A novel algorithm for 3-D visualization of electrogram duration for substrate-mapping in patients with ischemic heart disease and ventricular tachycardia.

BACKGROUND: Myocardial slow conduction is a cornerstone of ventricular tachycardia (VT). Prolonged electrogram (EGM) duration is a useful surrogate parameter and manual annotation of EGM characteristics are widely used during catheter-based ablation of the arrhythmogenic substrate. However, this remains time-consuming and prone to inter-operator variability. We aimed to develop an algorithm for 3-D visualization of EGM duration relative to the 17-segment American Heart Association model. METHODS: To calculate and visualize EGM duration, in sinus rhythm acquired high-density maps of patients with ischemic cardiomyopathy undergoing substrate-based VT ablation using a 64-mini polar basket-catheter with low noise of 0.01 mV were analyzed. Using a custom developed algorithm based on standard deviation and threshold, the relationship between EGM duration, endocardial voltage and ablation areas was studied by creating 17-segment 3-D models and 2-D polar plots. RESULTS: 140,508 EGMs from 272 segments (n = 16 patients, 94% male, age: 66±2.4, ejection fraction: 31±2%) were studied and 3-D visualization of EGM duration was performed. Analysis of signal processing parameters revealed that a 40 ms sliding SD-window, 15% SD-threshold and >70 ms EGM duration cutoff was chosen based on diagnostic odds ratio of 12.77 to visualize rapidly prolonged EGM durations. EGMs > 70 ms matched to 99% of areas within dense scar (<0.2 mV), in 95% of zones within scar border zone (0.2-1.0 mV) and detected ablated areas having resulted in non-inducibility at the end of the procedure. Ablation targets were identified with a sensitivity of 65.6% and a specificity of 94.6% avoiding false positive labeling of prolonged EGMs in segments with healthy myocardium. CONCLUSION: The novel algorithm allows rapid visualization of prolonged EGM durations. This may facilitate more objective characterization of arrhythmogenic substrate in patients with ischemic cardiomyopathy.

Relationship between ambient temperature and severe acute poisoning by alcohol and drugs.

AIM: To test the hypothesis that severe acute poisoning by alcohol and drugs is more frequent at higher rather than at lower ambient temperatures. METHOD: This was a prospective observational study performed in a prehospital setting under marine west coast climate conditions. Data from the Emergency Medical Service in Hamburg (Germany) and data from the local weather station were evaluated over a 5-year period. Temperature data were obtained and matched with the associated rescue mission data, which were divided into the following groups: 1) alcohol poisoning, 2) opioid poisoning, 3) poisoning by sedatives/hypnotics, multiple drugs, volatile solvents, and other psychoactive substances. Lowess-Regression analysis was performed to assess the relationship between ambient temperature and frequency of severe acute poisoning. Additionally, three temperature ranges were defined in order to compare them with each other with regard to frequency of severe poisoning (<10 °C vs. 10-20 °C vs. >20 °C). The severity of emergencies was assessed using the National Advisory Committee for Aeronautics (NACA) scoring system. RESULTS: In 1535 patients, severe acute alcohol or drug poisoning associated with loss of consciousness, hypotension, and impaired respiratory function was treated (alcohol: n = 604; opioids: n = 295; sedatives/hypnotics/multiple drugs: n = 636). Compared to mild temperatures (10-20 °C), the frequency of poisoning increased in all three groups at higher temperatures and decreased at lower temperatures (p < 0.01). No significant correlation was found between severity of emergencies and temperature. CONCLUSIONS: Our results suggest a continuously increasing probability of occurrence of severe acute poisoning by alcohol and drugs with rising temperature.

Subjective Evaluation of Performance in a Collaborative Task Is Better Predicted From Autonomic Response Than From True Achievements.

Whereas the fundamental role of the body in social cognition seems to be generally accepted, elucidating the bodily mechanisms associated with non-verbal communication and cooperation between two or more persons is still a challenging endeavor. In this article we propose a fresh approach for investigating the function of the autonomic nervous system that is reflected in parameters of heart rate variability, respiration, and electrodermal activity in a social setting. We analyzed autonomic parameters of dyads solving a target-tracking task together with the partner or individually. A machine classifier was trained to predict the subjects' rating of performance and collaboration either from tracking error data or from the set of autonomic parameters. When subjects collaborated, this classifier could predict the subjective performance ratings better from the autonomic response than from the objective performance of the subjects. However, when they solved the task individually, predictability from autonomic parameters dropped to the level of objective performance, indicating that subjects were more rational in rating their performance in this condition. Moreover, the model captured general knowledge about the population that allows it to predict the performance ratings of an unseen subject significantly better than chance. Our results suggest that, in particular in situations that require collaboration with others, evaluation of performance is shaped by the bodily processes that are quantified by autonomic parameters. Therefore, subjective performance assessments appear to be modulated not only by the output of a rational or discriminative system that tracks the objective performance but to a significant extent also by interoceptive processes.

Effects of Respiratory Rate on Heart Rate Variability in Neurologic Outpatients with Epilepsies or Migraine: A Preliminary Study.

BACKGROUND: Variation of spontaneous respiratory rates and influences of spontaneous and paced breathing rates on heart rate variability (HRV) were assessed in patients with epilepsy or migraine, and HRV parameters were compared between the groups. MATERIALS AND METHODS: Thirty neurologic outpatients, 16 diagnosed with epilepsies and 14 with migraine, were included. Autonomic testing consisted of short-term HRV, the deep breathing test (DBT), and measurement of HRV at systematically changed breathing rates (paced breathing, 5-18 breaths per minute, bpm). RESULTS: Spontaneous respiratory rate during short-term HRV varied from 9 to 23 bpm in the epileptic group and from 5 to 21 bpm in migraine patients and was significantly and negatively correlated with SD of all normal RR intervals (SDNN) and total power (TP) in epileptic patients but not in migraine patients. Paced breathing rate had a significant effect on all HRV parameters assessed in both groups. HRV (SD1, SDNN, TP) and DBT (E-I, SD1, SDNN) parameters were significantly lower in the epileptic group. Group differences were significantly greater during slow compared to fast breathing. CONCLUSIONS: An important and new finding is the wide variation of spontaneous respiratory rate in both groups, along with the significant negative correlation with the assessed HRV parameters. The reduction of HRV during slow breathing in epileptic patients may indicate a diminished cardiorespiratory coupling caused by a probable loss of sensitivity within the cardiovagal brainstem circuitry.

Chemosensory Event-Related Potentials in Response to Nasal Propylene Glycol Stimulation.

Propylene glycol, also denoted as 1.2 propanediol (C3H8O2), often serves as a solvent for dilution of olfactory stimuli. It is supposed to serve as a neutral substance and has been used in many behavioral and electrophysiological studies to dilute pure olfactory stimuli. However, the effect of propylene glycol on perception and on neuronal responses has hitherto never been studied. In this study we tested by means of a threshold test, whether a nasal propylene glycol stimulation is recognizable by humans. Participants were able to recognize propylene glycol at a threshold of 42% concentration and reported a slight cooling effect. In addition to the threshold test, we recorded electroencephalography (EEG) during nasal propylene glycol stimulation to study the neuronal processing of the stimulus. We used a flow olfactometer and stimulated 15 volunteers with three different concentrations of propylene glycol (40 trials each) and water as a control condition (40 trials). To evaluate the neuronal response, we analyzed the event-related potentials (ERPs) and power modulations. The task of the volunteers was to identify a change (olfactory, thermal, or tactile) in the continuous air flow generated by the flow olfactometer. The analysis of the ERPs showed that propylene glycol generates a clear P2 component, which was also visible in the frequency domain as an evoked power response in the theta-band. The source analysis of the P2 revealed a widespread involvement of brain regions, including the postcentral gyrus, the insula and adjacent operculum, the thalamus, and the cerebellum. Thus, it is possible that trigeminal stimulation can at least partly account for sensations and brain responses elicited by propylene glycol. Based on these results, we conclude that the use of high propylene glycol concentrations to dilute fragrances complicates the interpretation of presumed purely olfactory effects.

Process Variability-Technological Challenge and Design Issue for Nanoscale Devices.

Current advanced transistor architectures, such as FinFETs and (stacked) nanowires and nanosheets, employ truly three-dimensional architectures. Already for aggressively scaled bulk transistors, both statistical and systematic process variations have critically influenced device and circuit performance. Three-dimensional device architectures make the control and optimization of the device geometries even more important, both in view of the nominal electrical performance to be achieved and its variations. In turn, it is essential to accurately simulate the device geometry and its impact on the device properties, including the effect caused by non-idealized processes which are subject to various kinds of systematic variations induced by process equipment. In this paper, the hierarchical simulation system developed in the SUPERAID7 project to study the impact of variations from equipment to circuit level is presented. The software system consists of a combination of existing commercial and newly developed tools. As the paper focuses on technological challenges, especially issues resulting from the structuring processes needed to generate the three-dimensional device architectures are discussed. The feasibility of a full simulation of the impact of relevant systematic and stochastic variations on advanced devices and circuits is demonstrated.

Association between Weather-Related Factors and Cardiac Arrest of Presumed Cardiac Etiology: A Prospective Observational Study Based on Out-of-Hospital Care Data.

OBJECTIVE: The objective of this study was to determine the association between weather-related factors and out-of-hospital cardiac arrest (OHCA) of presumed cardiac etiology. METHODS: This was a prospective observational study performed in a prehospital setting. Data from the Emergency Medical Service in Hamburg (Germany) and data from the local weather station were evaluated over a 5-year period. Weather data (temperature, humidity, air pressure, wind speed) were obtained every minute and matched with the associated rescue mission data. Lowess-Regression analysis was performed to assess the relationship between the above-mentioned weather-related factors and OHCA of presumed cardiac etiology. Additionally, varying measuring-ranges were defined for each weather-related factor in order to compare them with each other with regard to the probability of occurrence of OHCA. RESULTS: During the observation period 1,558 OHCA with presumed cardiac etiology were registered (age: 67 ± 19 yrs; 62% male; hospital admission: 37%; survival to hospital discharge: 6.7%). Compared to moderate temperatures (5 - 25°C), probability of OHCA-occurrence increased significantly at temperatures above 25°C (p = 0.028) and below 5°C p = 0.011). Regarding air humidity, probability of OHCA-occurrence increased below a threshold-value of 75% compared to values above this cut-off (p = 0.006). Decreased probability was seen at moderate atmospheric pressure (1000 hPa - 1020 hPa), whereas increased probability was seen above 1020 hPa (p = 0.023) and below 1000 hPa (p = 0.035). Probability of OHCA-occurrence increased continuously with increasing wind speed (p < 0.001). CONCLUSIONS: There are associations between several weather-related factors such as temperature, humidity, air pressure, and wind speed, and occurrence of OHCA of presumed cardiac etiology. Particularly dangerous seem to be cold weather, dry air and strong wind.

Acupuncture analgesia involves modulation of pain-induced gamma oscillations and cortical network connectivity.

Recent studies support the view that cortical sensory, limbic and executive networks and the autonomic nervous system might interact in distinct manners under the influence of acupuncture to modulate pain. We performed a double-blind crossover design study to investigate subjective ratings, EEG and ECG following experimental laser pain under the influence of sham and verum acupuncture in 26 healthy volunteers. We analyzed neuronal oscillations and inter-regional coherence in the gamma band of 128-channel-EEG recordings as well as heart rate variability (HRV) on two experimental days. Pain ratings and pain-induced gamma oscillations together with vagally-mediated power in the high-frequency bandwidth (vmHF) of HRV decreased significantly stronger during verum than sham acupuncture. Gamma oscillations were localized in the prefrontal cortex (PFC), mid-cingulate cortex (MCC), primary somatosensory cortex and insula. Reductions of pain ratings and vmHF-power were significantly correlated with increase of connectivity between the insula and MCC. In contrast, connectivity between left and right PFC and between PFC and insula correlated positively with vmHF-power without a relationship to acupuncture analgesia. Overall, these findings highlight the influence of the insula in integrating activity in limbic-saliency networks with vagally mediated homeostatic control to mediate antinociception under the influence of acupuncture.

Reduced frequency of severe hypoglycemia at mild ambient temperatures between 10 and 20 °C: A population-based study under marine west coast climate conditions.

AIMS: To determine the association between ambient temperature and severe hypoglycemia. METHODS: This was a prospective observational study performed in a prehospital setting. Data from the Emergency Medical Service in Hamburg (Germany) and data from the local weather station were evaluated over a 5-year period. Lowess-regression analysis was conducted to assess the relationship between ambient temperature and frequency of severe hypoglycemia. Additionally, three temperature-ranges were defined in order to compare them with each other with regard to frequency of severe hypoglycemia (<10°C vs. 10-20°C vs. >20°C). RESULTS: In 2592 patients severe hypoglycemia was diagnosed and treated by emergency physicians (T1DM: n=829/32%; T2DM: n=1763/68%). The median age of patients was 64 (57-72 [20-85]) years. Compared to mild temperatures (10-20°C) the frequency of severe hypoglycemia increased significantly at temperatures above 20°C (+18% (95%-CI: [7%; 22%], p=0.007) and below 10°C (+15% (95%-CI: [6%; 24%], p<0.001). CONCLUSIONS: The results suggest the existence of a "thermal comfort zone" covering a temperature range from 10 to 20°C in which the frequency of severe hypoglycemia was significantly lower than below 10°C and above 20°C.

Relationship between ambient temperature and frequency and severity of cardiovascular emergencies: A prospective observational study based on out-of-hospital care data.

OBJECTIVE: To test the hypothesis that more cardiovascular emergencies occur at low rather than at high temperatures under moderate climatic conditions. METHODS: This was a prospective observational study performed in a prehospital setting. Data from the Emergency Medical Service in Hamburg (Germany) and from the local weather station were evaluated over a 5-year period. Temperature data were matched with the associated rescue mission data. Lowess-Regression analysis was performed to assess the relationship between the temperature and the frequency of individual cardiovascular emergencies. In addition, three threshold-temperatures (0°C, 10°C, 20°C) were defined in order to determine the frequency of cardiovascular emergencies above and below each cut-off value. The severity of emergencies was assessed using the National Advisory Committee for Aeronautics (NACA) scoring system. RESULTS: A total of 35,390 cardiovascular emergencies were treated by Emergency Physicians. Transient Loss of Consciousness increased at high temperatures (above 20°C): +43% (95%-CI: [27%; 59%]). In contrast, Coronary Artery Disease +26% (95%-CI: [17%; 34%]), Cardiac Pulmonary Edema +21% (95%-CI: [14%; 27%]), Hypertensive Urgency +18% (95%-CI: [10%; 25%]) and Cerebrovascular Accident +17% (95%-CI: [8%; 24%]) increased at low temperatures, particularly below 10°C (significance level for all: p<0.001). No temperature-related effect was seen in Cardiac Arrhythmia and Pulmonary Embolism and no significant correlation was found between the severity of emergencies and temperature. CONCLUSIONS: Our findings suggest that some cardiovascular emergencies such as Coronary Artery Disease, Cardiac Pulmonary Edema, Hypertensive Urgency and Cerebrovascular Accident are more frequent in low temperatures even under mild climatic conditions.

Heart rate variability (HRV) in deep breathing tests and 5-min short-term recordings: agreement of ear photoplethysmography with ECG measurements, in 343 subjects.

PURPOSE: We analyzed heart rate variability (HRV) taken by ECG and photoplethysmography (PPG) to assess their agreement. We also analyzed the sensitivity and specificity of PPG to identify subjects with low HRV as an example of its potential use for clinical applications. METHODS: The HRV parameters: mean heart rate (HR), amplitude, and ratio of heart rate oscillation (E-I difference, E/I ratio), RMSSD, SDNN, and Power LF, were measured during 1-min deep breathing tests (DBT) in 343 individuals, followed by a 5-min short-term HRV (s-HRV), where the HRV parameters: HR, SD1, SD2, SDNN, Stress Index, Power HF, Power LF, Power VLF, and Total Power, were determined as well. Parameters were compared through correlation analysis and agreement analysis by Bland-Altman plots. RESULTS: PPG derived parameters HR and SD2 in s-HRV showed better agreement than SD1, Power HF, and stress index, whereas in DBT HR, E/I ratio and SDNN were superior to Power LF and RMSSD. DBT yielded stronger agreement than s-HRV. A slight overestimation of PPG HRV over HCG HRV was found. HR, Total Power, and SD2 in the s-HRV, HR, Power LF, and SDNN in the DBT showed high sensitivity and specificity to detect individuals with poor HRV. Cutoff percentiles are given for the future development of PPG-based devices. CONCLUSION: HRV measured by PPG shows good agreement with ECG HRV when appropriate parameters are used, and PPG-based devices can be employed as an easy screening tool to detect individuals with poor HRV, especially in the 1-min DBT test.

Top-down and bottom-up modulation of pain-induced oscillations.

Attention is an important factor that is able to strongly modulate the experience of pain. In order to differentiate cortical mechanisms underlying subject-driven (i.e., top-down) and stimulus-driven (bottom-up) modes of attentional pain modulation, we recorded electric brain activity in healthy volunteers during painful laser stimulation while spatial attention and stimulus intensity were systematically varied. The subjects' task was to evaluate the pain intensity at the attended finger, while ignoring laser stimuli delivered to the other finger. Top-down (attention) and bottom up (intensity) influences differed in their effects on oscillatory response components. Attention towards pain induced a decrease in alpha and an increase in gamma band power, localized in the insula. Pain intensity modulated delta, alpha, beta and gamma band power. Source localization revealed stimulus driven modulation in the cingulate gyrus (CG) and somatosensory areas for gamma power changes. Our results indicate that bottom-up and top-down modes of processing exert different effects on pain-induced slow and fast oscillatory activities. Future studies may examine pain-induced oscillations using this paradigm to test for altered attentional pain control in patients with chronic pain.

The influence of music and music therapy on pain-induced neuronal oscillations measured by magnetencephalography.

Modern forms of music therapy are clinically established for various therapeutic or rehabilitative goals, especially in the treatment of chronic pain. However, little is known about the neuronal mechanisms that underlie pain modulation by music. Therefore, we attempted to characterize the effects of music therapy on pain perception by comparing the effects of 2 different therapeutic concepts, referred to as receptive and entrainment methods, on cortical activity recorded by magnetencephalography in combination with laser heat pain. Listening to preferred music within the receptive method yielded a significant reduction of pain ratings associated with a significant power reduction of delta-band activity in the cingulate gyrus, which suggests that participants displaced their focus of attention away from the pain stimulus. On the other hand, listening to self-composed "pain music" and "healing music" within the entrainment method exerted major effects on gamma-band activity in primary and secondary somatosensory cortices. Pain music, in contrast to healing music, increased pain ratings in parallel with an increase in gamma-band activity in somatosensory brain structures. In conclusion, our data suggest that the 2 music therapy approaches operationalized in this study seem to modulate pain perception through at least 2 different mechanisms, involving changes of activity in the delta and gamma bands at different stages of the pain processing system.

Cognitive and weight-related correlates of flexible and rigid restrained eating behaviour.

OBJECTIVES: Examine the association between components of restrained eating, cognitive performance and weight loss maintenance. METHODS: 106 women, all members of a commercial slimming organisation for at least 6 months (mean±SD: 15.7±12.4 months), were studied who, having lost 10.1±9.7 kg of their initial weight, were hoping to sustain their weight loss during the 6 month study. Dietary restraint subcomponents flexible and rigid restraint, as well as preoccupying cognitions with food, body-shape and diet were assessed using questionnaires. Attentional bias to food and shape-related stimuli was measured using a modified Stroop test. Working memory performance was assessed using the N-back test. These factors, and participant weight, were measured twice at 6 month intervals. RESULTS: Rigid restraint was associated with attentional bias to food and shape-related stimuli (r=0.43, p<0.001 resp. r=0.49, p<0.001) whereas flexible restraint correlated with impaired working memory (r=-0.25, p<0.05). In a multiple regression analyses, flexible restraint was associated with more weight lost and better weight loss maintenance, while rigid restraint was associated with less weight loss. CONCLUSIONS: Rigid restraint correlates with a range of preoccupying cognitions and attentional bias to food and shape-related stimuli. Flexible restraint, despite the impaired working memory performance, predicts better long-term weight loss. Explicitly encouraging flexible restraint may be important in preventing and treating obesity.

Psychophysical and cerebral responses to heat stimulation in patients with central pain, painless central sensory loss, and in healthy persons.

Patients with central pain (CP) typically have chronic pain within an area of reduced pain and temperature sensation, suggesting an impairment of endogenous pain modulation mechanisms. We tested the hypothesis that some brain structures normally activated by cutaneous heat stimulation would be hyperresponsive among patients with CP but not among patients with a central nervous system lesion causing a loss of heat or nociceptive sensation with no pain (NP). We used H(2)(15)O positron emission tomography to measure, in 15 healthy control participants, 10 NP patients, and 10 CP patients, increases in regional cerebral blood flow among volumes of interest (VOI) from the resting (no stimulus) condition during bilateral contact heat stimulation at heat detection, heat pain threshold, and heat pain tolerance levels. Both patient groups had a reduced perception of heat intensity and unpleasantness on the clinically affected side and a bilateral impairment of heat detection. Compared with the HC group, both NP and CP patients had more hyperactive and hypoactive VOI in the resting state and more hyperresponsive and hyporesponsive VOI during heat stimulation. Compared with NP patients, CP patients had more hyperresponsive VOI in the intralaminar thalamus and sensory-motor cortex during heat stimulation. Our results show that focal CNS lesions produce bilateral sensory deficits and widespread changes in the nociceptive excitability of the brain. The increased nociceptive excitability within the intralaminar thalamus and sensory-motor cortex of our sample of CP patients suggests an underlying pathophysiology for the pain in some central pain syndromes.

Somatotopy of placebo analgesia is independent of spatial attention.

Placebo analgesia is being increasingly appraised as an effective support of pharmacological and surgical treatments of pain. The understanding of its neurobiological and psychological basis is therefore of high clinical relevance. It has been shown that placebo analgesia is somatotopically organized and relies on endogenous opioids. However, it is not clear whether temporal fluctuations of cue-dependent spatial attention account for the site specificity of placebo analgesia or whether a somatotopic placebo effect is possible without an attentional focus on the respective location. To address this issue we induced placebo expectations for one specific foot in healthy subjects, the other foot serving as a control location. The feet were stimulated in random order by painful laser stimuli. Half of the pulses were cued for stimulus location, whereas in the other half of trials the subjects were naïve about the location. We found that about half of the subjects exhibited a somatotopic placebo effect that was statistically independent of the spatial cue. We suggest that, after the induction of an initial expectation, placebo analgesia is spatially specific but does not necessarily depend on momentary fluctuations of spatial attention. This result rather suggests that the somatotopy of placebo analgesia relies on the creation of spatially guided expectations or conditioning, but can be maintained without ongoing monitoring of the affected body part.

Laser-evoked potentials: prognostic relevance of pain pathway defects in patients with acute radiculopathy.

The radicular pain syndrome is a major problem in public health care that can lead to chronic back and leg pain in 30%. Ischalgia and back pain are the most prominent signs of dorsal root affection. Until now, no clinical or neurophysiological test procedure exists that evaluates the function of the dorsal root and predicts the prognosis of patients suffering from RPS. We have recently demonstrated that laser-evoked potentials (LEP) are able to demonstrate dorsal root damage. With this study, we investigated 54 patients with acute radicular symptoms and compared LEP parameters (side to side difference of latency and amplitude, transformed to a z-score) with their state of health after 3 months to calculate their predictive value for outcome prognosis. Most significantly, the latency difference between the LEP of the affected dermatome relative to the contralateral healthy dermatome was able to predict the prognosis. Latency z score above two demonstrates a 91% specificity (33% sensitivity) for a poor outcome at 3 months. A significant relation between amplitude changes and the main outcome measure could not be shown. Only extreme changes (z score >10) in amplitude show a high specificity for the persistence of ischialgia in particular (specificity 0.94; sensitivity 0.35). All other parameters, such as clinical scores or other LEP parameters, were not able to predict the outcome of patients. We propose that clinical testing using LEP with latency analysis is a useful tool for estimating the course of disease, so that patients with poor predictive parameters can be treated more invasively at early disease stages to avoid persistence of radiculopathy.

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.