Faculty Bibliography

Brain-machine interfaces (BMIs) have been widely used to study basic and translational neuroscience questions. In real-time closed-loop neuroscience experiments, many practical issues arise, such as trial-by-trial variability, and spike sorting noise or multi-unit activity. In this paper, we propose a new framework for change-point detection based on ensembles of independent detectors in the context of BMI application for detecting acute pain signals. Motivated from ensemble learning, our proposed "ensembles of change-point detectors" (ECPDs) integrate multiple decisions from independent detectors, which may be derived based on data recorded from different trials, data recorded from different brain regions, data of different modalities, or models derived from different learning methods. By integrating multiple sources of information, the ECPDs aim to improve detection accuracy (in terms of true positive and true negative rates) and achieve an optimal trade-off of sensitivity and specificity. We validate our method using computer simulations and experimental recordings from freely behaving rats. Our results have shown superior and robust performance of ECPDS in detecting the onset of acute pain signals based on neuronal population spike activity (or combined with local field potentials) recorded from single or multiple brain regions.

BACKGROUND:Traditional methods to assess pain in rodents depend on measures of nociceptive responses, most commonly from the hind paws. While these measures can quantify nociceptive responses to allow pharmacologic testing, they typically have high inter-experimenter variability and are not time-sensitive enough to correct with neural processes that occur on millisecond scales. NEW METHOD/UNASSIGNED:We have invented a pain detection device that uses changes in skin conductance to measure nocifensive withdrawal responses. This device automatically records how long it takes for a rodent to withdraw its paw from the onset of peripheral noxious stimulation. RESULTS:with this pain device, we can record accurate timing (on the millisecond scale) for nociceptive responses, with high accuracy and consistency. Furthermore, we demonstrate that this device can allow us to distinguish the nociceptive response to mechanical noxious stimuli of different intensities. Finally, we demonstrate that this device can be digitally integrated to correlate behavior with neural activities in real-time. CONCLUSIONS:This study demonstrates a new automated, temporally specific method for quantifying nociceptive responses to facilitate rodent pain studies.

BACKGROUND:When administered as a continuous infusion, ketamine is known to be a potent analgesic and general anaesthetic. Recent studies suggest that a single low-dose administration of ketamine can provide a long-lasting effect on mood, but its effects when given in the postoperative period have not been studied. OBJECTIVE:We hypothesised that a single low-dose administration of ketamine after bariatric surgery can improve pain and mood scores in the immediate postoperative period. DESIGN/METHODS:We performed a randomised, double-blind, placebo-controlled study to compare a single subanaesthetic dose of ketamine (0.4 mg kg) with a normal saline placebo in the postanaesthesia care unit after laparoscopic gastric bypass and gastrectomy. SETTING/METHODS:Single-centre, tertiary care hospital, October 2014 to January 2018. PATIENTS/METHODS:A total of 100 patients were randomised into the ketamine and saline groups. INTERVENTION/METHODS:Patients in the ketamine group received a single dose of ketamine infusion (0.4 mg kg) in the postanaesthesia care unit. Patients in the placebo groups received 0.9% saline. OUTCOME MEASURES/METHODS:The primary outcome was the visual analogue pain score. A secondary outcome was performance on the short-form McGill's Pain Questionnaire (SF-MPQ). RESULTS:There were no significant differences in visual analogue pain scores between groups (group-by-time interaction P = 0.966; marginal group effect P = 0.137). However, scores on the affective scale of SF-MPQ (secondary outcome) significantly decreased in the ketamine group as early as postoperative day (POD) 2 [mean difference = -2.2 (95% bootstrap CI -2.9 to 1.6), Bonferroni adjusted P < 0.001], compared with placebo group in which the scores decreased only by POD 7. Scores on the total scale of SF-MPQ for the ketamine group were smaller compared with the placebo group (P = 0.034). CONCLUSION/CONCLUSIONS:Although there was no significant difference between ketamine and placebo for the primary outcome measure, patients who received ketamine experienced statistically and clinically significant improvement in their comprehensive evaluation of pain, particularly the affective component of pain, on POD 2. However, future studies are needed to confirm the enduring effects of ketamine on the affective response to postoperative pain. CLINICAL TRIAL REGISTRATION/BACKGROUND:NCT02452060.

BACKGROUND:The current opioid epidemic highlights the urgent need for effective adjuvant therapies to complement postoperative opioid analgesia. Intra-operative ketamine infusion has been shown to reduce postoperative opioid consumption and improve pain control in opioid-tolerant patients after spinal fusion surgery. Its efficacy for opioid-naïve patients, however, remains controversial. OBJECTIVE:We hypothesised that low-dose ketamine infusion after major spinal surgery reduces opioid requirements in opioid-tolerant patients, but not in opioid-naïve patients. DESIGN/METHODS:Randomised placebo-controlled prospective study. SETTING/METHODS:Single-centre, tertiary care hospital, November 2012 until November 2014. PATIENTS/METHODS:A total of 129 patients were classified as either opioid-tolerant (daily use of opioid medications during 2 weeks preceding the surgery) or opioid-naïve group, then randomised to receive either ketamine or placebo; there were thus four groups of patients. All patients received intravenous hydromorphone patient-controlled analgesia postoperatively. INTERVENTION/METHODS:Patients in the ketamine groups received a ketamine infusion (bolus 0.2 mg kg over 30 min followed by 0.12 mg kg h for 24 h). Patients in the placebo groups received 0.9% saline. MAIN OUTCOME MEASURES/METHODS:The primary outcome was opioid consumption during the first 24 h postoperatively. The secondary outcome was numerical pain scores during the first 24 h and central nervous system side effects. RESULTS:Postoperative hydromorphone consumption was significantly reduced in the opioid-tolerant ketamine group, compared with the opioid-tolerant placebo group [0.007 (95% CI 0.006 to 0.008) versus 0.011 (95% CI 0.010 to 0.011) mg kg h, Bonferroni corrected P < 0.001]. There was no difference in hydromorphone use between the opioid-naïve groups (0.004 and 0.005 mg kg h in the opioid-naïve ketamine and placebo group, respectively, P = 0.118). Pain scores did not differ significantly between the opioid-tolerant ketamine group and the opioid-naïve groups. There was no significant difference in side effects among groups. CONCLUSION/CONCLUSIONS:Postoperative low-dose ketamine infusion reduces opioid requirements for the first 24 h following spinal fusion surgery in opioid-tolerant, but not in opioid-naïve patients. TRIAL REGISTRATION/BACKGROUND:NCT03274453 with clinicaltrials.gov.

Pain is a salient and complex sensory experience with important affective and cognitive dimensions. The current definition of pain relies on subjective reports in both humans and experimental animals. Such definition lacks basic mechanistic insights and can lead to a high degree of variability. Research on biomarkers for pain has previously focused on genetic analysis. However, recent advances in human neuroimaging and research in animal models have begun to show the promise of a circuit-based neural signature for pain. At the treatment level, pharmacological therapy for pain remains limited. Neuromodulation has emerged as a specific form of treatment without the systemic side effects of pharmacotherapies. In this review, we will discuss some of the current neuromodulatory modalities for pain, research on newer targets, as well as emerging possibility for an integrated brain-computer interface approach for pain management.

Pain is a complex multidimensional experience encompassing sensory-discriminative, affective-motivational and cognitive-emotional components mediated by different neural mechanisms. Investigations of neurophysiological signals from simultaneous recordings of two or more cortical circuits may reveal important circuit mechanisms on cortical pain processing. The anterior cingulate cortex (ACC) and primary somatosensory cortex (S1) represent two most important cortical circuits related to sensory and affective processing of pain. Here, we recorded in vivo extracellular activity of the ACC and S1 simultaneously from male adult Sprague-Dale rats (n = 5), while repetitive noxious laser stimulations were delivered to animalÕs hindpaw during pain experiments. We identified spontaneous pain-like events based on stereotyped pain behaviors in rats. We further conducted systematic analyses of spike and local field potential (LFP) recordings from both ACC and S1 during evoked and spontaneous pain episodes. From LFP recordings, we found stronger phase-amplitude coupling (theta phase vs. gamma amplitude) in the S1 than the ACC (n = 10 sessions), in both evoked (p = 0.058) and spontaneous pain-like behaviors (p = 0.017, paired signed rank test). In addition, pain-modulated ACC and S1 neuronal firing correlated with the amplitude of stimulus-induced event-related potentials (ERPs) during evoked pain episodes. We further designed statistical and machine learning methods to detect pain signals by integrating ACC and S1 ensemble spikes and LFPs. Together, these results reveal differential coding roles between the ACC and S1 in cortical pain processing, as well as point to distinct neural mechanisms between evoked and putative spontaneous pain at both LFP and cellular levels.

Ca2+-sensing receptor (CaSR) represents a potential therapeutic target for inflammatory bowel diseases and strongly prefers aromatic amino acid ligands. We investigated the regulatory effects of dietary supplementation with aromatic amino acids - tryptophan, phenylalanine and tyrosine (TPT) - on the CaSR signalling pathway and intestinal inflammatory response. The in vivo study was conducted with weanling piglets using a 2 × 2 factorial arrangement in a randomised complete block design. Piglets were fed a basal diet or a basal diet supplemented with TPT and with or without inflammatory challenge. The in vitro study was performed in porcine intestinal epithelial cell line to investigate the effects of TPT on inflammatory response using NPS-2143 to inhibit CaSR. Dietary supplementation of TPT alleviated histopathological injury and decreased myeloperoxidase activity in intestine challenged with lipopolysaccharide. Dietary supplementation of TPT decreased serum concentration of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-12, granulocyte-macrophage colony-stimulating factor, TNF-α), as well as the mRNA abundances of pro-inflammatory cytokines in intestine but enhanced anti-inflammatory cytokines IL-4 and transforming growth factor-β mRNA levels compared with pigs fed control diet and infected by lipopolysaccharide. Supplementation of TPT increased CaSR and phospholipase Cβ2 protein levels, but decreased inhibitor of NF-κB kinase α/β and inhibitor of NF-κB (IκB) protein levels in the lipopolysaccharide-challenged piglets. When the CaSR signalling pathway was blocked by NPS-2143, supplementation of TPT decreased the CaSR protein level, but enhanced phosphorylated NF-κB and IκB levels in IPEC-J2 cells. To conclude, supplementation of aromatic amino acids alleviated intestinal inflammation as mediated through the CaSR signalling pathway.

OBJECTIVE:In the context of the current opioid epidemic, there has been a renewed interest in the use of ketamine as an analgesic agent. METHODS:We have reviewed ketamine analgesia. RESULTS:Ketamine is well-known as an antagonist for N-methyl-D-aspartate receptors. In addition, it can regulate the function of opioid receptors and sodium channels. Ketamine also increases signaling through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. These myriad of molecular and cellular mechanisms are responsible for a number of pharmacological functions including pain relief and mood regulation. Clinically, a number of studies have investigated the role of ketamine in the setting of acute and chronic pain, and there is evidence that ketamine can provide analgesia in a variety of pain syndromes. DISCUSSION/CONCLUSIONS:In this review, we have examined basic mechanisms of ketamine and its current clinical use as well as potential novel use in pain management.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC/UNASSIGNED:WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Hypotension is a risk factor for adverse perioperative outcomes. Machine learning methods allow large amounts of data for development of robust predictive analytics. The authors hypothesized that machine learning methods can provide prediction for the risk of postinduction hypotension METHODS:: Data was extracted from the electronic health record of a single quaternary care center from November 2015 to May 2016 for patients over age 12 that underwent general anesthesia, without procedure exclusions. Multiple supervised machine learning classification techniques were attempted, with postinduction hypotension (mean arterial pressure less than 55 mmHg within 10 min of induction by any measurement) as primary outcome, and preoperative medications, medical comorbidities, induction medications, and intraoperative vital signs as features. Discrimination was assessed using cross-validated area under the receiver operating characteristic curve. The best performing model was tuned and final performance assessed using split-set validation. RESULTS:Out of 13,323 cases, 1,185 (8.9%) experienced postinduction hypotension. Area under the receiver operating characteristic curve using logistic regression was 0.71 (95% CI, 0.70 to 0.72), support vector machines was 0.63 (95% CI, 0.58 to 0.60), naive Bayes was 0.69 (95% CI, 0.67 to 0.69), k-nearest neighbor was 0.64 (95% CI, 0.63 to 0.65), linear discriminant analysis was 0.72 (95% CI, 0.71 to 0.73), random forest was 0.74 (95% CI, 0.73 to 0.75), neural nets 0.71 (95% CI, 0.69 to 0.71), and gradient boosting machine 0.76 (95% CI, 0.75 to 0.77). Test set area for the gradient boosting machine was 0.74 (95% CI, 0.72 to 0.77). CONCLUSIONS:The success of this technique in predicting postinduction hypotension demonstrates feasibility of machine learning models for predictive analytics in the field of anesthesiology, with performance dependent on model selection and appropriate tuning.

Chronic pain is known to induce an amplified aversive reaction to peripheral nociceptive inputs. This enhanced affective response constitutes a key pathologic feature of chronic pain syndromes such as fibromyalgia. However, the neural mechanisms that underlie this important aspect of pain processing remain poorly understood, hindering the development of treatments. Here, we show that a single dose of ketamine can produce a persistent reduction in the aversive response to noxious stimuli in rodent chronic pain models, long after the termination of its anti-nociceptive effects. Furthermore, we demonstrated that this anti-aversive property is mediated by prolonged suppression of the hyperactivity of neurons in the anterior cingulate cortex (ACC), a brain region well known to regulate pain affect. Therefore, our results indicate that it is feasible to dissociate the affective from the sensory component of pain, and demonstrate the potential for low-dose ketamine to be an important therapy for chronic pain syndromes.