Faculty Bibliography

PURPOSE/OBJECTIVE:Obstructive sleep apnea (OSA) is a risk factor for complications with postoperative opioid use, and in those patients with known or suspected OSA, minimization of postoperative opioids is recommended. We hypothesize that despite these recommendations, surgical patients with known or suspected OSA are prescribed postoperative opioids at hospital discharge at similar doses to those without OSA. METHODS:This was a retrospective analysis of the electronic health records of surgical patients from 1 November 2016 to 30 April 2017 at a single academic institution. Patients with a known diagnosis of OSA or a STOP-Bang score ≥ 5 were compared with those without OSA for the amount of postoperative discharge opioid medication using multivariable linear regression. RESULTS:Of the 17,671 patients analyzed, 1,692 (9.6%) had known or suspected OSA with 1,450 (86%) of these patients discharged on opioid medications. Of the 15,979 patients without OSA, 12,273 (77%) were discharged on opioid medications. The total median [interquartile range (IQR)] oral morphine equivalents (OME) for all patients was 150 [0-338] mg and for patients with known or suspected OSA was 160 [0-450] mg, an unadjusted comparison showing an 18% difference in OME (95% confidence interval [CI], 3% to 35%; P = 0.02). The analysis, after adjusting for confounders, showed no significant difference in the amount of opioids prescribed to OSA or non-OSA patients (8% difference in total OME; 95% CI, -6% to 25%; P = 0.26). CONCLUSION/CONCLUSIONS:This study shows that surgical patients at risk for OSA or confirmed OSA are prescribed opioids at similar rates and doses upon discharge despite guidelines that recommend minimizing opioid use in OSA patients. These findings indicate a need to implement different strategies to reduce the prescription of opioids to patients with OSA.

Pain is a complex sensory and affective experience. Through its anticipation, animals can learn to avoid pain. Much is known about passive avoidance during a painful event; however, less is known about active pain avoidance. The anterior cingulate cortex (ACC) is a critical hub for affective pain processing. However, there is currently no mechanism that links ACC activities at the cellular level with behavioral anticipation or avoidance. Here we asked whether distinct populations of neurons in the ACC can encode information for pain anticipation. We used tetrodes to record from ACC neurons during a conditioning assay to train rats to avoid pain. We found that in rats that successfully avoid acute pain episodes, neurons that responded to pain shifted their firing rates to an earlier time, whereas neurons that responded to the anticipation of pain increased their firing rates prior to noxious stimulation. Furthermore, we found a selected group of neurons that shifted their firing from a pain-tuned response to an anticipatory response. Unsupervised learning analysis of ensemble spike activity indicates that temporal spiking patterns of ACC neurons can indeed predict the onset of pain avoidance. These results suggest rate and temporal coding schemes in the ACC for pain avoidance.

Pain is a complex sensory and affective experience. The current definition for pain relies on verbal reports in clinical settings and behavioral assays in animal models. These definitions can be subjective and do not take into consideration signals in the neural system. Local field potentials (LFPs) represent summed electrical currents from multiple neurons in a defined brain area. Although single neuronal spike activity has been shown to modulate the acute pain, it is not yet clear how ensemble activities in the form of LFPs can be used to decode the precise timing and intensity of pain. The anterior cingulate cortex (ACC) is known to play a role in the affective-aversive component of pain in human and animal studies. Few studies, however, have examined how neural activities in the ACC can be used to interpret or predict acute noxious inputs. Here, we recorded in vivo extracellular activity in the ACC from freely behaving rats after stimulus with non-noxious, low-intensity noxious, and high-intensity noxious stimuli, both in the absence and chronic pain. Using a supervised machine learning classifier with selected LFP features, we predicted the intensity and the onset of acute nociceptive signals with high degree of precision. These results suggest the potential to use LFPs to decode acute pain.

Acute pain evokes protective neural and behavioral responses. Chronic pain, however, disrupts normal nociceptive processing. The prefrontal cortex (PFC) is known to exert top-down regulation of sensory inputs; unfortunately, how individual PFC neurons respond to an acute pain signal is not well characterized. We found that neurons in the prelimbic region of the PFC increased firing rates of the neurons after noxious stimulations in free-moving rats. Chronic pain, however, suppressed both basal spontaneous and pain-evoked firing rates. Furthermore, we identified a linear correlation between basal and evoked firing rates of PFC neurons, whereby a decrease in basal firing leads to a nearly 2-fold reduction in pain-evoked response in chronic pain states. In contrast, enhancing basal PFC activity with low-frequency optogenetic stimulation scaled up prefrontal outputs to inhibit pain. These results demonstrate a cortical gain control system for nociceptive regulation and establish scaling up prefrontal outputs as an effective neuromodulation strategy to inhibit pain.

Sequential change-point detection from time series data is a common problem in many neuroscience applications, such as seizure detection, anomaly detection, and pain detection. In our previous work (Chen et al., 2017, J. Neural Eng.), we have developed a latent state space model, known as Poisson linear dynamical system (PLDS), for detecting abrupt changes in neuronal ensemble spike activity. In online brain-machine interface (BMI) applications, a recursive filtering algorithm is used to track the changes in the latent variable. However, previous methods have restricted to Gaussian dynamical noise and have used Gaussian approximation for the Poisson likelihood. To improve the detection speed, we introduce non-Gaussian dynamical noise for modeling a stochastic jump process in the latent state space. To efficiently estimate the state posterior that accommodates non-Gaussian noise and non-Gaussian likelihood, we propose particle filtering and smoothing algorithms for the change-point detection problem. To speed up the computation, we implement the proposed particle filtering algorithms using advanced GPU (graphic processing unit) computing technology. We validate our algorithms using both computer simulations and experimental data for acute pain detection. Finally, we discuss several important practical issues in the context of real-time closed-loop BMI applications.

BACKGROUND:Next-generation sequencing of cell-free DNA (cfDNA) has been shown to be a useful noninvasive test for detecting mutations in solid tumors. METHODS:Targeted gene sequencing was performed with a panel of 263 cancer-related genes for cfDNA and genomic DNA of peripheral blood mononuclear cells (PBMCs) obtained from presurgical specimens of 6 lung cancer patients, and mutation calls in these samples were compared with those of primary tumors and corresponding patient-derived xenografts (PDXs). RESULTS:Approximately 67% of the mutations detected in the tumor samples (primary tumors and/or PDXs) were also detected in genomic DNA from PBMCs as background mutations. These background mutations consisted of germline polymorphisms and a group of mutations with low allele frequencies, mostly <10%. These variants with a low allele frequency were repeatedly detected in all types of samples from the same patients and at similarly low allele frequency levels in PBMCs from different patients; this indicated that their detection might be derived from common causes, such as homologous sequences in the human genome. Allele frequencies of mutations detected in both primary tumors and cfDNA showed 2 patterns: 1) low allele frequencies (approximately 1%-10%) in cfDNA but high allele frequencies (usually >10% or >3-fold increase) in primary tumors and further enrichment in PDXs and 2) similar allele frequencies across samples. CONCLUSIONS:Because only a small fraction of total cfDNA might be derived from tumor cells, only mutations with the first allele frequency pattern may be regarded as tumor-specific mutations in cfDNA. Effective filtering of background mutations will be required to improve the accuracy of mutation calls in cfDNA. Cancer 2018;124:1061-9. © 2017 American Cancer Society.

Cortical mechanisms that regulate acute or chronic pain remain poorly understood. The prefrontal cortex (PFC) exerts crucial control of sensory and affective behaviors. Recent studies show that activation of the projections from the PFC to the nucleus accumbens (NAc), an important pathway in the brain's reward circuitry, can produce inhibition of both sensory and affective components of pain. However, it is unclear whether this circuit is endogenously engaged in pain regulation. To answer this question, we disrupted this circuit using an optogenetic strategy. We expressed halorhodopsin in pyramidal neurons from the PFC, and then selectively inhibited the axonal projection from these neurons to neurons in the NAc core. Our results reveal that inhibition of the PFC or its projection to the NAc, heightens both sensory and affective symptoms of acute pain in naïve rats. Inhibition of this corticostriatal pathway also increased nociceptive sensitivity and the aversive response in a chronic neuropathic pain model. Finally, corticostriatal inhibition resulted in a similar aversive phenotype as chronic pain. These results strongly suggest that the projection from the PFC to the NAc plays an important role in endogenous pain regulation, and its impairment contributes to the pathology of chronic pain.

The anterior cingulate cortex (ACC) is thought to be important for acute pain perception as well as the development of chronic pain after peripheral nerve injury. Nevertheless, how ACC neurons respond to sensory stimulation under chronic pain states is not well understood. Here, we used an in vivo two-photon imaging technique to monitor the activity of individual neurons in the ACC of awake, head restrained mice. Calcium imaging in the dorsal ACC revealed robust somatic activity in layer 5 (L5) pyramidal neurons in response to peripheral noxious stimuli, and the degree of evoked activity was correlated with the intensity of noxious stimulation. Furthermore, the activation of ACC neurons occurred bilaterally upon noxious stimulation to either contralateral or ipsilateral hind paws. Notably, with nerve injury-induced neuropathic pain in one limb, L5 pyramidal neurons in both sides of the ACC showed enhanced activity in the absence or presence of pain stimuli. These results reveal hyperactivity of L5 pyramidal neurons in the bilateral ACC during the development of neuropathic pain.

Pain is a complex experience. The aversive component of pain has been assessed through conditioned place aversion in rodents. However, this behavioral test does not allow the evaluation of the aversion of an acute pain stimulus. In Zhang et al. (2017), we provide an updated version of a Conditioned Place Aversion paradigm to address this challenge. In this protocol, a detailed version of this method is described.

Glutamate signaling in the central nervous system is known to play a key role in pain regulation. AMPAkines can enhance glutamate signaling through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. previous studies have shown that AMPAkines are effective analgesic agents, and their site of action is likely in the brain. It is not known, however, if AMPAkines can provide complementary analgesia in combination with opioids, the most commonly used analgesics. Here, we show that the co-administration of an AMPAkine with morphine can provide additional analgesia, both in naive rats and in rats that experience postoperative pain. Furthermore, we show that this AMPAkine can be administered directly into the prefrontal cortex to provide analgesia, and that prefrontal AMPAkine infusion, similar to systemic administration, can provide added pain relief to complement morphine analgesia.