Faculty Bibliography

We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.

Pain is a complex multidimensional experience, and pain perception is still incompletely understood. Here we combine animal behavior, electrophysiology, and computer modeling to dissect mechanisms of evoked and spontaneous pain. We record the local field potentials (LFPs) from the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC) of freely behaving rats during pain episodes, and develop a predictive coding model to investigate the temporal coordination of oscillatory activity between the S1 and ACC. Our preliminary results from computational simulations support the experimental findings and provide new predictions.

Effective pharmacological treatment options for chronic pain remain very limited, and continued reliance on opioid analgesics has contributed to an epidemic in the U.S. On the other hand, non-pharmacologic neuromodulatory interventions provide a promising avenue for relief of chronic pain without the complications of dependence and addiction. An especially attractive neuromodulation strategy is to optimize endogenous pain regulatory circuits. The prefrontal cortex (PFC) is known to provide top-down control of pain, and hence neuromodulation methods that selectively enhance the activities in this brain region during pain episodes have the potential to provide analgesia. In this study, we designed a low-frequency (2 Hz) electrical stimulation protocol to provide temporally and spatially specific enhancement of the prefrontal control of pain in rats. We showed that low-frequency electrical stimulation of the prelimbic region of the PFC relieved both sensory and affective responses to acute pain in naïve rats. Furthermore, we found that low-frequency electrical stimulation of the PFC also attenuated mechanical allodynia in a rat model of chronic pain. Together, our findings demonstrated that low-frequency electrical stimulation of the PFC represents a promising new method of neuromodulation to inhibit pain.

Pain is a salient sensory experience with affective and cognitive dimensions. However, central mechanisms for pain remain poorly understood, hindering the development of effective therapeutics. Intracranial pharmacology presents an important tool for understanding the molecular and cellular mechanisms of pain in the brain, as well as for novel treatments. Here we present a protocol that integrates intracranial pharmacology with pain behavior testing. Specifically, we show how to infuse analgesic drugs into a select brain region, which may be responsible for pain modulation. Furthermore, to determine the effect of the candidate drug in the central nerve system, pain assays are performed after intracranial treatment. Our results demonstrate that intracranial administration of analgesic drugs in a targeted region can provide relief of pain in rodents. Thus, our protocol successfully demonstrates that intracranial pharmacology, combined with pain behavior testing, can be a powerful tool for the study of pain mechanisms in the brain.

OBJECTIVE:Sleep spindles have been implicated in memory consolidation and synaptic plasticity during NREM sleep. Detection accuracy and latency in automatic spindle detection are critical for real-time applications. APPROACH/METHODS:Here we propose a novel deep learning strategy (SpindleNet) to detect sleep spindles based on a single EEG channel. While the majority of spindle detection methods are used for off-line applications, our method is well suited for online applications. MAIN RESULTS/RESULTS:Compared with other spindle detection methods, SpindleNet achieves superior detection accuracy and speed, as demonstrated in two publicly available expert-validated EEG sleep spindle datasets. Our real-time detection of spindle onset achieves detection latencies of 150-350 ms (~2-3 spindle cycles) and retains excellent performance under low EEG sampling frequencies and low signal-to-noise ratios. SpindleNet has good generalization across different sleep datasets from various subject groups of different ages and species. SIGNIFICANCE/CONCLUSIONS:SpindleNet is ultra-fast and scalable to multichannel EEG recordings, with an accuracy level comparable to human experts, making it appealing for long-term sleep monitoring and closed-loop neuroscience experiments. &#13.

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: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.

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.

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.