Ulrike Bingel

Activation of the opioidergic descending pain control system underlies placebo analgesia.

Placebo analgesia involves the endogenous opioid system, as administration of the opioid antagonist naloxone decreases placebo analgesia. To investigate the opioidergic mechanisms that underlie placebo analgesia, we combined naloxone administration with functional magnetic resonance imaging. Naloxone reduced both behavioral and neural placebo effects as well as placebo-induced responses in pain-modulatory cortical structures, such as the rostral anterior cingulate cortex (rACC). In a brainstem-specific analysis, we observed a similar naloxone modulation of placebo-induced responses in key structures of the descending pain control system, including the hypothalamus, the periaqueductal gray (PAG), and the rostral ventromedial medulla (RVM). Most importantly, naloxone abolished placebo-induced coupling between rACC and PAG, which predicted both neural and behavioral placebo effects as well as activation of the RVM. These findings show that opioidergic signaling in pain-modulating areas and the projections to downstream effectors of the descending pain control system are crucially important for placebo analgesia.

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

Abstract 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.

The Effect of Treatment Expectation on Drug Efficacy: Imaging the Analgesic Benefit of the Opioid Remifentanil

An individual’s expectation that a pain treatment will or will not work can alter both its subjective effectiveness and the pain-related activity in the brain. Gloomy Forecasts Prove True A pessimist walks into a hospital. His grim prediction that doctors will be unable to alleviate his back pain proved correct—after several days of various treatments, his pain persisted. According to new results from Bingel and colleagues, the gloomy outlook this patient brought with him into his pain treatment may have ensured that his prediction was a self-fulfilling prophesy. Using sophisticated brain imaging techniques, the authors show that one’s expectation of the success of a pain treatment can markedly influence its effectiveness. In this new study, healthy people were exposed to pain-provoking heat and also given the painkilling opioid drug remifentanil. In advance of each instance of drug administration, the authors informed the subjects that the drug would have no effect, that it would diminish the sensation of pain, or that it would make the pain worse. When subjects expected the drug to be effective, they were not disappointed—they experienced twice as much pain relief as they did when they expected to obtain no benefit from the drug (but did, in fact, get some relief). In contrast, when they expected remifentanil to make the heat pain worse they found that their pain was unchanged. But these subjective reports could be influenced by a host of variables. What was actually happening within the brains of these individuals to shift their pain perceptions so dramatically? With functional magnetic resonance imaging (fMRI), the authors of Bingel et al. examined brain activity during the experiment. Thermal pain itself causes activation of a so-called pain circuit, which encompasses numerous brain regions including the somatosensory cortex, the cingulate cortex, insula, thalamus, and brainstem. Expectation of increased pain was accompanied by more neural activity in the hippocampus, midcingulate cortex, and medial prefrontal cortex—brain areas that mediate mood and anxiety—than was observed in these regions during expectation of analgesia. Conversely, individuals who expected the drug to mitigate their pain showed increases in the anterior cingulate cortex and the striatum, signs that descending mechanisms of pain inhibition were engaged. These clues about how our beliefs can affect the way we experience medical treatment for pain can improve the practice of medicine. A drug with a true biological effect may appear to be ineffective to a patient conditioned to expect failure, whether the patient is enrolled in a clinical trial or treated in a physician’s office. Patient education about treatments can help counteract this problem by shaping beliefs to maximize drug effectiveness. If appropriate treatments are accompanied by encouraging words, a pessimist could become an optimist about his future robust health, and thereby make it so. Evidence from behavioral and self-reported data suggests that the patients’ beliefs and expectations can shape both therapeutic and adverse effects of any given drug. We investigated how divergent expectancies alter the analgesic efficacy of a potent opioid in healthy volunteers by using brain imaging. The effect of a fixed concentration of the μ-opioid agonist remifentanil on constant heat pain was assessed under three experimental conditions using a within-subject design: with no expectation of analgesia, with expectancy of a positive analgesic effect, and with negative expectancy of analgesia (that is, expectation of hyperalgesia or exacerbation of pain). We used functional magnetic resonance imaging to record brain activity to corroborate the effects of expectations on the analgesic efficacy of the opioid and to elucidate the underlying neural mechanisms. Positive treatment expectancy substantially enhanced (doubled) the analgesic benefit of remifentanil. In contrast, negative treatment expectancy abolished remifentanil analgesia. These subjective effects were substantiated by significant changes in the neural activity in brain regions involved with the coding of pain intensity. The positive expectancy effects were associated with activity in the endogenous pain modulatory system, and the negative expectancy effects with activity in the hippocampus. On the basis of subjective and objective evidence, we contend that an individual’s expectation of a drug’s effect critically influences its therapeutic efficacy and that regulatory brain mechanisms differ as a function of expectancy. We propose that it may be necessary to integrate patients’ beliefs and expectations into drug treatment regimes alongside traditional considerations in order to optimize treatment outcomes.

Direct evidence for spinal cord involvement in placebo analgesia.

Functional magnetic resonance imaging of the human spinal cord reveals a mechanism for placebo analgesia. Placebo analgesia is a prime example of the impact that psychological factors have on pain perception. We used functional magnetic resonance imaging of the human spinal cord to test the hypothesis that placebo analgesia results in a reduction of nociceptive processing in the spinal cord. In line with behavioral data that show decreased pain responses under placebo, pain-related activity in the spinal cord is strongly reduced under placebo. These results provide direct evidence for spinal inhibition as one mechanism of placebo analgesia and highlight that psychological factors can act on the earliest stages of pain processing in the central nervous system.

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

&NA; 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.

Habituation to painful stimulation involves the antinociceptive system.

Abstract The perception of pain results from an interaction between nociceptive and antinociceptive mechanisms. A better understanding of the neural circuitry underlying these physiological interactions provides an important opportunity to develop better treatment strategies for and ultimately even prevent pain. Here, we investigated how repeated painful stimulation over several days is processed, perceived and finally modulated in the healthy human brain. Twenty healthy subjects were stimulated daily with a 20 min pain paradigm for 8 consecutive days, and functional MRI performed on days 1, 8 and 22. Repeated painful stimulation over several days resulted in substantially decreased pain ratings to identical painful stimuli. The decreased perception of pain over time is reflected in decreased BOLD responses to nociceptive stimuli in classical pain areas, including thalamus, insula, SII and the putamen. In contrast to this finding, we found that pain‐related responses in the rACC, specifically the subgenual anterior cingulate cortex (sgACC), significantly increased over time. Given this area’s predominant role in endogenous pain control, this response pattern suggests that habituation to pain is at least in part mediated by increased antinociceptive activity.

Imaging CNS modulation of pain in humans.

Pain is a highly complex and subjective experience that is not linearly related to the nociceptive input. What is clear from anecdotal reports over the centuries and more recently from animal and human experimentation is that nociceptive information processing and consequent pain perception is subject to significant pro- and anti-nociceptive modulations. These modulations can be initiated reflexively or by contextual manipulations of the pain experience including cognitive and emotional factors. This provides a necessary survival function since it allows the pain experience to be altered according to the situation rather than having pain always dominate. The so-called descending pain modulatory network involving predominantly medial and frontal cortical areas, in combination with specific subcortical and brain stem nuclei appears to be one key system for the endogenous modulation of pain. Furthermore, recent findings from functional and anatomical neuroimaging support the notion that an altered interaction of pro- and anti-nociceptive mechanisms may contribute to the development or maintenance of chronic pain states. Research on the involved circuitry and implemented mechanisms is a major focus of contemporary neuroscientific research in the field of pain and should provide new insights to prevent and treat chronic pain states.

Prestimulus functional connectivity determines pain perception in humans.

Pain is a highly subjective experience that can be substantially influenced by differences in individual susceptibility as well as personality. How susceptibility to pain and personality translate to brain activity is largely unknown. Here, we report that the functional connectivity of two key brain areas before a sensory event reflects the susceptibility to a subsequent noxious stimulus being perceived as painful. Specifically, the prestimulus connectivity among brain areas related to the subjective perception of the body and to the modulation of pain (anterior insular cortex and brainstem, respectively) determines whether a noxious event is perceived as painful. Further, these effects of prestimulus connectivity on pain perception covary with pain-relevant personality traits. More anxious and pain-attentive individuals display weaker descending connectivity to pain modulatory brain areas. We conclude that variations in functional connectivity underlie personality-related differences in individual susceptibility to pain.

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.

Somatotopic organization of human somatosensory cortices for pain: a single trial fMRI study

The ability to locate pain plays a pivotal role in immediate defense and withdrawal behavior. However, how the brain localizes nociceptive information without additional information from somatotopically organized mechano-receptive pathways is not well understood. To investigate the somatotopic organization of the nociceptive system, we applied Thulium-YAG-laser evoked pain stimuli, which have no concomitant tactile component, to the dorsum of the left hand and foot in randomized order. We used single-trial functional magnetic resonance imaging (fMRI) to assess differential hemodynamic responses to hand and foot stimulation for the group and in a single subject approach. The primary somatosensory cortex (SI) shows a clear somatotopic organization ipsi- and contralaterally to painful stimulation. Furthermore, a differential representation of hand and foot stimulation appeared within the contralateral opercular--insular region of the secondary somatosensory cortex (SII). This result provides evidence that both SI and SII encode spatial information of nociceptive stimuli without additional information from the tactile system and highlights the concept of a redundant representation of basic discriminative stimulus features in human somatosensory cortices, which seems adequate in view of the evolutionary importance of pain perception.