Activation of LXRs alleviates neuropathic pain-induced cognitive dysfunction by modulation of microglia polarization and synaptic plasticity via PI3K/AKT pathway.

OBJECTIVE: Cognitive dysfunction is a common comorbidity in patients with chronic pain. Activation of Liver X receptors (LXRs) plays a potential role in improving cognitive disorders in central nervous diseases. In this study, we investigated the role of LXRs in cognitive deficits induced by neuropathic pain. METHODS: We established the spared nerve injury (SNI) model to investigate pain-induced memory dysfunction. Pharmacological activation of LXRs with T0901317 or inhibition with GSK2033 was applied. PI3K inhibitor LY294002 was administered to explore the underlying mechanism of LXRs. Changes in neuroinflammation, microglia polarization, and synaptic plasticity were assessed using biochemical technologies. RESULTS: We found that SNI-induced cognitive impairment was associated with reduced LXRß expression, increased M1-phenotype microglia, decreased synaptic proteins, and inhibition of PI3K/AKT signaling pathway in the hippocampus. Activation of LXRs using T0901317 effectively alleviated SNI-induced cognitive impairment. Additionally, T0901317 promoted the polarization of microglia from M1 to M2, reduced pro-inflammatory cytokines, and upregulated synaptic proteins in the hippocampus. However, administration of GSK2033 or LY294002 abolished these protective effects of T0901317 in SNI mice. CONCLUSIONS: LXRs activation alleviates neuropathic pain-induced cognitive impairment by modulating microglia polarization, neuroinflammation, and synaptic plasticity, at least partly via activation of PI3K/AKT signaling in the hippocampus. LXRs may be promising targets for addressing pain-related cognitive deficits.

The pleiotropic of GLP-1/GLP-1R axis in central nervous system diseases.

Glucagon-like peptide-1(GLP-1) is a multifunctional polypeptide throughout the lifespan via activating Glucagon-like peptide-1 receptor (GLP-1R).GLP-1 can affect food ingestion, enhance the secretion of insulin from pancreatic islets induced by glucose and be utilized to treat type 2 diabetes mellitus(T2DM).But, accumulating evidences from the decades suggest that activation GLP-1R can not only regulate the blood glucose, but also sustain the homeostasis of intracellular environment and protect neuron from various damaged responses such as oxidative stress, inflammation, excitotoxicity, ischemia and so on. And more and more pre-clinical and clinical studies identified that GLP-1 and its analogues may play a significant role in improving multiple central nervous system (CNS) diseases including neurodegenerative diseases, epilepsy, mental disorders, ischemic stroke, hemorrhagic stroke, traumatic brain injury, spinal cord injury, chronic pain, addictive disorders, other diseases neurological complications and so on. In order to better reveal the relationship between GLP-1/GLP-1R axis and the growth, development and survival of neurons, herein, this review is aimed to summarize the multi-function of GLP-1/GLP-1R axis in CNS diseases.

A novel technology for in vivo detection of cell type-specific neural connection with AQP1-encoding rAAV2-retro vector and metal-free MRI.

A mammalian brain contains numerous neurons with distinct cell types for complex neural circuits. Virus-based circuit tracing tools are powerful in tracking the interaction among the different brain regions. However, detecting brain-wide neural networks in vivo remains challenging since most viral tracing systems rely on postmortem optical imaging. We developed a novel approach that enables in vivo detection of brain-wide neural connections based on metal-free magnetic resonance imaging (MRI). The recombinant adeno-associated virus (rAAV) with retrograde ability, the rAAV2-retro, encoding the human water channel aquaporin 1 (AQP1) MRI reporter gene was generated to label neural connections. The mouse was micro-injected with the virus at the Caudate Putamen (CPU) region and subjected to detection with Diffusion-weighted MRI (DWI). The prominent structure of the CPU-connected network was clearly defined. In combination with a Cre-loxP system, rAAV2-retro expressing Cre-dependent AQP1 provides a CPU-connected network of specific type neurons. Here, we established a sensitive, metal-free MRI-based strategy for in vivo detection of cell type-specific neural connections in the whole brain, which could visualize the dynamic changes of neural networks in rodents and potentially in non-human primates.

Activation of spinal PDGFRß in microglia promotes neuronal autophagy via p38 MAPK pathway in morphine-tolerant rats.

The adverse side effects of opioids, especially antinociceptive tolerance, limit their clinical application. A recent study reported that platelet-derived growth factor receptor ß (PDGFRß) blockage selectively inhibited morphine tolerance. Autophagy has been reported to contribute to the cellular and behavioral responses to morphine. However, little is known about the relationship between PDGFRß and autophagy in the mechanisms of morphine tolerance. In this study, rats were intrathecally administered with morphine twice daily for 7 days to induce antinociceptive tolerance, which was evaluated using a tail-flick latency test. By administration autophagy inhibitor 3-Methyladenine, PDGFRß inhibitor imatinib, p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 hydrochloride and minocycline hydrochloride, western blot, immunofluorescence, and transmission electron microscopy techniques were used to elucidate the roles of PDGFRß, autophagy, and related signaling pathways in morphine tolerance. This study demonstrated for the first time that spinal PDGFRß in microglia promotes autophagy in gamma-aminobutyric acid (GABA) interneurons through activating p38 MAPK pathway during the development of morphine tolerance, which suggest a potential strategy for preventing the development of morphine tolerance clinically, thereby improving the use of opioids in pain management.

GLP-1R activation ameliorated novel-object recognition memory dysfunction via regulating hippocampal AMPK/NF-κB pathway in neuropathic pain mice.

Growing evidences indicate that neuropathic pain is frequently accompanied with cognitive impairments, which aggravate the decrease in the quality of life of chronic pain patients. Furthermore, it has been shown that the activation of Glucagon-like-peptide-1receptor (GLP-1R) improved memory deficit in multiple diseases, including Alzheimer's disease (AD), stroke. However, whether GLP-1R activation could improve memory impairment induced by neuropathic pain and the mechanisms underlying the effect of the activation of GLP-1R on memory protection have not yet been established. The spared nerve injury (SNI) model was established as a kind of neuropathic pain. And novel-object recognition memory (hippocampus-dependent memory) was tested by the novel object recognition test (NORT). The expression levels of GLP-1, GLP-1R, adenosine monophosphate-activated protein kinase (AMPK), p-AMPKThr172, nuclear factor κ B p65 (NF-κB p65), interleukin-1beta (IL-1ß), IL-1ß p17 (mature IL-1ß), tumor necrosis factor-alpha (TNF-α) and the synaptic proteins were tested in the murine hippocampus with memory deficits caused by neuropathic pain. Then, exenatide acetate (Ex-4, a GLP-1R agonist), exendin (9-39) (Ex(9-39), a GLP-1R antagonist) and Compound C dihydrochloride (CC, an AMPK inhibitor) were used to test the effects of the activation of GLP-1R in the mice with neuropathic pain. First, we uncovered that neuropathic pain could inhibit GLP-1/GLP-R axis, disturb inflammatory signaling pathway, increase the expression of IL-1ß, IL-1ß p17 and TNF-α, downregulate the synaptic proteins (postsynaptic density protein 95 (PSD95) and Arc). Subsequently, we reported that Ex-4 treatment could improve recognition memory impairment, increase the ratio of p-AMPKThr172/AMPK, inhibit the phosphorylation NF-κB p65 and decrease the expression of IL-1ß, IL-1ß p17 and TNF-α, upregulate the levels of PSD95 and Arc. Moreover, we found that Ex(9-39) and CC treatment could abrogate the memory protection of activation of GLP-1R in mice with neuropathic pain. The results indicated that the activation of GLP-1R could improve recognition memory impairment via regulating AMPK/NF-κB pathway, improving neuroinflammation, reversing the decreased level of synaptic proteins in neuropathic pain mice.

Risk factors for mortality of critically ill patients with COVID-19 receiving invasive ventilation.

Rationale: Early invasive ventilation may improve outcomes for critically ill patients with COVID-19. The objective of this study is to explore risk factors for 28-day mortality of COVID-19 patients receiving invasive ventilation. Methods: 74 consecutive adult invasively ventilated COVID-19 patients were included in this retrospective study. The demographic and clinical data were compared between survivors and non-survivors, and Cox regression analysis was used to explore risk factors for 28-day mortality. The primary outcome was 28-day mortality after initiation of invasive ventilation. Secondary outcome was the time from admission to intubation. Results: Of 74 patients with COVID-19, the median age was 68.0 years, 53 (71.6%) were male, 47 (63.5%) had comorbidities with hypertension, and diabetes commonly presented. The most frequent symptoms were fever and dyspnea. The median time from hospital admission to intubation was similar in survivors and non-survivors (6.5 days vs. 5.0 days). The 28-day mortality was 81.1%. High Sequential Organ Failure Assessment (SOFA) score (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.23-1.92; p < 0.001) and longer time from hospital admission to intubation (HR, 2.41; 95% CI, 1.15-5.07; p = 0.020) were associated with 28-day mortality in invasively ventilated COVID-19 patients. Conclusions: The mortality of invasively ventilated COVID-19 patients was particularly striking. Patients with high SOFA score and receiving delayed invasive ventilation were at high risk of mortality.

Sufentanil EC50 for endotracheal intubation with aerosol inhalation of carbonated lidocaine by ultrasonic atomizer.

BACKGROUND: Nebulized lidocaine reduced stress response for endotracheal intubation. However, the impact of novel lidocaine aerosol inhalation for intubation by ultrasonic atomizer was unclear. Hence, we designed aerosol inhalation of lidocaine by ultrasonic atomizer, to seek whether the dosage of sufentanil for intubation could be less or not. METHODS: Intravenous injection of sufentanil started at 0.5 µg/kg, and sufentanil dosage was increased/decreased (step-size 0.05 µg/kg for sufentanil) using Dixon's up and down method. The observation was terminated after 8 reflexes. RESULTS: The EC50 and EC95 of sufentanil with lidocaine by ultrasonic atomizer for intubation were found to be 0.232 µg/kg (95% CI: 0.187-0.270 µg/kg) and 0.447 µg/kg (95% CI: 0.364-0.703 µg/kg). 55.88% out of 34 patients showed hemodynamic index change < 20% of baseline during intubation. CONCLUSION: Aerosol inhalation of lidocaine by ultrasonic atomizer reduced the dosage of sufentanil for endotracheal intubation. Lidocaine inhalation by ultrasonic atomizer for airway anesthesia with minimal dosage of sufentanil could be recommended, particularly in patients who need more stable hemodynamic changes or spontaneous respiration. TRIAL REGISTRATION: Chinese Registry of Central Trial, ChiCTR-IOR-17014198 . Registered 28 December 2017.

Involvement of chemokine CXCL11 in the development of morphine tolerance in rats with cancer-induced bone pain.

Morphine is viewed as one of the classical treatments for intractable pain, but its role is limited by side effects, including analgesic tolerance. A few chemokines have been reported to be engaged in the mechanisms of morphine tolerance. However, the exact roles of CXC chemokine 11 (CXCL11) in chronic morphine tolerance remain unknown. In this study, Walker 256 mammary gland carcinoma cells were inoculated into the tibia of rats to provoke cancer-induced bone pain. Then, morphine was intrathecally administered twice daily for seven consecutive days to induce drug tolerance. We found that the level of CXCL11 in lumbar spinal cord was increased during the development of morphine tolerance in cancer-induced bone pain rats. Meanwhile, CXCL11 was co-localized with markers of astrocytes and neurons in the spinal cord. Inhibition of CXCL11 by neutralizing antibodies could remarkably attenuate the degree of morphine tolerance and decrease the activation of astrocytes. Moreover, blocking astrocyte activation by d, l-Fluorocitric acid could distinctly alleviate morphine tolerance and reduce the expression of CXCL11. Finally, morphine stimulation could induce the release of CXCL11 by cultured astrocytes and neurons in vitro. In summary, our results provide evidence that spinal CXCL11 plays a powerful modulatory role in the development of morphine tolerance through cross-talking between astrocytes and neurons. Read the Review series "Pain".

Specific patterns of spinal metabolites underlying α-Me-5-HT-evoked pruritus compared with histamine and capsaicin assessed by proton nuclear magnetic resonance spectroscopy.

The mechanism behind itching is not well understood. Proton nuclear magnetic resonance (1H-NMR) spectroscopic analysis of spinal cord extracts provides a quick modality for evaluating the specific metabolic activity of α-Me-5-HT-evoked pruritus mice. In the current study, four groups of young adult male C57Bl/6 mice were investigated; one group treated with saline, while the other groups intradermally injected with α-Me-5-HT (histamine independent pruritogen), histamine (histamine dependent pruritogen) and capsaicin (algogenic substance), respectively. The intradermal microinjection of α-Me-5-HT and histamine resulted in a dramatic increase in the itch behavior. Furthermore, the results of NMR studies of the spinal cord extracts revealed that the metabolites show very different patterns for these different drugs, especially when comparing α-Me-5-HT and capsaicin. All the animals in the groups of α-Me-5-HT and capsaicin were completely separated using the metabolite parameters and principal component analysis. For α-Me-5-HT, the concentrations of glutamate, GABA, glycine and aspartate increased significantly, especially for GABA (increased 17.2%, p=0.008). Furthermore, the concentration of NAA increased, but there was no significant difference (increased 11.3%, p=0.191) compared to capsaicin (decreased 29.1%, p=0.002). Thus the application of magnetic resonance spectroscopy technique, coupled with statistical analysis, could further explain the mechanism behind itching evoked by α-Me-5-HT or other drugs. It can thus improve our understanding of itch pathophysiology and pharmacological therapies which may contribute to itch relief.

Intraperitoneal ropivacaine and early postoperative pain and postsurgical outcomes after laparoscopic herniorrhaphy in toddlers: a randomized clinical trial.

BACKGROUND: Postoperative pain can cause physiological distress, postoperative complications, and extended lengths of hospitalized stay. In children, management of postoperative pain is still recognized as being inadequate. OBJECTIVE: The aim of this trial was to investigate the effects of intraperitoneal ropivacaine on postoperative pain, and recovery of bowel function and emetic events after laparoscopic herniorrhaphy in toddlers. METHODS: Seventy-six children aged from 9 months to 3 years were recruited between August 2013 and June 2014 at Tongji Hospital and randomly assigned into two groups. One group received intraperitoneal ropivacaine right before surgery and the control group received intraperitoneal saline. A standard combined general anesthesia procedure was performed under regular monitoring. Postoperative pain was assessed by the FLACC scale. Postoperative analgesic consumption, time to flatus, time to first stool, and postoperative emetic events were also recorded. RESULTS: When compared with the control group, children who received intraperitoneal ropivacaine experienced less pain 0-4 h after surgery [P < 0.001, difference in median FLACC (95% CI) for 2 h time point is 2.00 (0.87-3.13), for 4 h time point is 1.00 (0.55-1.45)]. In addition, the number of toddlers who received analgesia 0-24 h after surgery in the ropivacaine group was lower than that in the control group [P < 0.001, difference in proportions (95% CI) is 0.575 (0.3865-0.7638)]. Compared with the control group, time to flatus in ropivacaine group was also much shorter [21.1 h vs 16.7 h, P = 0.04, difference in mean (95% CI) is 4.4 (1.49-7.28)], and the time to first stool after surgery was earlier in the ropivacaine group [30.7 h vs 25.6 h, P = 0.003, difference in mean (95% CI) is 5.1 (1.78-8.45)]. Furthermore, the incidence of emetic events in the ropivacaine group was significantly lower than the control group [32.4% vs 11.1%, P = 0.03, difference in proportions (95% CI) is 0.212 (0.0246-0.4002)]. CONCLUSION: The present results indicate that intraperitoneal ropivacaine reduces early postoperative pain and improves recovery after laparoscopic herniorrhaphy in toddlers. Therefore, IPLA is a good stratagem for postoperative pain management after laparoscopic surgery in toddlers.

Enhancement of morphine analgesia and prevention of morphine tolerance by downregulation of ß-arrestin 2 with antigene RNAs in mice.

ß-arrestin 2, a regulatory molecule of G protein-coupled receptor, has been proved to play an important role in regulating functions of mu opioid receptor. Changes of ß-arrestin 2 expression might affect the function of mu opioid receptors and the effect of its agonists. In this study, antigene RNAs (agRNAs), which could selectively target gene transcription start sites and potently inhibit gene expression, were used to downregulate the expression of ß-arrestin 2 to investigate its effects on morphine analgesia and tolerance in mice. After intracerebroventricular administration of recombinant lentivirus encoding ß-arrestin 2 agRNAs to the mice, ß-arrestin 2 expression was significantly decreased for more than 3 weeks. Mice treated with ß-arrestin 2 agRNAs showed enhanced analgesic effects in response to morphine and failed to develop antinociceptive tolerance. These results suggest that inhibition of ß-arrestin 2 in the brain with specific agRNAs can improve morphine efficacy, and consequently provide us a useful strategy for treatment of chronic intractable pain and morphine tolerance in vivo.

Spinal IFN-γ-induced protein-10 (CXCL10) mediates metastatic breast cancer-induced bone pain by activation of microglia in rat models.

Cancer-induced bone pain (CIBP) is a common clinical problem in breast cancer patients with bone metastasis. Recent studies shows chemokines are novel targets for treatment of CIBP. In this study, we intra-tibial inoculated with Walker 256 rat mammary gland carcinoma cells into rat bone to established metastatic breast cancer. Then we measured the expression of CXCL10 in the spinal cord of metastatic bone cancer rats, investigated the role of CXCL10 in the development of CIBP, and the underlying mechanism. Results revealed that after intra-tibial inoculation with Walker 256 cells, rats showed up-regulation of CXCL10 and its receptor CXCR3 in the spinal cord. Interestingly, intrathecally injection of recombinant CXCL10 protein induced mechanical allodynia in naïve rats. Blocking the function of CXCL10/CXCR3 pathway via anti-CXCL10 antibody or CXCR3 antagonist prevented the development of CIBP and microglial activation. Moreover, CXCL10-induced mechanical allodynia was rescued by minocycline treatment during the late-stage of CIBP, days 10-14. The regulation of CXCL10 expression involved microglial activation in a manner of autocrine positive feedback. These results suggest that CXCL10 may be a necessary algogenic molecule, especially in the development of CIBP. Its function was partly mediated via spinal microglial activation. This study provides a novel insight into the biological function of chemokine CXCL10 in the molecular mechanism underlying cancer pain. It also provides new target for clinical treatment of metastatic breast cancer-induced bone pain in future.

Anti-arthritic effects of FasL gene transferred intra-articularly by an inducible lentiviral vector containing improved tet-on system.

The objective of this study is to construct and identify an inducible lentiviral vector containing improved tet-on system and FasL gene and observe its effects on pristane-induced arthritis (PIA). FasL gene was amplified from the spleen of Lewis rats by RT-PCR. The tet-on system was improved with insertion of a chicken chromatin insulator (cHS4) element and an rtTA-dependent, tet-responsive element containing modifications of the tetO sequence (TRE-tight1). Pro-apoptosis effect of the vector pTREFasLcHS4V16 on synovial cells was evaluated by flow cytometer in vitro. Anti-arthritis effects of the vector on PIA after intra-articular injection were observed by clinical evaluation and joint histology. Cytokines in synovial tissue were measured by ELISA. The recombinant inducible lentiviral vector pTREFasLcHS4V16 was successfully constructed. The expression response and the pro-apoptosis effects of the vector were doxycycline dose-dependent. The vector injected intra-articularly attenuated the severity of PIA and decreased the level of cytokines in inflamed joints. pTREFasLcHS4V16 with an improved tet-on system can precisely regulate the expression of FasL gene and apoptosis. Anti-arthritis effects were observed after intra-articular injection of the inducible vector.

Chronic Pain-Related Cognitive Deficits: Preclinical Insights into Molecular, Cellular, and Circuit Mechanisms.

Cognitive impairment is a common comorbidity of chronic pain, significantly disrupting patients' quality of life. Despite this comorbidity being clinically recognized, the underlying neuropathological mechanisms remain unclear. Recent preclinical studies have focused on the fundamental mechanisms underlying the coexistence of chronic pain and cognitive decline. Pain chronification is accompanied by structural and functional changes in the neural substrate of cognition. Based on the developments in electrophysiology and optogenetics/chemogenetics, we summarized the relevant neural circuits involved in pain-induced cognitive impairment, as well as changes in connectivity and function in brain regions. We then present the cellular and molecular alternations related to pain-induced cognitive impairment in preclinical studies, mainly including modifications in neuronal excitability and structure, synaptic plasticity, glial cells and cytokines, neurotransmitters and other neurochemicals, and the gut-brain axis. Finally, we also discussed the potential treatment strategies and future research directions.

Spinal voltage-gated potassium channel Kv1.3 contributes to neuropathic pain via the promotion of microglial M1 polarization and activation of the NLRP3 inflammasome.

BACKGROUD: Studies have shown that the activation of microglia is the main mechanism of neuropathic pain. Kv1.3 channel is a novel therapeutic target for treating neuroinflammatory disorders due to its crucial role in subsets of microglial cells. As such, it may be involved in the processes of neuropathic pain, however, whether Kv1.3 plays a role in neuroinflammation following peripheral nerve injury is unclear. METHOD: The spared nerve injury model (SNI) was used to establish neuropathic pain. Western blot and immunofluorescence were used to examine the effect of Kv1.3 in the SNI rats. PAP-1, a Kv1.3 specific blocker was administered to alleviate neuropathic pain in the SNI rats. RESULTS: Neuropathic pain and allodynia occurred after SNI, the levels of M1 (CD68, iNos) and M2 (CD206, Arg-1) phenotypes were up-regulated in the spinal cord, and the protein levels of NLRP3, caspase-1 and IL-1ß were also increased. Pharmacological blocking of Kv1.3 with PAP-1 alleviated hyperpathia induced by SNI. Meanwhile, intrathecal injection of PAP-1 reduced M1 polarization and decreased NLRP3, caspase-1 and IL-1ß expressions of protein levels. CONCLUSION: Our research indicates that the Kv1.3 channel in the spinal cord contributes to neuropathic pain by promoting microglial M1 polarization and activating the NLRP3 inflammasome.

Rapid injection of lumbar dorsal root ganglia under direct vision: Relevant anatomy, protocol, and behaviors.

Introduction: Dorsal root ganglia (DRG) are anatomically well-defined structures that contain all primary sensory neurons and are distension nodules of the dorsal root in the spinal cord near the medial surface of each foramen. Therefore, DRG is considered to be a desirable target for injection to manage chronic pain. But it presents a limitation in probing deep into it without in vivo injection technology. Methods: Here, we described a technique for administering intraganglionic injections of lumbar DRG under direct vision. We use partial osteotomy rather than laminectomy, which removes more bone, to preserve spinal structures while gaining adequate DRG access. To monitor the intraoperative progress of the DRG injection, a non-toxic dye was utilized. The effectiveness of the injection on the diffusion of AAV (adeno-associated virus) within the ganglion was assessed by histopathology at postoperative day 21. Results: Behavioral tests showed that neither motor nor sensory abilities were affected by saline or AAV injections. Meanwhile, the decreased pain threshold of SNI (spared nerve injury) was considerably restored by pharmacological inhibition of DRG neurons. Discussion: Our research achieved a new minimally invasive and intuitive intra-ganglionic injection in mice. In addition, the present protocol may serve as a valuable resource for planning preclinical studies of DRG injection.

Inhibition of glial activation in rostral ventromedial medulla attenuates mechanical allodynia in a rat model of cancer-induced bone pain.

Descending nociceptive modulation from the supraspinal structures plays an important role in cancer-induced bone pain (CIBP). Rostral ventromedial medulla (RVM) is a critical component of descending nociceptive facilitation circuitry, but so far the mechanisms are poorly known. In this study, we investigated the role of RVM glial activation in the descending nociceptive facilitation circuitry in a CIBP rat model. CIBP rats showed significant activation of microglia and astrocytes, and also up-regulation of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and pro-inflammatory mediators released by glial cells (IL-1ß, IL-6, TNF-α and brain-derived neurotrophic factor) in the RVM. Stereotaxic microinjection of the glial inhibitors (minocycline and fluorocitrate) into CIBP rats' RVM could reverse the glial activation and significantly attenuate mechanical allodynia in a time-dependent manner. RVM microinjection of p38 MAPK inhibitor (SB203580) abolished the activation of microglia, reversed the associated up-regulation of pro-inflammatory mediators and significantly attenuated mechanical allodynia. Taken together, these results suggest that RVM glial activation is involved in the pathogenesis of CIBP. RVM microglial p38 MAPK signaling pathway is activated and leads to the release of downstream pro-inflammatory mediators, which contribute to the descending facilitation of CIBP.

Effective Connectivity in Cortical Networks During Deception: A Lie Detection Study Based on EEG.

Thus far, when deception behaviors occur, the connectivity patterns and the communication between different brain areas remain largely unclear. In this study, the most important information flows (MIIFs) between different brain cortices during deception were explored. First, the guilty knowledge test protocol was employed, and 64 electrodes' electroencephalogram (EEG) signals were recorded from 30 subjects (15 guilty and 15 innocent). Cortical current density waveforms were then estimated on the 24 regions of interest (ROIs). Next, partial directed coherence (PDC), an effective connectivity (EC) analysis was applied in the cortical waveforms to obtain the brain EC networks for four bands: delta (1-4 Hz), theta (4-8 Hz), alpha (8-13 Hz) and beta (13-30 Hz). Furthermore, using the graph theoretical analysis, the network parameters with significant differences in the EC network were extracted as features to identify the two groups. The high classification accuracy of the four bands demonstrated that the proposed method was suitable for lie detection. In addition, based on the optimal features in the classification mode, the brain "hub" regions were identified, and the MIIFs were significantly different between the guilty and innocent groups. Moreover, the fronto-parietal network was found to be most prominent among all MIIFs at the four bands. Furthermore, combining the neurophysiology significance of the four frequency bands, the roles of all MIIFs were analyzed, which could help us to uncover the underlying cognitive processes and mechanisms of deception.

Targeting α7 nicotinic acetylcholine receptors for chronic pain.

Despite rapid advances in the field of chronic pain, it remains extremely challenging in the clinic. Pain treatment strategies have not improved for decades as opioids remain the main prescribed drugs for chronic pain management. However, long-term use of opioids often leads to detrimental side effects. Therefore, uncovering the mechanisms underlying the development and maintenance of chronic pain may aid the discovery of novel therapeutics to benefit patients with chronic pain. Substantial evidence indicates downregulation of α7 nicotinic acetylcholine receptors (α7 nAChR) in the sciatic nerve, dorsal root ganglia, and spinal cord dorsal horn in rodent models of chronic pain. Moreover, our recent study and results from other laboratories demonstrate that potentiation of α7 nAChR attenuates pain behaviors in various murine models of chronic pain. This review summarized and discussed the preclinical evidence demonstrating the therapeutic potential of α7 nAChR agonists and allosteric modulators in chronic pain. This evidence indicates that potentiation of α7 nAChR is beneficial in chronic pain, mostly by alleviating neuroinflammation. Overall, α7 nAChR-based therapy for chronic pain is an area with great promise, but more research regarding its detailed mechanisms is warranted.

Dysfunction of the Brain-derived Neurotrophic Factor-Tyrosine Kinase B Signaling Pathway Contributes to Learning and Memory Impairments Induced by Neuroinflammation in Mice.

Accumulating evidence suggests that neuroinflammation is the main mechanism in cognitive dysfunction and that brain-derived neurotrophic factor (BDNF) is involved in learning and memory by binding to tyrosine kinase B (TrkB) receptors. Herein, we tested the roles of the BDNF-TrkB signaling pathway and its downstream cascade in lipopolysaccharide (LPS) induced cognitive dysfunction in mice. Mice were treated with LPS (0.25 mg/kg) for 7 days, and learning and memory function was evaluated by the novel object recognition test (NORT). Western blotting was performed to elucidate roles of the BDNF-TrkB signaling pathway and its downstream cascades in LPS mice. The NORT showed that LPS induced learning and memory deficits in mice. The levels of IL-1ß, IL-6, and TNF-α in the serum and central nervous system decreased in LPS mice. In addition, LPS reduced the protein levels of BDNF, p-TrkB, Bcl-2, p-ERK1/2, p-CaMK2, p-CREB and p-GluR1 and increased the expression of Bax in the hippocampus and medial prefrontal cortex regions. In the entorhinal cortex, the protein levels of BDNF, p-TrkB, Bcl-2, p-CaMK2 and p-CREB were decreased, and the protein level of Bax was increased in LPS mice. Interestingly, 7,8-DHF alleviated these disorders in LPS mice and improved learning and memory function; however, the TrkB antagonist ANA12 effectively reversed effects of 7,8-DHF. Therefore, we conclude that the BDNF-TrkB signaling pathway and its downstream cascades disorders in different regions are main mechanisms of cognitive dysfunction, and 7,8-DHF maybe useful as a new treatment for preventing or treating cognitive dysfunction induced by neuroinflammation in neurodegenerative diseases.