Dan-Mikael Ellingsen

Placebo improves pleasure and pain through opposite modulation of sensory processing

Significance Placebo effects illustrate the power of the human brain; simply expecting an improvement can alter pain processing and produce analgesia. We induced placebo improvement of both negative and positive feelings (painful and pleasant touch) in healthy humans, and compared the brain processing using functional MRI. Pain reduction dampened sensory processing in the brain, whereas increased touch pleasantness increased sensory processing. Neurocircuitry associated with emotion and reward underpinned improvement of both pain and pleasant touch. Our findings suggest that expectation of improvement can recruit common neurocircuitry, which up- or down-regulates sensory processing, depending on whether the starting point is painful or pleasant. These results promote widening the scope of medical research to improvement of positive experiences and pleasure. Placebo analgesia is often conceptualized as a reward mechanism. However, by targeting only negative experiences, such as pain, placebo research may tell only half the story. We compared placebo improvement of painful touch (analgesia) with placebo improvement of pleasant touch (hyperhedonia) using functional MRI and a crossover design. Somatosensory processing was decreased during placebo analgesia and increased during placebo hyperhedonia. Both placebo responses were associated with similar patterns of activation increase in circuitry involved in emotion appraisal, including the pregenual anterior cingulate, medial orbitofrontal cortex, amygdala, accumbens, and midbrain structures. Importantly, placebo-induced coupling between the ventromedial prefrontal cortex and periaqueductal gray correlated with somatosensory decreases to painful touch and somatosensory increases to pleasant touch. These findings suggest that placebo analgesia and hyperhedonia are mediated by activation of shared emotion appraisal neurocircuitry, which down- or up-regulates early sensory processing, depending on whether the expectation is reduced pain or increased pleasure.

State-dependent μ-opioid modulation of social motivation.

Social mammals engage in affiliative interactions both when seeking relief from negative affect and when searching for pleasure and joy. These two motivational states are both modulated by μ-opioid transmission. The μ-opioid receptor (MOR) system in the brain mediates pain relief and reward behaviors, and is implicated in social reward processing and affiliative bonding across mammalian species. However, pharmacological manipulation of the μ-opioid system has yielded opposite effects on rodents and primates: in rodents, social motivation is generally increased by MOR agonists and reduced by antagonists, whereas the opposite pattern has been shown in primates. Here, we address this paradox by taking into account differences in motivational state. We first review evidence for μ-opioid mediation of reward processing, emotion regulation, and affiliation in humans, non-human primates, rodents and other species. Based on the consistent cross-species similarities in opioid functioning, we propose a unified, state-dependent model for μ-opioid modulation of affiliation across the mammalian species. Finally, we show that this state-dependent model is supported by evidence from both rodent and primate studies, when species and age differences in social separation response are taken into account.

The Neurobiology Shaping Affective Touch: Expectation, Motivation, and Meaning in the Multisensory Context.

Inter-individual touch can be a desirable reward that can both relieve negative affect and evoke strong feelings of pleasure. However, if other sensory cues indicate it is undesirable to interact with the toucher, the affective experience of the same touch may be flipped to disgust. While a broad literature has addressed, on one hand the neurophysiological basis of ascending touch pathways, and on the other hand the central neurochemistry involved in touch behaviors, investigations of how external context and internal state shapes the hedonic value of touch have only recently emerged. Here, we review the psychological and neurobiological mechanisms responsible for the integration of tactile “bottom–up” stimuli and “top–down” information into affective touch experiences. We highlight the reciprocal influences between gentle touch and contextual information, and consider how, and at which levels of neural processing, top-down influences may modulate ascending touch signals. Finally, we discuss the central neurochemistry, specifically the μ-opioids and oxytocin systems, involved in affective touch processing, and how the functions of these neurotransmitters largely depend on the context and motivational state of the individual.

Cyclic Vomiting Syndrome is characterized by altered functional brain connectivity of the insular cortex: a cross‐comparison with migraine and healthy adults

Cyclic Vomiting Syndrome (CVS) has been linked to episodic migraine, yet little is known about the precise brain‐based mechanisms underpinning CVS, and whether these associated conditions share similar pathophysiology. We investigated the functional integrity of salience (SLN) and sensorimotor (SMN) intrinsic connectivity networks in CVS, migraine and healthy controls using brain functional Magnetic Resonance Imaging. CVS, relative to both migraine and controls, showed increased SLN connectivity to middle/posterior insula, a key brain region for nausea and viscerosensory processing. In contrast, this same region showed diminished SMN connectivity in both CVS and migraine. These results highlight both unique and potentially shared pathophysiology between these conditions, and suggest a potential target for therapeutics in future studies.

How Do C-Tactile Skin Afferents Contribute to Erotic Affect?

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Encoding of Self-Referential Pain Catastrophizing in the Posterior Cingulate Cortex in Fibromyalgia

Pain catastrophizing is a common feature of chronic pain, including fibromyalgia (FM), and is strongly associated with amplified pain severity and disability. While previous neuroimaging studies have focused on evoked pain response modulation by catastrophizing, the brain mechanisms supporting pain catastrophizing itself are unknown. We designed a functional magnetic resonance imaging (fMRI)–based pain catastrophizing task whereby patients with chronic pain engaged in catastrophizing‐related cognitions. We undertook this study to test our hypothesis that catastrophizing about clinical pain would be associated with amplified activation in nodes of the default mode network (DMN), which encode self‐referential cognition and show altered functioning in chronic pain.

The Neurochemical Basis of Motivation for Affiliative Touch

Affiliative touch interactions are often rewarding. They can on one hand alleviate stress and negative affect, while on the other hand induce intense feelings of pleasure. The behavioral nature of touch interactions (e.g., soothing soft touch or rough-and-tumble play) is often very different depending on whether the motivation for touch is primarily relief of negative affect or social exploration and joy, which is guided by the individual’s underlying needs. Here we discuss the central neurochemistry involved in motivation for affiliative touch interactions, with a focus on the mu-opioid receptor (MOR) and oxytocin systems. While both of these neurochemical systems play critical roles in various aspects of social affiliation, there are inconsistencies regarding their specific role in driving motivation for social touch interactions. We discuss this in the light of test subjects’ motivational state (distress or comfort) and appraisal of the situational context, and propose that many of these apparent discrepancies can be resolved by accounting for these factors.

Brain Mechanisms of Anticipated Painful Movements and Their Modulation by Manual Therapy in Chronic Low Back Pain

Heightened anticipation and fear of movement-related pain has been linked to detrimental fear-avoidance behavior in chronic low back pain (cLBP). Spinal manipulative therapy (SMT) has been proposed to work partly by exposing patients to nonharmful but forceful mobilization of the painful joint, thereby disrupting the relationship among pain anticipation, fear, and movement. Here, we investigated the brain processes underpinning pain anticipation and fear of movement in cLBP, and their modulation by SMT, using functional magnetic resonance imaging. Fifteen cLBP patients and 16 healthy control (HC) subjects were scanned while observing and rating video clips depicting back-straining or neutral physical exercises, which they knew they would have to perform at the end of the visit. This task was repeated after a single session of spinal manipulation (cLBP and HC group) or mobilization (cLBP group only), in separate visits. Compared with HC subjects, cLBP patients reported higher expected pain and fear of performing the observed exercises. These ratings, along with clinical pain, were reduced by SMT. Moreover, cLBP, relative to HC subjects, demonstrated higher blood oxygen level-dependent signal in brain circuitry that has previously been implicated in salience, social cognition, and mentalizing, while observing back straining compared with neutral exercises. The engagement of this circuitry was reduced after SMT, and especially the spinal manipulation session, proportionally to the magnitude of SMT-induced reduction in anticipated pain and fear. This study sheds light on the brain processing of anticipated pain and fear of back-straining movement in cLBP, and suggests that SMT may reduce cognitive and affective-motivational aspects of fear-avoidance behavior, along with corresponding brain processes. PERSPECTIVE: This study of cLBP patients investigated how SMT affects clinical pain, expected pain, and fear of physical exercises. The results indicate that one of the mechanisms of SMT may be to reduce pain expectancy, fear of movement, and associated brain responses.