to be involved in pain processing. Focusing on the trigeminal pain pathway, significant activations were observed bilaterally in brainstem areas at the trigeminal nerve entry zone, which are agreeable with the principal trigeminal nuclei. Furthermore, increased signal changes could be detected ipsilaterally at anatomical localization of the trigeminal ganglion and bilaterally in the rostral medulla, which probably represents the spinal trigeminal nuclei. However, brainstem areas involved in the endogenous pain control system that are close to this anatomical localization, such as raphe nuclei, have to be discussed. Our findings suggest that mapping trigeminal pain processing using fMRI with this non-invasive experimental design is feasible and capable of evoking specific activations in the trigeminal nociceptive system. This method will provide an ideal opportunity to study the trigeminal pain system in both health and pathological conditions such as idiopathic headache disorders.

[Mechanisms of endogenous pain modulation illustrated by placebo analgesia : functional imaging findings]. / Mechanismen der endogenen Schmerzmodulation am Beispiel der Placeboanalgesie : Befunde aus der funktionellen Bildgebung.

Nociceptive information processing and related pain perception are subject to substantial pro- and antinociceptive modulation. Research on the involved circuitry and the implemented mechanisms is a major focus of contemporary neuroscientific studies in the field of pain and will provide new insights into the prevention and treatment of chronic pain states. Placebo analgesia is a powerful clinical example of the cognitive modulation of pain perception. In placebo analgesia the administration of an inert substance will produce an analgesic effect if the subject is convinced that the substance is a potent analgesic. Recent neuroimaging studies have started to characterize the neural circuitry supporting the placebo analgesic effect. The converging evidence from these studies supports the concept that during placebo analgesia cingulo-frontal regions interact with subcortical structures involved in endogenous antinociception to produce the placebo-induced reduction in pain perception. The subject's report of reduced pain during placebo analgesia coincides with decreased activity in the classic pain areas. This indicates that the altered pain experience during placebo analgesia results from active inhibition of nociceptive input. This cognitively triggered endogenous modulation of pain involves, at least in part, the endogenous opioid system. Most recently, functional magnetic resonance imaging data of the human spinal cord revealed that these mechanisms involve the inhibition of nociceptive processing at the level of the dorsal horn of the spinal cord. Here we discuss recent advances in pain imaging research focusing on cognitively triggered endogenous pain control mechanisms and respective implications for future research strategies.

[Functional imaging in pain research]. / Funktionelle Bildgebung in der Schmerzforschung.

Functional brain imaging techniques allow to noninvasively visualize neuronal activity and associated metabolic consequences. In combination with elegant experimental paradigms in both healthy volunteers and, increasingly, in patients, functional brain imaging has led to a vast accumulation of knowledge concerning the CNS mechanisms involved in pain perception and pain modulation in humans. The so-called "pain matrix" represents a dynamic network of cortical and subcortical brain regions regularly activated by acute pain. This includes the somatosensory cortices (SI, SII), insular cortex, the cingulate cortex, prefrontal areas, amygdala, thalamus, brainstem and cerebellum. The subjective perception of pain is substantially influenced by context-dependent intracortical modulations and the descending pain modulatory system. This system includes cingulo-frontal brain areas together with specific brainstem nuclei that can exert control over nociceptive input at the level of the dorsal horn of the spinal cord. Recent studies support the view that a dysfunctional interaction between the ascending and descending pain system may contribute to the development or maintenance of chronic pain states. Here we provide an overview of the principles, applications, key findings and recent advances of functional imaging in pain research.

Changes in brain gray matter due to repetitive painful stimulation.

Using functional imaging, we recently investigated how repeated painful stimulation over several days is processed, perceived and modulated in the healthy human brain. Considering that activation-dependent brain plasticity in humans on a structural level has already been demonstrated in adults, we were interested in whether repeated painful stimulation may lead to structural changes of the brain. 14 healthy subjects were stimulated daily with a 20 min pain paradigm for 8 consecutive days, using structural MRI performed on days 1, 8, 22 and again after 1 year. Using voxel based morphometry, we are able to show that repeated painful stimulation resulted in a substantial increase of gray matter in pain transmitting areas, including mid-cingulate and somatosensory cortex. These changes are stimulation dependent, i.e. they recede after the regular nociceptive input is stopped. This data raises some interesting questions regarding structural plasticity of the brain concerning the experience of both acute and chronic pain.

Common neural systems for contact heat and laser pain stimulation reveal higher-level pain processing.

Our current knowledge of pain-related neuronal responses is largely based on experimental pain studies using contact heat or nontactile laser painful stimulation. Both stimuli evoke pain, yet they differ considerably in their physical and perceptual properties. In sensory cortex, cerebral responses to either stimulus should therefore substantially differ. However, given that both stimuli evoke pain, we hypothesized that at a certain subset of cortical regions the different physical properties of the stimuli become less important and are therefore activated by both stimuli. In contrast, regions with clearly dissociable activity may belong to "lower-level" pain processing mechanisms depending on the physical properties of the administered stimuli. We used functional magnetic resonance (fMRI) to intraindividually compare pain-related activation patterns between laser and contact heat stimulation using four different intensities of laser and contact heat stimuli. Common and dissociable neural responses were identified by correlating perceived pain intensities with blood oxygenation level dependent (BOLD) signal changes. Only neuronal responses to stimuli that were perceived as painful were analyzed. Pain-related BOLD signal increases independent of stimulus modality were detected in the anterior insula, anterior cingulate cortex, medial secondary somatosensory cortex, and the prefrontal cortex. These similarities are likely to reflect higher-level pain processing, which is largely independent of the single physical parameters that determine the painful nature of the stimuli.

The importance of placebo in headache research.

The best way to appreciate the efficacy of drug and behavioural therapy in the acute and prophylactic treatment of headache is to perform placebo-controlled randomized trials. In order to plan and conduct these studies in the most appropriate way, it is desirable to know which factors influence the placebo response. This paper reviews factors which influence the placebo response in clinical trials, such as expectation, blinding, route of application of drugs and age, gender and geographical distribution. Response rates of placebo in the treatment of acute headache episodes are higher than in headache prophylaxis. Invasive procedures such as injections have a higher placebo response compared with oral drugs. Variables known to influence the placebo response have to be taken into consideration to calculate properly the power of planned randomized trials.

Expectation influences the interruptive function of pain: Behavioural and neural findings.

BACKGROUND: Expectations can dramatically influence the perception of pain, as has been shown in placebo analgesia or nocebo hyperalgesia. Here, we investigated the role of expectation on the interruptive function of pain - the negative consequences of pain on cognitive task performance - in 42 healthy human subjects. METHODS: Verbal and written instructions were used to manipulate the subjects' expectation of how pain would influence their task performance in an established visual categorization task which was performed with or without concomitant painful thermal stimulation during 3T fMRI scanning. The categorization task was followed by a surprise recognition task. RESULTS: We observed a significant interaction between stimulation (pain/no pain) and expectancy (positive expectation/negative expectation): categorization accuracy decreased during painful stimulation in the negative expectancy group (N = 21), while no difference was observed in the positive expectancy group (N = 21). On the neural level, the positive expectancy group showed stronger activity in the anterior cingulate cortex (ACC) and hippocampus during painful stimulation compared to the negative group. Moreover, we detected a decrease in connectivity between ACC and fusiform gyrus during painful stimulation in the negative expectancy group, which was absent in the positive expectancy group. CONCLUSION: Taken together, our data show that expectation can modulate the effect of pain on task performance and that these expectancy effects on the interruptive function of pain are mediated by activity and connectivity changes in brain areas involved in pain processing and task performance. The possibility of changing cognitive task performance by verbal information in clinical population warrants further investigation. SIGNIFICANCE: We show that the interruptive function of pain on concurrent visual task performance is influenced by expectation. Positive expectation can abolish the detrimental effects of pain on cognition. These expectancy effects on the interruptive function of pain are mediated by changes in functional connectivity between rostral ACC, posterior fusiform cortex and the hippocampus.

Learning by experience? Visceral pain-related neural and behavioral responses in a classical conditioning paradigm.

BACKGROUND: Studies investigating mechanisms underlying nocebo responses in pain have mainly focused on negative expectations induced by verbal suggestions. Herein, we addressed neural and behavioral correlates of nocebo responses induced by classical conditioning in a visceral pain model. METHODS: In two independent studies, a total of 40 healthy volunteers underwent classical conditioning, consisting of repeated pairings of one visual cue (CSHigh ) with rectal distensions of high intensity, while a second cue (CSLow ) was always followed by low-intensity distensions. During subsequent test, only low-intensity distensions were delivered, preceded by either CSHigh or CSLow . Distension intensity ratings were assessed in both samples and functional magnetic resonance imaging data were available from one study (N=16). As a consequence of conditioning, we hypothesized CSHigh -cued distensions to be perceived as more intense and expected enhanced cue- and distension-related neural responses in regions encoding sensory and affective dimensions of pain and in structures associated with pain-related fear memory. KEY RESULTS: During test, distension intensity ratings did not differ depending on preceding cue. Greater distension-induced neural activation was observed in somatosensory, prefrontal, and cingulate cortices and caudate when preceded by CSHigh . Analysis of cue-related responses revealed strikingly similar activation patterns. CONCLUSIONS & INFERENCES: We report changes in neural activation patterns during anticipation and visceral stimulation induced by prior conditioning. In the absence of behavioral effects, markedly altered neural responses may indicate conditioning with visceral signals to induce hypervigilance rather than hyperalgesia, involving altered attention, reappraisal, and perceptual acuity as processes contributing to the pathophysiology of visceral pain.

Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network.

Placebo analgesia is one of the most striking examples of the cognitive modulation of pain perception and the underlying mechanisms are finally beginning to be understood. According to pharmacological studies, the endogenous opioid system is essential for placebo analgesia. Recent functional imaging data provides evidence that the rostral anterior cingulate cortex (rACC) represents a crucial cortical area for this type of endogenous pain control. We therefore hypothesized that placebo analgesia recruits other brain areas outside the rACC and that interactions of the rACC with these brain areas mediate opioid-dependent endogenous antinociception as part of a top-down mechanism. Nineteen healthy subjects received and rated painful laser stimuli to the dorsum of both hands, one of them treated with a fake analgesic cream (placebo). Painful stimulation was preceded by an auditory cue, indicating the side of the next laser stimulation. BOLD-responses to the painful laser-stimulation during the placebo and no-placebo condition were assessed using event-related fMRI. After having confirmed placebo related activity in the rACC, a connectivity analysis identified placebo dependent contributions of rACC activity with bilateral amygdalae and the periaqueductal gray (PAG). This finding supports the view that placebo analgesia depends on the enhanced functional connectivity of the rACC with subcortical brain structures that are crucial for conditioned learning and descending inhibition of nociception.

Chemosensory stimulation during sleep - Arousal responses to gustatory stimulation.

The processing of nociceptive, visual, vibrotactile, thermal and acoustic stimuli during sleep has been extensively investigated in the past. Recently, interest has focused on the impact of olfactory stimulation on sleep. In contrast to all other sensory systems, olfactory stimulation does not lead to an increased arousal frequency, regardless of hedonicity and concentration. The impact of the second chemosensory system, gustation, on sleep however has not been investigated to date. Twenty-one normosmic and normogeusic volunteers of both genders, aged 19-33 years, participated in the trial. Stimulation was performed with a gustometer using the following aqueous solutions: saccharose 20% (sweet), sodium chloride (NaCl) 7.5% (salty), citrate 5% (sour), and quinine 0.02% (bitter). A tasteless solution was used as negative control. Capsaicin, a strong trigeminal stimulus, served as positive control. Primary outcome was arousal frequency per stimulus in each sleep stage, as assessed with polysomnography. The frequency of arousals decreased in deeper sleep stages (N1: 211 arousals of 333 stimuli=63%, N2: 676/2728=25%, N3: 43/1378=3%, REM: 57/1010=6%). Statistically significant differences in terms of arousal frequency were found in N2 between the negative control and NaCl 100 µl (p<0.001), saccharose 100 µl, citrate 50 µl & 100 µl, and quinine 100 µl (p<0.05). Capsaicin led to complete awakenings in 94% of stimuli (30/32). These results demonstrate that gustatory stimulation during sleep induces arousals depending on stimulus intensity and sleep stage, which is different to olfactory stimulation and may be related to differences in central processing of the two chemosensory systems.

Experimental pain impairs recognition memory irrespective of pain predictability.

BACKGROUND: Pain is hardwired to signal threat and tissue damage and therefore automatically attracts attention to initiate withdrawal or defensive behaviour. This well-known interruptive function of pain interferes with cognitive functioning and is modulated by bottom-up and top-down variables. Here, we applied predictable or unpredictable painful heat stimuli simultaneously to the presentation of neutral images to investigate (I) whether the predictability of pain modulated its effect on the encoding of images (episodic memory) and (II) whether subjects remember that certain images have been previously presented with pain (source memory). METHODS: Twenty-four healthy subjects performed a categorization task in which 80 images had to be categorized into living or non-living objects. We compared the processing and encoding of these images during cued and non-cued pain trials as well as cued and non-cued pain-free trials. Effects on recognition performance and source memory for pain were immediately tested using a surprise recognition task. RESULTS: Painful thermal stimulation impaired recognition accuracy (d', recollection, familiarity). This negative effect of pain was positively correlated with the individual expectation of pain interference and the attentional avoidance of pain-related words. However, the interruptive effect of pain was not modulated by the predictability of pain. Source memory for painful stimulation was at chance level, indicating that subjects did not explicitly remember that images had been paired with pain. CONCLUSIONS: Targeting negative expectations and a maladaptive attentional bias for pain-related material might help reducing frequently reported pain-induced cognitive impairments.

Rethinking psychopharmacotherapy: The role of treatment context and brain plasticity in antidepressant and antipsychotic interventions.

Emerging evidence indicates that treatment context profoundly affects psychopharmacological interventions. We review the evidence for the interaction between drug application and the context in which the drug is given both in human and animal research. We found evidence for this interaction in the placebo response in clinical trials, in our evolving knowledge of pharmacological and environmental effects on neural plasticity, and in animal studies analyzing environmental influences on psychotropic drug effects. Experimental placebo research has revealed neurobiological trajectories of mechanisms such as patients' treatment expectations and prior treatment experiences. Animal research confirmed that "enriched environments" support positive drug effects, while unfavorable environments (low sensory stimulation, low rates of social contacts) can even reverse the intended treatment outcome. Finally we provide recommendations for context conditions under which psychotropic drugs should be applied. Drug action should be steered by positive expectations, physical activity, and helpful social and physical environmental stimulation. Future drug trials should focus on fully controlling and optimizing such drug×environment interactions to improve trial sensitivity and treatment outcome.

Subcortical structures involved in pain processing: evidence from single-trial fMRI.

Pain is processed in multiple cortical and subcortical brain areas. Subcortical structures are substantially involved in different processes that are closely linked to pain processing, e.g. motor preparation, autonomic responses, affective components and learning. However, it is unclear to which extent nociceptive information is relayed to and processed in subcortical structures. We used single-trial functional magnetic resonance imaging (fMRI) to identify subcortical regions displaying hemodynamic responses to painful stimulation. Thulium-YAG (yttrium-aluminum-granate) laser evoked pain stimuli, which have no concomitant tactile component, were applied to either hand of healthy volunteers in a randomized order. This procedure allowed identification of areas displaying differential fMRI responses to right- and left-sided stimuli. Hippocampal complex, amygdala, red nucleus, brainstem and cerebellum were activated in response to painful stimuli. Structures related to the affective processing of pain showed bilateral activation, whereas structures involved in the generation of withdrawal behavior, namely red nucleus, putamen and cerebellum displayed differential (i.e. asymmetric) responses according to the side of stimulation. This suggests that spatial information about the nociceptive stimulus is made available in these structures for the guidance of defensive and withdrawal behavior.