The neural processes of acquiring placebo effects through observation.
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ABSTRACT:
SUBMITTER: Schenk LA
PROVIDER: S-EPMC7107761 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:High placebo responses have been observed across a wide range of pathologies, severely impacting drug development.To examine neurochemical mechanisms underlying the formation of placebo effects in patients with major depressive disorder (MDD).In this study involving 2 placebo lead-in phases followed by an open antidepressant administration, we performed a single-blinded 2-week crossover randomized clinical trial of 2 identical oral placebos (described as having either active or inactive fast-acting antidepressant-like effects) followed by a 10-week open-label treatment with a selective serotonin reuptake inhibitor or, in some cases, another agent as clinically indicated. The volunteers (35 medication-free patients with MDD at a university health system) were studied with positron emission tomography and the µ-opioid receptor-selective radiotracer [11C]carfentanil after each 1-week inactive and active oral placebo treatment. In addition, 1 mL of isotonic saline was administered intravenously within sight of the volunteer during positron emission tomographic scanning every 4 minutes over 20 minutes only after the 1-week active placebo treatment, with instructions that the compound may be associated with the activation of brain systems involved in mood improvement. This challenge stimulus was used to test the individual capacity to acutely activate endogenous opioid neurotransmision under expectations of antidepressant effect.Changes in depressive symptoms in response to active placebo and antidepressant. Baseline and activation measures of µ-opioid receptor binding.Higher baseline µ-opioid receptor binding in the nucleus accumbens was associated with better response to antidepressant treatment (r?=?0.48; P?=?.02). Reductions in depressive symptoms after 1 week of active placebo treatment, compared with the inactive, were associated with increased placebo-induced µ-opioid neurotransmission in a network of regions implicated in emotion, stress regulation, and the pathophysiology of MDD, namely, the subgenual anterior cingulate cortex, nucleus accumbens, midline thalamus, and amygdala (nucleus accumbens: r?=?0.6; P?<?.001). Placebo-induced endogenous opioid release in these regions was associated with better antidepressant treatment response, predicting 43% of the variance in symptom improvement at the end of the antidepressant trial.These data demonstrate that placebo-induced activation of the µ-opioid system is implicated in the formation of placebo antidepressant effects in patients with MDD and also participate in antidepressant responses, conferring illness resiliency, during open administration.clinicaltrials.gov Identifier:NCT02178696.
| S-EPMC4758856 | biostudies-literature
Project description:BACKGROUND:Patient expectancy of therapeutic improvement is a primary mediator of placebo effects in antidepressant clinical trials, but its mechanisms are poorly understood. This study employed a novel antidepressant trial design, with integrated functional magnetic resonance imaging (fMRI), to manipulate patient outcome expectancy and examine its neural mediators. METHOD:Twenty-three depressed outpatients, in a randomized controlled trial were assigned to either Open (high outcome expectancy) or Placebo-controlled (low outcome expectancy) treatment with citalopram for eight weeks. fMRI scans were acquired before and after the expectancy manipulation (before medication treatment), while participants performed a masked emotional face task. Focusing on an amygdala region-of-interest (ROI), we tested a model where reduction in amygdala activation mediated outcome expectancy effects on the slope of change in depressive symptoms. RESULTS:Following the manipulation, significant differences between conditions were found in neural activation changes in the amygdala, as well as in superior temporal gyrus, insula, and thalamus. Findings support the proposed mediation model according to which activation in the left amygdala ROI decreased significantly in the Open as opposed to the Placebo-controlled group following randomization (p?=?0.009) for sad vs. neutral face contrast. The reduced left amygdala activation, in turn, was a significant predictor of decreased depressive symptoms during the trial (p?=?0.007), and the mediation model was significant. CONCLUSIONS:Results from this study, the first designed to identify the neural mechanisms of expectancy augmentation in an antidepressant randomized control trial, suggest that therapeutic modulation of amygdala activity may be an important pathway by which patient outcome expectancy influences depressive symptoms. CLINICALTRIALS. GOV IDENTIFIER:NCT01919216; Trial name: Placebo Effects in the Treatment of Depression: Cognitive and Neural Mechanisms, URL: https://clinicaltrials.gov/ct2/show/NCT01919216.
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Project description:Research on language comprehension using event-related potentials (ERPs) reported distinct ERP components reliably related to the processing of semantic (N400) and syntactic information (P600). Recent ERP studies have challenged this well-defined distinction by showing P600 effects for semantic and pragmatic anomalies. So far, it is still unresolved whether the P600 reflects specific or rather common processes. The present study addresses this question by investigating ERPs in response to a syntactic and pragmatic (irony) manipulation, as well as a combined syntactic and pragmatic manipulation. For the syntactic condition, a morphosyntactic violation was applied, whereas for the pragmatic condition, such as "That is rich", either an ironic or literal interpretation was achieved, depending on the prior context. The ERPs at the critical word showed a LAN-P600 pattern for syntactically incorrect sentences relative to correct ones. For ironic compared to literal sentences, ERPs showed a P200 effect followed by a P600 component. In comparison of the syntax-related P600 to the irony-related P600, distributional differences were found. Moreover, for the P600 time window (i.e., 500-900 ms), different changes in theta power between the syntax and pragmatics effects were found, suggesting that different patterns of neural activity contributed to each respective effect. Thus, both late positivities seem to be differently sensitive to these two types of linguistic information, and might reflect distinct neurocognitive processes, such as reanalysis of the sentence structure versus pragmatic reanalysis.
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Project description:Task-related functional magnetic resonance imaging (fMRI) is a widely-used tool for studying the neural processing correlates of human behavior in both healthy and clinical populations. There is growing interest in mapping individual differences in fMRI task behavior and neural responses. By utilizing neuroadaptive task designs accounting for such individual differences, task durations can be personalized to potentially optimize neuroimaging study outcomes (e.g., classification of task-related brain states). To test this hypothesis, we first retrospectively tracked the volume-by-volume changes of beta weights generated from general linear models (GLM) for 67 adult subjects performing a stop-signal task (SST). We then modeled the convergence of the volume-by-volume changes of beta weights according to their exponential decay (ED) in units of half-life. Our results showed significant differences in beta weight convergence estimates of optimal stopping times (OSTs) between go following successful stop trials and failed stop trials for both cocaine dependent (CD) and control group (Con), and between go following successful stop trials and go following failed stop trials for Con group. Further, we implemented support vector machine (SVM) classification for 67 CD/Con labeled subjects and compared the classification accuracies of fMRI-based features derived from (1) the full fMRI task versus (2) the fMRI task truncated to multiples of the unit of half-life. Among the computed binary classification accuracies, two types of task durations based on 2 half-lives significantly outperformed the accuracies using fully acquired trials, supporting this length as the OST for the SST. In conclusion, we demonstrate the potential of a neuroadaptive task design that can be widely applied to personalizing other task-based fMRI experiments in either dynamic real-time fMRI applications or within fMRI preprocessing pipelines.
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Project description:We demonstrate that the kinematics of the polishing process is more intriguing than an idealized planetary movement as all the previous studies reported. In reality, the workpiece is pseudo-constrained by the planetary carrier and because of this its relative motion to the polishing pad also incurs a 'parasitic' movement that previously has not been observed. Here, we report and model this parasitic movement and quantify its effect upon the workpiece surface roughness. Using a motion capture system, the principal and 'parasitic' movements between the sample and polishing tool have been tracked and our models validated. It is proved that considering this parasitic movement the prediction of workpiece surface morphology can be significantly improved when compared with the idealized approach (i.e. planetary). Our observations and modelling framework open the avenue to carefully consider the compliance between the tools and workpiece in other manufacturing processes for accurate predictions of the process outcomes.
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Project description:In deformation processes, the presence of grain boundaries has a crucial influence on dislocation behavior; these boundaries drastically change the mechanical properties of polycrystalline materials. It has been considered that grain boundaries act as effective barriers for dislocation glide, but the origin of this barrier-like behavior has been a matter of conjecture for many years. We directly observe how the motion of individual dislocations is impeded at well-defined high-angle and low-angle grain boundaries in SrTiO3, via in situ nanoindentation experiments inside a transmission electron microscope. Our in situ observations show that both the high-angle and low-angle grain boundaries impede dislocation glide across them and that the impediment of dislocation glide does not simply originate from the geometric effects; it arises as a result of the local structural stabilization effects at grain boundary cores as well, especially for low-angle grain boundaries. The present findings indicate that simultaneous consideration of both the geometric effects and the stabilization effects is necessary to quantitatively understand the dislocation impediment processes at grain boundaries.
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Project description:For over a millennium, mind-body interactions have fascinated scientists and doctors for their abilities to shape human perceptions of the external world 1,2. Placebo effects are striking demonstrations of mind-body interactions in which, in the absence of any treatment, a positive expectation of pain relief can reduce or even abolish the experience of pain 3–6. However, despite widespread recognition of the strength of placebo effects and their impact on everyday human experience and clinical trials for new analgesics, the neural circuit basis of the placebo effect has remained a mystery. Here, we show that analgesia from the expectation of pain relief is mediated by a distinct population of rostral anterior cingulate cortex (rACC) neurons that project to the pontine nuclei (rACC→Pn), a pair of brainstem pre-cerebellar nuclei with no established function in pain processing. To do this, we created a behavioral assay that models placebo analgesia by conditioning mice to expect pain relief when moving from a chamber with a heated floor to a second chamber. In this assay, an expectation of pain relief induces an analgesic effect that, like placebo analgesia in humans, is mediated by endogenous opioids. Calcium imaging of neural activity in freely moving mice and electrophysiological studies in cingulate cortical brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an unusual abundance of opioid receptors in these cells, further suggesting a role in pain modulation. Selective inhibition of either the rACC→Pn pathway or of opioid-receptor-expressing Pn neurons disrupted placebo analgesia and decreased pain thresholds. Finally, a subset of cerebellar Purkinje cells exhibits activity patterns resembling those of rACC→Pn neurons during pain relief expectation, providing cellular-level evidence of a role for the cerebellum in cognitive pain modulation. Altogether, these findings elucidate longstanding mysteries surrounding the placebo effect by identifying a specific neural pathway that mediates expectation-based pain relief. This discovery opens the possibility of targeting this novel pathway with drugs or neurostimulation methods to treat pain. More broadly, our studies provide a framework for investigating the neural circuit basis of other mind-body interactions beyond those involving pain, and point to prefrontocortical-cerebellar communication as a potential basis for such effects.
2024-09-12 | GSE267265 | GEO
Project description:A crucial component of social cognition is to observe and understand the social interactions of other individuals. A promising nonhuman primate model for investigating the neural basis of social interaction observation is the common marmoset (Callithrix jacchus), a small New World primate that shares a rich social repertoire with humans. Here, we used functional magnetic resonance imaging acquired at 9.4 T to map the brain areas activated by social interaction observation in awake marmosets. We discovered a network of subcortical and cortical areas, predominately in the anterior lateral frontal and medial frontal cortex, that was specifically activated by social interaction observation. This network resembled that recently identified in Old World macaque monkeys. Our findings suggest that this network is largely conserved between New and Old World primates and support the use of marmosets for studying the neural basis of social cognition.
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Project description:AbstractIntermediate care units (ImCUs) have been shown as appropriate units for the management of selected septic patients. Developing specific protocols for residents in training may be useful for their medical performance. The objective of this study was to analyze whether a simulation-based learning bundle is useful for residents while acquiring competencies in the management of sepsis during their internship in an ImCU.A prospective study, set in a tertiary-care academic medical center was performed enrolling residents who performed their internship in an ImCU from 2014 to 2017. The pillars of the simulation-based learning bundle were sepsis scenario in the simulation center, instructional material, and sepsis lecture, and management of septic patients admitted in the ImCU. Each resident was evaluated in the beginning and at the end of their internship displaying a sepsis-case scenario in the simulation center. The authors developed a sepsis-checklist that residents must fulfill during their performance which included 5 areas: hemodynamics (0-10), oxygenation (0-5), antibiotic therapy (0-9), organic injury (0-5), and miscellaneous (0-4).Thirty-four residents from different years of residency and specialties were evaluated. The total median score (interquartile range) increased significantly after training: 12 (25) vs 23 (16), P = .001. First-year residents scored significantly lower than older residents at baseline: 10 (14) vs 14.5 (19), P = .024. However, the performance at the end of the training period was similar in both groups: 21.5 (11) vs 23 (16), P = 1.000. Internal Medicine residents scored significantly higher than residents from other specialties: 18 (17) vs 10.5 (21), P = .007. Nonetheless, the performance at the end of the training period was similar in both groups: 24.5 (9) vs 22 (13), P = 1.000.Combining medical simulation with didactic lectures and a rotation in an ImCU staffed by hospitalists seems to be useful in acquiring competencies to manage critically ill patients with sepsis. We designed a checklist to assure an objective evaluation of the performance of the residents and to identify those aspects that could be potentially improved.
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Project description:Assessing and improving test-retest reliability is critical to efforts to address concerns about replicability of task-based functional magnetic resonance imaging. The current study uses two statistical approaches to examine how scanner and task-related factors influence reliability of neural response to face-emotion viewing. Forty healthy adult participants completed two face-emotion paradigms at up to three scanning sessions across two scanners of the same build over approximately 2 months. We examined reliability across the main task contrasts using Bayesian linear mixed-effects models performed voxel-wise across the brain. We also used a novel Bayesian hierarchical model across a predefined whole-brain parcellation scheme and subcortical anatomical regions. Scanner differences accounted for minimal variance in temporal signal-to-noise ratio and task contrast maps. Regions activated during task at the group level showed higher reliability relative to regions not activated significantly at the group level. Greater reliability was found for contrasts involving conditions with clearly distinct visual stimuli and associated cognitive demands (e.g., face vs. nonface discrimination) compared to conditions with more similar demands (e.g., angry vs. happy face discrimination). Voxel-wise reliability estimates tended to be higher than those based on predefined anatomical regions. This work informs attempts to improve reliability in the context of task activation patterns and specific task contrasts. Our study provides a new method to estimate reliability across a large number of regions of interest and can inform researchers' selection of task conditions and analytic contrasts.
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