Associations Between Neuroinflammation-Related Conditions and Alzheimer's Disease: A Study of US Insurance Claims Data.

Background: Early detection of Alzheimer's disease (AD) is a key component for the success of the recently approved lecanemab and aducanumab. Patients with neuroinflammation-related conditions are associated with a higher risk for developing AD. Objective: Investigate the incidence of AD among patients with neuroinflammation-related conditions including epilepsy, hemorrhage stroke, multiple sclerosis (MS), and traumatic brain injury (TBI). Methods: We used Optum's de-identified Clinformatics Data Mart Database (CDM). We derived covariate-matched cohorts including patients with neuroinflammation-related conditions and controls without the corresponding condition. The matched cohorts were: 1) patients with epilepsy and controls (N = 67,825 matched pairs); 2) patients with hemorrhage stroke and controls (N = 81,510 matched pairs); 3) patients with MS and controls (N = 9,853 matched pairs); and 4) patients TBI and controls (N = 104,637 matched pairs). We used the Cox model to investigate the associations between neuroinflammation-related conditions and AD. Results: We identified that epilepsy, hemorrhage stroke, and TBI were associated with increased risks of AD in both males and females (hazard ratios [HRs]≥1.74, p < 0.001), as well as in gender- and race-conscious subpopulations (HRs≥1.64, p < 0.001). We identified that MS was associated with increased risks of AD in both males and females (HRs≥1.47, p≤0.004), while gender- and race-conscious subgroup analysis shown mixed associations. Conclusions: Patients with epilepsy, hemorrhage stroke, MS, and/or TBI are associated with a higher risk of developing AD. More attention on cognitive status should be given to older patients with these conditions.

Understanding Patterns of Preserved Retinal Ganglion Cell Layer in Advanced Glaucoma as seen with OCT.

PRECIS: Using OCT, eyes with advanced glaucoma were found to have a wide range of patterns of damage that were consistent with the natural history of progression based upon a model of macular progression. PURPOSE: To understand the patterns of preserved retinal ganglion cells in eyes with advanced glaucoma using OCT and a model of progression of the central macula. METHODS: OCT GCL thickness was measured in 94 eyes with advanced glaucoma, defined as glaucomatous eyes with a 24-2 MD (mean deviation) worse than -12 dB. A commercial report supplied the GCL thickness in 6 sectors of the thick, donut-shaped GCL region around the fovea. For each eye, the 6 sectors were coded as green (within normal limits, WNL), yellow (≤5th, ≥1st percentile), or red (<1st percentile). RESULTS: In all 94 eyes, one or more of the 6 sectors of the donut were abnormal (red or yellow), while all 6 sectors were red in 52 (55%) of the eyes. On the other hand, 33 eyes had one or more sectors WNL (green). While the pattern of donut damage varied widely across these 33 eyes, 61 of the 66 hemiretinas were consistent with a temporal-to-nasal progression of damage within each hemiretina as predicted by our model. CONCLUSION: All eyes with advanced glaucoma had damage to the critically important central, donut-shaped GCL region. This region showed a wide range of patterns of damage, but these patterns were consistent with the natural history of progression based upon a model of macular progression. These results have implications for the clinical identification of macular progression, as well as for inclusion criteria for clinical trials seeking to preserve central macular function.

Application of an Innovative Data Mining Approach Towards Safe Polypharmacy Practice in Older Adults.

INTRODUCTION: Polypharmacy is common and is associated with higher risk of adverse drug event (ADE) among older adults. Knowledge on the ADE risk level of exposure to different drug combinations is critical for safe polypharmacy practice, while approaches for this type of knowledge discovery are limited. The objective of this study was to apply an innovative data mining approach to discover high-risk and alternative low-risk high-order drug combinations (e.g., three- and four-drug combinations). METHODS: A cohort of older adults (≥ 65 years) who visited an emergency department (ED) were identified from Medicare fee-for-service and MarketScan Medicare supplemental data. We used International Classification of Diseases (ICD) codes to identify ADE cases potentially induced by anticoagulants, antidiabetic drugs, and opioids from ED visit records. We assessed drug exposure data during a 30-day window prior to the ED visit dates. We investigated relationships between exposure of drug combinations and ADEs under the case-control setting. We applied the mixture drug-count response model to identify high-order drug combinations associated with an increased risk of ADE. We conducted therapeutic class-based mining to reveal low-risk alternative drug combinations for high-order drug combinations associated with an increased risk of ADE. RESULTS: We investigated frequent high-order drug combinations from 8.4 million ED visit records (5.1 million from Medicare data and 3.3 million from MarketScan data). We identified 5213 high-order drug combinations associated with an increased risk of ADE by controlling the false discovery rate at 0.01. We identified 1904 high-order, high-risk drug combinations had potential low-risk alternative drug combinations, where each high-order, high-risk drug combination and its corresponding low-risk alternative drug combination(s) have similar therapeutic classes. CONCLUSIONS: We demonstrated the application of a data mining technique to discover high-order drug combinations associated with an increased risk of ADE. We identified high-risk, high-order drug combinations often have low-risk alternative drug combinations in similar therapeutic classes.

A targeted antibody-based array reveals a serum protein signature as biomarker for adolescent idiopathic scoliosis patients.

BACKGROUND: Evident adolescent idiopathic scoliosis (AIS) incurs high treatment costs, low quality of life, and many complications. Early screening of AIS is essential to avoid progressing to an evident stage. However, there is no valid serum biomarker for AIS for early screening. METHODS: Antibody-based array is a large-scale study of proteins, which is expected to reveal a serum protein signature as biomarker for AIS. There are two segments of the research, including biomarkers screening and validation. In the biomarkers screening group, a total of 16 volunteers participated in this study, and we carried out differentially expressed proteins screening via protein array assay between No-AIS group and the AIS group, through which GeneSet enrichment analysis was performed. In the validation group with a total of 62 volunteers, the differentially expressed proteins from screening group were verified by Enzyme-Linked immunosorbent assay (ELISA), and then multiple regression analysis. RESULTS: In our study, there were twenty-nine differentially expressed proteins in AIS, through Protein array assay and GeneSet enrichment analysis in the biomarkers screening group. Then the expression of FAP, CD23 and B2M decreased as the degree of AIS increased via ELISA in validation group (FAP, p < 0.0001; CD23, p = 0.0002; B2M, p < 0.0001). Further, the results of multiple regression analysis showed that FAP, CD23 are linked to Cobb angle, whereas B2M were excluded because of multicollinearity. CONCLUSIONS: Altogether, we found that serum protein FAP and CD23 are intimately related to AIS, suggesting FAP and CD23 are expected to serve as the serum biomarkers, which significantly facilitate frequent longitudinal monitoring as to keep track of disease progression and tailor treatment accordingly.

An Early Adverse Drug Event Detection Approach with False Discovery Rate Control.

Adverse drug event (ADE) is a significant challenge in clinical practice. Many ADEs have not been identified timely after the approval of the corresponding drugs. Despite the use of drug similarity network demonstrates early success on improving ADE detection, false discovery rate (FDR) control remains unclear in its application. Additionally, performance of early ADE detection has not been explicitly investigated under the time-to-event framework. In this manuscript, we propose to use the drug similarity based posterior probability of null hypothesis for early ADE detection. The proposed approach is also able to control FDR for monitoring a large number of ADEs of multiple drugs. The proposed approach outperforms existing approaches on mining labeled ADEs in the US FDA's Adverse Event Reporting System (FAERS) data, especially in the first few years after the drug initial reporting time. Additionally, the proposed approach is able to identify more labeled ADEs and has significantly lower time to ADE detection. In simulation study, the proposed approach demonstrates proper FDR control, as well as has better true positive rate and an excellent true negative rate. In our exemplified FAERS analysis, the proposed approach detects new ADE signals and identifies ADE signals in a timelier fashion than existing approach. In conclusion, the proposed approach is able to both reduce the time and improve the FDR control for ADE detection.

Is depression in patients with temporal lobe epilepsy related to hippocampal sclerosis? A meta-analysis.

OBJECTIVE: To systematically evaluate the association between hippocampal sclerosis (HS) and depression in patients with temporal lobe epilepsy (TLE) through a meta-analysis. METHODS: Chinese and English databases, such as the China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals (VIP), WanFang, the Chinese Biomedical Literature Service System (SinoMed), PubMed and the Web of Science, were searched. RESULTS: Two evaluators independently screened the literature, extracted data and evaluated the risk of bias in the included studies in accordance with the inclusion and exclusion criteria. RevMan 5.1 was used to analyze the data. A total of 786 patients with epilepsy were included in the study, including 82 depressive patients with HS and 64 depressive patients without HS. The results showed that the TLE patients with HS were more likely to develop depression than those without HS (odds ratio (OR)= 2.14, 95% confidence interval (CI) [1.45, 3.16], Z = 3.85, p = 0.0001). CONCLUSION: HS can be considered a high-risk factor for depression in patients with TLE, and the correlation is significant. However, the sample size included in the study was small; additional high-quality studies are needed in the future.

Association of Catalase Gene Polymorphisms with Idiopathic Nephrotic Syndrome in a Chinese Pediatric Population.

OBJECTIVE: Our aim was to investigate the association between gene polymorphisms in catalase (CAT), a well-known oxidative stress regulator, and susceptibility to idiopathic nephrotic syndrome (INS) or responses to steroid therapy in a Chinese pediatric population. METHODS: We analyzed 3 CAT single-nucleotide polymorphisms (SNVs; rs7943316, rs769217, and rs12270780) using multi-polymerase chain reaction combined with next-generation sequencing in 183 INS patients and 100 healthy controls. RESULTS: For the allele and genotype frequencies of the CAT SNVs, no significant differences were observed between INS patients and controls. Patients with C allele of CAT rs769217 had a higher risk of developing steroid-dependent nephrotic syndrome than the steroid-sensitive nephrotic syndrome patients (P = 0.018; odds ratio = 1.76). CONCLUSION: Our data suggests that genetic variations in CAT were unlikely to confer susceptibility to INS in Chinese children, whereas the C allele of the CAT rs769217 polymorphism showed a strong association with steroid-dependent responses in Chinese INS children.

Lithium-sensing riboswitch classes regulate expression of bacterial cation transporter genes.

Lithium is rare in Earth's crust compared to the biologically relevant alkali metal cations sodium and potassium but can accumulate to toxic levels in some environments. We report the experimental validation of two distinct bacterial riboswitch classes that selectively activate gene expression in response to elevated Li+ concentrations. These RNAs commonly regulate the expression of nhaA genes coding for ion transporters that weakly discriminate between Na+ and Li+. Our findings demonstrated that the primary function of Li+ riboswitches and associated NhaA transporters is to prevent Li+ toxicity, particularly when bacteria are living at high pH. Additional riboswitch-associated genes revealed how some cells defend against the deleterious effects of Li+ in the biosphere, which might become more problematic as its industrial applications increase.

Association of polymorphisms in the IL-10 promoter region with Crohn's disease.

BACKGROUND: IL-10 is thought to play an important role in preventing inflammatory bowel disease (IBD), although its efficacy is limited in IBD inflammation treatment. The purpose of this study is to investigate the association between SNP polymorphism in the promoter region of the IL-10 gene and Crohn's disease (CD). METHODS: In 86 children with CD disease and 142 healthy controls, polymorphisms of three SNPs (rs3790622, rs1800872, and rs1800896) in the IL-10 promoter region were successfully identified. The risk alleles, genotypes, and haplotypes were also analyzed in the CD patient group and the control group. 2 × 2 chi-square test was used to identify whether there is a statistically significant association between CD risk and SNP polymorphisms. RESULTS: According to the chi-square test results, only the polymorphism of rs1800872 was associated with pediatric CD. T allele in rs1800872 showed a high risk for pediatric CD (Pearson χ2 p = 0.030). TT genotype of rs1800872 was associated with a higher risk of CD in the pediatric population (OR 1.986, 95% CI 1.146-3.442, p = 0.020, TT vs. TG + GG). Finally, a risk haplotype GTT (rs3790622-rs1800872-rs1800896) in IL-10 was found (OR 1.570, 95% CI 1.054-2.341, p = 0.028). CONCLUSIONS: Our data suggested that T allele, TT genotype, and haplotype GTT in rs1800872 were associated with the susceptibility to pediatric CD in China.

Na+ riboswitches regulate genes for diverse physiological processes in bacteria.

Organisms presumably have mechanisms to monitor and physiologically adapt to changes in cellular Na+ concentrations. Only a single bacterial protein has previously been demonstrated to selectively sense Na+ and regulate gene expression. Here we report a riboswitch class, previously called the 'DUF1646 motif', whose members selectively sense Na+ and regulate the expression of genes relevant to sodium biology. Many proteins encoded by Na+-riboswitch-regulated genes are annotated as metal ion transporters, whereas others are involved in mitigating osmotic stress or harnessing Na+ gradients for ATP production. Na+ riboswitches exhibit dissociation constants in the low mM range, and strongly reject all other alkali and alkaline earth ions. Likewise, only Na+ triggers riboswitch-mediated transcription and gene expression changes. These findings reveal that some bacteria use Na+ riboswitches to monitor, adjust and exploit Na+ concentrations and gradients, and in some instances collaborate with c-di-AMP riboswitches to coordinate gene expression during osmotic stress.

Gene-by-environment modulation of lifespan and weight gain in the murine BXD family.

How lifespan and body weight vary as a function of diet and genetic differences is not well understood. Here we quantify the impact of differences in diet on lifespan in a genetically diverse family of female mice, split into matched isogenic cohorts fed a low-fat chow diet (CD, n = 663) or a high-fat diet (HFD, n = 685). We further generate key metabolic data in a parallel cohort euthanized at four time points. HFD feeding shortens lifespan by 12%: equivalent to a decade in humans. Initial body weight and early weight gains account for longevity differences of roughly 4-6 days per gram. At 500 days, animals on a HFD typically gain four times as much weight as control, but variation in weight gain does not correlate with lifespan. Classic serum metabolites, often regarded as health biomarkers, are not necessarily strong predictors of longevity. Our data indicate that responses to a HFD are substantially modulated by gene-by-environment interactions, highlighting the importance of genetic variation in making accurate individualized dietary recommendations.

Diagnostic Yield of Pneumococcal Antigen Detection in Cerebrospinal Fluid for Diagnosis of Pneumococcal Meningitis Among Children in China.

OBJECTIVE: To determine the diagnostic accuracy of pneumococcal antigen detection in diagnosis of pneumococcal meningitis in children. METHODS: Purulent meningitis was diagnosed according to European Society for Clinical Microbiology and Infectious Diseases (ESCMID) guideline between July 2014 and June 2016. Along with a cerebrospinal fluid (CSF) culture, pneumococcal antigen detection in cerebrospinal fluid (CSF) was performed, and further identification of pathogens was done with 16S rDNA-PCR and high-throughput sequencing. RESULTS: CSF samples collected from 184 children (median age of 1.92 mo). CSF culture was used as the gold standard. 46 (25%) had positive results for culture and 10 (5.4%) were pneumococci; 34 (18.5%) were pneumococcal antigen positive. The sensitivity and specificity of pneumococcal antigen detection were 100% (95% CI: 89.4%-100%) and 86.2% (95% CI: 96.4%-99.9%), respectively. 92.3% (12/13) were confirmed by nucleic acid detection to be pneumococci. CONCLUSIONS: Pneumococcal antigen detection in CSF has adequate sensitivity and specificity in diagnosing pneumococcal meningitis.

Extracellular Signal-Regulated Kinase in Nucleus Accumbens Mediates Propofol Self-Administration in Rats.

Clinical and animal studies have indicated that propofol has potential for abuse, but the specific neurobiological mechanism underlying propofol reward is not fully understood. The purpose of this study was to investigate the role of extracellular signal-regulated kinase (ERK) signal transduction pathways in the nucleus accumbens (NAc) in propofol self-administration. We tested the expression of p-ERK in the NAc following the maintenance of propofol self-administration in rats. We also assessed the effect of administration of SCH23390, an antagonist of the D1 dopamine receptor, on the expression of p-ERK in the NAc in propofol self-administering rats, and examined the effects of intra-NAc injection of U0126, an MEK inhibitor, on propofol reinforcement in rats. The results showed that the expression of p-ERK in the NAc increased significantly in rats maintained on propofol, and pre-treatment with SCH23390 inhibited the propofol self-administration and diminished the expression of p-ERK in the NAc. Moreover, intra-NAc injection of U0126 (4 µg/side) attenuated the propofol self-administration. The data suggest that ERK signal transduction pathways coupled with D1 dopamine receptors in the NAc may be involved in the maintenance of propofol self-administration and its rewarding effects.

Activation of AMPA receptor in the infralimbic cortex facilitates extinction and attenuates the heroin-seeking behavior in rats.

Infralimbic cortex (IL) is proposed to suppress cocaine seeking after extinction, but whether the IL regulates the extinction and reinstatement of heroin-seeking behavior is unknown. To address this issue, the male SD rats were trained to self-administer heroin under a FR1 schedule for consecutive 14 days, then the rats underwent 7 daily 2h extinction session in the operant chamber. The activation of IL by microinjection PEPA, an allosteric AMPA receptor potentiator into IL before each of extinction session facilitated the extinction responding after heroin self-administration, but did not alter the locomotor activity in an open field testing environment. Other rats were first trained under a FR1 schedule for heroin self-administration for 14 days, followed by 14 days of extinction training, and reinstatement of heroin-seeking induced by cues was measured for 2h. Intra-IL microinjecting of PEPA at 15min prior to test inhibited the reinstatement of heroin-seeking induced by cues. Moreover, the expression of GluR1 in the IL and NAc remarkably increased after treatment with PEPA during the reinstatement. These finding suggested that activation of glutamatergic projection from IL to NAc shell may be involved in the extinction and reinstatement of heroin-seeking.

Decrease of phosphorylated CREB and ERK in nucleus accumbens is associated with the incubation of heroin seeking induced by cues after withdrawal.

cAMP response element binding protein (CREB) signaling is involved in the heroin reward, but whether the CREB signaling is involved in the incubation of heroin-seeking remains unknown. Here we aim to explore the expression of p-CREB and the p-ERK, an upstream molecular of CREB, in the nucleus accumbens (NAc) in the incubation of heroin-seeking induced by cue after withdrawal. First, rats were trained to self-administer heroin for 14 days, and then assessed heroin-seeking induced by context cue (CC)or by conditioned cues (CS)after 1 or 14 d withdrawal. We found that the active responses induced by CC or CS was higher after 14 d withdrawal than that after 1 d withdrawal, and the extent increased was more significant by CS than that by CC. Meanwhile, the expression of p-ERK decreased significantly when rats exposed to the CS, and decreased more after 14 d withdrawal. In contrast, reduction of the expression of p-CREB was more obvious with exposure to CS after 14 d withdrawal. Furthermore, microinjection of rolipram into the NAc decreased the heroin-seeking behavior induced by CS after 14 d withdrawal, which was correlated to an enhancement in the expression of p-CREB in the NAc. These findings suggest that the inactivation of CREB and ERK may be involved in the incubation of heroin-seeking induced by cues after prolonged withdrawal.

Sample size determination for equivalence assessment with multiple endpoints.

Equivalence assessment between a reference and test treatment is often conducted by two one-sided tests (TOST). The corresponding power function and sample size determination can be derived from a joint distribution of the sample mean and sample variance. When an equivalence trial is designed with multiple endpoints, it often involves several sets of two one-sided tests. A naive approach for sample size determination in this case would select the largest sample size required for each endpoint. However, such a method ignores the correlation among endpoints. With the objective to reject all endpoints and when the endpoints are uncorrelated, the power function is the production of all power functions for individual endpoints. With correlated endpoints, the sample size and power should be adjusted for such a correlation. In this article, we propose the exact power function for the equivalence test with multiple endpoints adjusted for correlation under both crossover and parallel designs. We further discuss the differences in sample size for the naive method without and with correlation adjusted methods and illustrate with an in vivo bioequivalence crossover study with area under the curve (AUC) and maximum concentration (Cmax) as the two endpoints.

The phosphodiesterase-4 inhibitor rolipram attenuates heroin-seeking behavior induced by cues or heroin priming in rats.

Inhibition of phosphodiesterase-4 (PDE4), an enzyme that specifically hydrolyzes cyclic adenosine monophosphate (cAMP) increases intracellular cAMP/cAMP-response element binding protein (CREB) signaling. Activation of this signaling is considered as an important compensatory response that decreases motivational properties of drugs of abuse. However, it is not known whether PDE4 is involved in heroin seeking. Self-administration of heroin (50 µg/kg/infusion) was performed under the fixed ratio 1 (FR1) schedule for 14 d and then drug seeking was extinguished for 10 d. The progressive ratio schedule was used to evaluate the relative motivational value of heroin reinforcement. After training, the conditioned cue or heroin priming (250 µg/kg) was introduced for the reinstatement of heroin-seeking behavior. Pretreatment (i.p.) with rolipram (0.03-0.3 mg/kg), a prototypical, selective PDE4 inhibitor, failed to inhibit heroin self-administration under the FR1 schedule, but decreased the reward values under the progressive ratio schedule in a dose-dependent manner. In addition, rolipram decreased the reinstatement of heroin seeking induced by cues or heroin priming even at the lowest dose (0.03 mg/kg); in contrast, the highest dose (0.3 mg/kg) of rolipram was required to decrease sucrose reinforcement. Finally, the effects of rolipram on heroin-seeking behavior were correlated with the increases in expression of phosphorylated CREB in the nucleus accumbens. The study demonstrated that rolipram inhibited heroin reward and heroin-seeking behavior. The results suggest that PDE4 plays an essential role in mediating heroin seeking and that PDE4 inhibitors may be used as a potential pharmacotherapeutic approach for heroin addiction.

Sample size of thorough QTc clinical trial adjusted for multiple comparisons.

A thorough QT trial is typically designed to test for two sets of hypotheses. The primary set of hypotheses is for demonstrating that the test treatment will not prolong QT interval. The second set of hypotheses is to demonstrate the assay sensitivity of the positive control treatment in the study population. Both analyses require multiple comparisons by testing the treatment difference measured repeatedly at multiple selected time points. Tsong and Zhong (2010) indicated that for prolongation testing, this involves an intersection-union test that leads to the reduction of study power. It requires type II error rate adjustment in order to maintain proper sample size and power of the test. Tsong et al. (2010) indicated also that the assay sensitivity analysis is carried out using a union-intersection test that leads to the inflation of the family-wise type I error rate. Type I error rate adjustment is required to control the family-wise type I error rate. Zhang and Machado (2008) proposed the sample size calculation of test-placebo QT response difference based on simulation with a multivariate normal distribution model. Even though the results are generally used as guidance for sample size determination for balanced arm TQT trials, they are limited in generalization to various advanced and adaptive designs of TQT trials (Zhang, 2011 ; Tsong, 2013). In this article, we propose a power equation based on multivariate normal distribution of TQT trials. Sample sizes of various TQT designs can be obtained through numerical iteration of the equation.

Galantamine attenuates the heroin seeking behaviors induced by cues after prolonged withdrawal in rats.

BACKGROUND AND OBJECTIVE: Evidence shows that acetylcholinergic transmission in the ventral tegmental area (VTA) or nucleus accumbens (NAc) plays an important role in heroin-seeking induced by cues. Cholinergic modulation of VTA neurons arises from the lateral dorsal tegmental nucleus (LDT). The present studies investigated the effect of systemic or intra- LDT administration of galantamine, an inhibitor of acetylcholinesterase, on heroin-seeking induced by cues. METHODS: Rats were trained to self-administer heroin for 12 days, underwent extinction training for 12 days followed by two weeks in their home cages. Then the conditioned cues were introduced for the reinstatement of heroin-seeking. RESULTS: The reinstatement of heroin-seeking induced by cues was attenuated by the administration of galantamine (0, 0.3, 1 or 3mg/kg, i.p.) in a dose-dependent manner. In contrast, galantamine only at the dose of 3mg/kg could inhibit the reinstatement of sucrose-seeking. Galantamine at those doses failed to alter the locomotor activity in heroin-withdrawn rats. The inhibition of drug-seeking by galantamine was reversed by pretreatment with scopolamine (0.5mg/kg) but not with mecamylamine (3mg/kg) or scopolamine methobromide (1mg/kg). Moreover, the microinjection of galantamine into the LDT blocked cue-induced heroin-seeking, while the microinjection of scopolamine into the LDT reversed the inhibitory effect of galantamine on drug-seeking behavior. CONCLUSION: The results suggest that cholinergic transmission in the LDT may play a critical role in heroin-seeking behavior induced by cues and that galantamine may have the beneficial effect of blocking heroin-seeking behavior, which is mediated through its actions on the muscarinic receptors.

Vagus nerve stimulation inhibits heroin-seeking behavior induced by heroin priming or heroin-associated cues in rats.

Vagus nerve stimulation has been used for the treatment of neuropsychiatric disorders, such as epilepsy. However, little is known whether it is also effective for the treatment of heroin dependence, in particular for relapse to heroin seeking. In the present study, we investigated the effects of vagus nerve stimulation on reinstatement (relapse) of heroin-seeking behavior induced by heroin priming or heroin-associated cues. The rats were trained for heroin self-administration for 14days and followed by extinction training in which heroin was replaced by saline and heroin-associated cues were turned off. In addition, animals were also received daily electric stimulation of vagus nerve (30Hz, pulse width of 0.5ms, 0.5mA (low-intensity) or 1mA (high-intensity); 30s on, 5min off; 10 continuous cycle per day) or false stimulation during extinction training. We found that such vagus nerve stimulation significantly inhibited heroin priming (0.25mg/kg, s.c.) - or heroin-associated conditioned cue-induced reinstatement of drug-seeking behavior, when compared to false stimulation control. Further, such a behavioral inhibition was correlated to a reduction in the expression of FosB and an increase in the expression of phosphorylation of cAMP response element binding protein (p-CREB) in nucleus accumbens. The data suggest that vagus nerve stimulation may inhibit heroin- or heroin cue-induced relapse, possibly by regulation of the expression of Fos and CREB in nucleus accumbens.