Molecular Mechanisms of Placebo Responses in Humans

Peciña, Marta; Zubieta, Jon-Kar

doi:10.1016/b978-0-12-397928-5.00004-0

Cited by 24 publications

(26 citation statements)

References 91 publications

(53 reference statements)

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“…Specifically, the rACC alone predicted 65% of the response variance. This finding potentially advances a more general understanding of the neurobiology of placebo effects across diseases: Both opioidergic and BOLD activity within the rACC have been consistently implicated in placebo analgesia (48, 52, 53) which evinces a hypothesis that corresponding mechanisms of action are involved in the formation of placebo effects across disorders (47), with recent evidence in further support of this notion (61). Our data, to our knowledge, are also the first demonstration of SN involvement in MDD placebo effects and thus, supplement the small existing body of work in the neurobiology of placebo in patients with MDD (15, 61).…”

Section: Discussionmentioning

confidence: 78%

Salience Network Functional Connectivity Predicts Placebo Effects in Major Depression

Sikora¹,

Heffernan²,

Avery³

et al. 2016

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

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Background Recent neuroimaging studies have demonstrated resting-state functional connectivity (rsFC) abnormalities among intrinsic brain networks in Major Depressive Disorder (MDD); however, their role as predictors of treatment response has not yet been explored. Here, we investigate whether network-based rsFC predicts antidepressant and placebo effects in MDD. Methods We performed a randomized controlled trial of two weeklong, identical placebos (described as having either “active” fast-acting, antidepressant effects or as “inactive”) followed by a ten-week open-label antidepressant medication treatment. Twenty-nine participants underwent a rsFC fMRI scan at the completion of each placebo condition. Networks were isolated from resting-state blood-oxygen-level-dependent signal fluctuations using independent component analysis. Baseline and placebo-induced changes in rsFC within the default-mode, salience, and executive networks were examined for associations with placebo and antidepressant treatment response. Results Increased baseline rsFC in the rostral anterior cingulate (rACC) within the salience network, a region classically implicated in the formation of placebo analgesia and the prediction of treatment response in MDD, was associated with greater response to one week of active placebo and ten weeks of antidepressant treatment. Machine learning further demonstrated that increased salience network rsFC, mainly within the rACC, significantly predicts individual responses to placebo administration. Conclusions These data demonstrate that baseline rsFC within the salience network is linked to clinical placebo responses. This information could be employed to identify patients who would benefit from lower doses of antidepressant medication or non-pharmacological approaches, or to develop biomarkers of placebo effects in clinical trials.

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Section: Discussionmentioning

confidence: 78%

Salience Network Functional Connectivity Predicts Placebo Effects in Major Depression

Sikora¹,

Heffernan²,

Avery³

et al. 2016

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

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“…After several decades of studies, research worldwide has clearly demonstrated that the expectation of clinical benefit shapes human perception and experience, triggering the beginning of a psychobiological phenomenon called the “placebo effect.” This promotes a series of healing effects through the activation of the endogenous reward network involving the ventral striatum (nucleus accumbens [NA]), ventromedial prefrontal cortex, orbitofrontal cortex, amygdala, and anterior cingulate cortex (ACC) . This activation is mediated by the release of dopamine in the ventral striatum (mesolimbic system), which in turn drives a cascade of brain activations and biochemical events, thus resulting in a clinical benefit.…”

mentioning

confidence: 99%

Neurobiology of placebo effect in Parkinson's disease: What we have learned and where we are going

et al. 2018

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The placebo effect is a phenomenon produced when an inert substance administered like a regular treatment improves the clinical outcome. Parkinson's disease (PD) is one of the main clinical disorders for which the placebo response rates are high. The first evidence of the neurobiological mechanisms underlying the placebo effect in PD stems from 2001, when de la Fuente-Fernandez and colleagues demonstrated that a placebo injection led to the release of dopamine in the striatal nuclei of PD measured with positron emission tomography technology. Since then, several studies have been conducted to investigate the neurobiological underpinnings of placebo responses. This article presents a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Of an initial yield of 143 papers, 19 were included. The lessons learned from these studies are threefold: (i) motor improvement is dependent on the activation of the entire nigrostriatal pathway induced by dopamine release in the dorsal striatum; (ii) the magnitude of placebo-induced effects is modulated by an expectancy of improvement, which is in turn related to the release of dopamine within the ventral striatum; (iii) the functioning of the neural pathways underlying the placebo response can be tuned by prior exposure and learning strategies. In conclusion, although the neural network underlying the placebo effect in PD has been largely confirmed and accepted, what remains to be established is how, when, and where the expectation of reward (mediated by the ventral striatum) interacts with the primary motor system (mediated by the dorsal striatum) to induce clinical improvement in motor symptoms. © 2018 International Parkinson and Movement Disorder Society.

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“…For example, clinical studies report that personality traits related to stress resiliency and genetic factors significantly influence development of placebo effects (Jaksic et al, 2013; Pecina and Zubieta, 2014). Similarly, the present study shows that variability exists in affective response triggered by repeated i.p injections of saline within outbred rat populations.…”

Section: Discussionmentioning

confidence: 99%

Revealing a latent variable: Individual differences in affective response to repeated injections.

Aydın¹,

Frohmader²,

Akil³

2015

Behavioral Neuroscience

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Latent variables may exist in experimental designs and may interfere with reproducibility of findings. The present study reveals one such variable, the individual differences in affective response to chronic injection stress, by using the novelty-seeking phenotype as a model of differential emotional reactivity. The phenotype is identified by exposing a population of experimentally-naïve outbred rats to the mild stress of a novel environment and classifying them as high responders (HR; upper 1/3rd) and low responders (LR; lower 1/3rd) based on their locomotor reactivity. Research has shown that HR/LR animals differ in their basal levels of anxiety- and depressive-like behavior, as well as in their response to environmental and pharmacological challenges; suggesting validity of this model in studying individual differences in stress reactivity. The present data showed that 14 daily, intraperitoneal saline injections did not alter the phenotypic differences in social behavior observed basally in HR/LR rats. However, injections significantly increased time spent immobile in the forced swim test in LRs, while the identical regimen significantly decreased the same measure in HRs, compared to handled-controls. These data indicate that individual differences in stress reactivity can have a significant impact on the depressive-like responses to repeated intraperitoneal injections in rats. Given that such underlying emotional variability exists within standard, outbred rat populations, this study highlights the importance of accounting for such variability in any study investigating the effects of repeated drug administration on depressive-like behavior for reliability and replicability of findings. Thus, we recommend including an uninjected control group in all studies.

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Molecular Mechanisms of Placebo Responses in Humans

Cited by 24 publications

References 91 publications

Salience Network Functional Connectivity Predicts Placebo Effects in Major Depression

Salience Network Functional Connectivity Predicts Placebo Effects in Major Depression

Neurobiology of placebo effect in Parkinson's disease: What we have learned and where we are going

Revealing a latent variable: Individual differences in affective response to repeated injections.

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