The brain systems underlying placebo analgesia are insufficiently understood. Here we performed a systematic, participant-level meta-analysis of experimental functional neuroimaging studies of evoked ...pain under stimulus-intensity-matched placebo and control conditions, encompassing 603 healthy participants from 20 (out of 28 eligible) studies. We find that placebo vs. control treatments induce small, widespread reductions in pain-related activity, particularly in regions belonging to ventral attention (including mid-insula) and somatomotor networks (including posterior insula). Behavioral placebo analgesia correlates with reduced pain-related activity in these networks and the thalamus, habenula, mid-cingulate, and supplementary motor area. Placebo-associated activity increases occur mainly in frontoparietal regions, with high between-study heterogeneity. We conclude that placebo treatments affect pain-related activity in multiple brain areas, which may reflect changes in nociception and/or other affective and decision-making processes surrounding pain. Between-study heterogeneity suggests that placebo analgesia is a multi-faceted phenomenon involving multiple cerebral mechanisms that differ across studies.
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.
Psychological distress is prevalent in students and can predispose to psychiatric disorders. Recent findings indicate that distress might be linked to impaired cognitive performance in students. ...Experimental findings in healthy participants suggest that placebo interventions can improve cognition. However, whether non-deceptive (i.e., open-label, OLP) placebos can enhance cognitive function and emotional well-being is unclear. Using a randomized-controlled design we demonstrate a positive impact of OLP on subjective well-being (i.e., stress, fatigue, and confusion) after a 21-day OLP application in healthy students during midterm exams. OLP did not improve test performance, but, within the OLP group, test performance was positively correlated with measures of general belief in the benefit of medication. These results show that OLP can counteract negative effects of acute stress on psychological well-being and might improve cognitive performance if supported by positive treatment expectations. Additionally, our findings in healthy volunteers warrant further investigation in exploring the potential of OLP in reducing stress-related psychological effects in patients. The trial was preregistered at the German Clinical Trials Register on December 20, 2017 (DRKS00013557).
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.
In the past years, there have been increasing research activities focusing on somatosensory symptoms following stroke. However, as compared to the large number of clinical and neuroimaging studies on ...motor symptoms, the number of studies tracing somatosensory symptoms after stroke and their recovery is rather small. It is an ongoing discussion, to which extent somatosensory deficits after stroke influence patient's long-term outcome in motor and sensory performance and functional independence in activities of daily living. Modern brain imaging techniques allow for studying the impact of stroke lesion localization and size on acute and persisting clinical impairment. Here, we review the literature on somatosensory symptoms after stroke. We summarize epidemiological information on frequency and characteristics of somatosensory symptoms affecting all parts of the body in the acute and chronic stage of stroke. We further give an overview of brain imaging studies of stroke affecting the somatosensory system. Finally, we identify open questions which need to be addressed in future research and summarize the implications for clinical practice.
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.
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.
Background: Placebo and nocebo effects occur in clinical or laboratory medical contexts after administration of an inert treatment or as part of active treatments and are due to psychobiological ...mechanisms such as expectancies of the patient. Placebo and nocebo studies have evolved from predominantly methodological research into a far-reaching interdisciplinary field that is unravelling the neurobiological, behavioural and clinical underpinnings of these phenomena in a broad variety of medical conditions. As a consequence, there is an increasing demand from health professionals to develop expert recommendations about evidence-based and ethical use of placebo and nocebo effects for clinical practice. Methods: A survey and interdisciplinary expert meeting by invitation was organized as part of the 1st Society for Interdisciplinary Placebo Studies (SIPS) conference in 2017. Twenty-nine internationally recognized placebo researchers participated. Results: There was consensus that maximizing placebo effects and minimizing nocebo effects should lead to better treatment outcomes with fewer side effects. Experts particularly agreed on the importance of informing patients about placebo and nocebo effects and training health professionals in patient-clinician communication to maximize placebo and minimize nocebo effects. Conclusions: The current paper forms a first step towards developing evidence-based and ethical recommendations about the implications of placebo and nocebo research for medical practice, based on the current state of evidence and the consensus of experts. Future research might focus on how to implement these recommendations, including how to optimize conditions for educating patients about placebo and nocebo effects and providing training for the implementation in clinical practice.
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.
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