Hippocampus mediates nocebo impairment of opioid analgesia through changes in functional connectivity.

The neural mechanisms underlying placebo analgesia have attracted considerable attention over the recent years. In contrast, little is known about the neural underpinnings of a nocebo-induced increase in pain. We previously showed that nocebo-induced hyperalgesia is accompanied by increased activity in the hippocampus that scaled with the perceived level of anxiety. As a key node of the neural circuitry of perceived threat and fear, the hippocampus has recently been proposed to coordinate defensive behaviour in a context-dependent manner. Such a role requires close interactions with other regions involved in the detection of and responses to threat. Here, we investigated the functional connectivity of the hippocampus during nocebo-induced hyperalgesia. Our results show an increase in functional connectivity between hippocampus and brain regions implicated in the processing of sensory-discriminative aspects of pain (posterior insula and primary somatosensory/motor cortex) as well as the periaqueductal grey. This nocebo-induced increase in connectivity scaled with an individual's increase in anxiety. Moreover, hippocampus connectivity with the amygdala was negatively correlated with the pain intensity reported during nocebo hyperalgesia relative to the placebo condition. Our findings suggest that the hippocampus links nocebo-induced anxiety to a heightened responsiveness to nociceptive input through changes in its crosstalk with pain-modulatory brain areas.

Ultrasound-guided continuous deep serratus anterior plane block versus continuous thoracic paravertebral block for perioperative analgesia in videoscopic-assisted thoracic surgery.

BACKGROUND: The deep serratus anterior plane block (SAPB) is a promising novel regional anaesthesia technique for blockade of the anterolateral chest wall. Evidence for the efficacy of SAPB versus other analgesic techniques in thoracic surgery remains inadequate. AIMS: This study compared ultrasound-guided continuous SAPB with a surgically placed continuous thoracic paravertebral block (SPVB) technique in patients undergoing videoscopic-assisted thoracic surgery (VATS). METHODS: In a single-centre, double-blinded, randomized, non-inferiority study, we allocated 40 patients undergoing VATS to either SAPB or SPVB, with both groups receiving otherwise standardized treatment, including multimodal analgesia. The primary outcome was 48-hr opioid consumption. Secondary outcomes included numerical rating scale (NRS) for postoperative pain, patient-reported worst pain score (WPS) as well as functional measures (including mobilization distance and cough strength). RESULTS: A 48-hr opioid consumption for the SAPB group was non-inferior compared with SPVB. SAPB was associated with improved NRS pain scores at rest, with cough and with movement at 24 hr postoperatively (p = .007, p = .001 and p = .012, respectively). SAPB was also associated with a lower WPS (p = .008). Day 1 walking distance was improved in the SAPB group (p = .012), whereas the difference in cough strength did not reach statistical significance (p = .071). There was no difference in haemodynamics, opioid side effects, length of hospital stay or patient satisfaction between the two groups. CONCLUSIONS: The SAPB, as part of a multimodal analgesia regimen, is non-inferior in terms of 48-hr opioid consumption compared to SPVB and is associated with improved functional measures in thoracic surgical patients. ClinicalTrials.gov Identifier: NCT03768193. SIGNIFICANCE: The SAPB interfascial plane block is an efficacious alternative method of opioid-sparing analgesia in high-risk thoracic surgical patients as part of an enhanced recovery programme.

Accuracy of ultrasound in measurement of the pediatric cricothyroid membrane.

BACKGROUND: Emergency front of neck airway is a recommended airway rescue strategy in children over 1 year old. Surgical tracheostomy is advocated as the first-line technique, but in the absence of an ear, nose and throat surgeon cricothyroidotomy or tracheostomy is proposed. Recent research shows that clinical identification of the cricothyroid membrane is frequently inaccurate in older children and adults and has prompted investigation of ultrasound as a potential clinical tool for emergency front of neck airway. Advance knowledge of the dimensions of the pediatric cricothyroid membrane may assist clinicians in determining the feasibility of emergency front of neck airway, optimum technique, and equipment. AIMS: The aim of this study was to assess the accuracy of ultrasound-assisted pediatric cricothyroid membrane localization and dimension measurement using magnetic resonance imaging as the reference standard. METHODS: After structured training, two pediatric anesthesiology trainees used ultrasound to identify and measure the dimensions of the cricothyroid membrane in pediatric patients undergoing elective magnetic resonance imaging of the head and neck under general anesthesia. A pediatric radiologist reviewed the corresponding magnetic resonance imaging scans and measured the height of the cricothyroid membrane. The accuracy of the cricothyroid membrane height as measured by ultrasound was compared to that measured by magnetic resonance imaging. RESULTS: Twenty-two patients were included in the study. The cricothyroid membrane was accurately identified by ultrasound in all cases. The correlation coefficient for cricothyroid membrane height measured by ultrasound and that measured by magnetic resonance imaging was 0.98 (95% C.I 0.95-0.99, P < 0.0001). The bias was -0.16 mm and the precision was 0.19 mm. All differences were within the a priori limits of agreement. The 95% limits of agreement were -0.54 to 0.22 mm. CONCLUSION: Ultrasound can be used to accurately identify and measure cricothyroid membrane height in pediatric patients. This approach could have clinical and research utility.

Anesthesia-induced Suppression of Human Dorsal Anterior Insula Responsivity at Loss of Volitional Behavioral Response.

BACKGROUND: It has been postulated that a small cortical region could be responsible for the loss of behavioral responsiveness (LOBR) during general anesthesia. The authors hypothesize that any brain region demonstrating reduced activation to multisensory external stimuli around LOBR represents a key cortical gate underlying this transition. Furthermore, the authors hypothesize that this localized suppression is associated with breakdown in frontoparietal communication. METHODS: During both simultaneous electroencephalography and functional magnetic resonance imaging (FMRI) and electroencephalography data acquisition, 15 healthy volunteers experienced an ultraslow induction with propofol anesthesia while a paradigm of multisensory stimulation (i.e., auditory tones, words, and noxious pain stimuli) was presented. The authors performed separate analyses to identify changes in (1) stimulus-evoked activity, (2) functional connectivity, and (3) frontoparietal synchrony associated with LOBR. RESULTS: By using an FMRI conjunction analysis, the authors demonstrated that stimulus-evoked activity was suppressed in the right dorsal anterior insula cortex (dAIC) to all sensory modalities around LOBR. Furthermore, the authors found that the dAIC had reduced functional connectivity with the frontoparietal regions, specifically the dorsolateral prefrontal cortex and inferior parietal lobule, after LOBR. Finally, reductions in the electroencephalography power synchrony between electrodes located in these frontoparietal regions were observed in the same subjects after LOBR. CONCLUSIONS: The authors conclude that the dAIC is a potential cortical gate responsible for LOBR. Suppression of dAIC activity around LOBR was associated with disruption in the frontoparietal networks that was measurable using both electroencephalography synchrony and FMRI connectivity analyses.

Slow-wave activity saturation and thalamocortical isolation during propofol anesthesia in humans.

The altered state of consciousness produced by general anesthetics is associated with a variety of changes in the brain's electrical activity. Under hyperpolarizing influences such as anesthetic drugs, cortical neurons oscillate at ~1 Hz, which is measurable as slow waves in the electroencephalogram (EEG). We have administered propofol anesthesia to 16 subjects and found that, after they had lost behavioral responsiveness (response to standard sensory stimuli), each individual's EEG slow-wave activity (SWA) rose to saturation and then remained constant despite increasing drug concentrations. We then simultaneously collected functional magnetic resonance imaging and EEG data in 12 of these subjects during propofol administration and sensory stimulation. During the transition to SWA saturation, the thalamocortical system became isolated from sensory stimuli, whereas internal thalamocortical exchange persisted. Rather, an alternative and more fundamental cortical network (which includes the precuneus) responded to all sensory stimulation. We conclude that SWA saturation is a potential individualized indicator of perception loss that could prove useful for monitoring depth of anesthesia and studying altered states of consciousness.

The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil.

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.