Introduction As we emerge from the current pandemic, hospitals, staff, and resources will need to continue to adjust to meet ongoing healthcare demands. Lessons learned during past shortages can be used to optimize peri-procedural protocols to safely improve the utilization of hospital resources. Methods Retrospective review of patients who underwent elective endovascular intracranial aneurysm treatment was performed. Multivariable logistic regression was used to identify factors associated with patients who were able to be discharged within 24 h of elective procedures. Rates of complications (particularly readmission) were determined. Results 330 patients underwent elective endovascular aneurysm treatment with 86 (26.1%) discharged within 24 h. Factors associated with earlier discharge included procedure years (2019–2021) and male sex. Patients were more likely to be discharged later (after 24 h) if they underwent stent-coil embolization or flow-diversion. There was no association between discharge timing and likelihood of readmission. Discussion Our review highlights the safety of earlier discharge and allowed us to prepare a fast-track protocol for same-day discharge in these patients. This protocol will be studied prospectively in the next phase of this study. As we gain more comfort with emerging, minimally invasive endovascular therapies, we hope to safely achieve same-day discharge on a protocolized and routine basis, reducing the demand of elective aneurysm treatments on our healthcare system. Conclusion We retrospectively demonstrate that early discharge following elective aneurysm treatment is safe in our cohort and provide a fast-track pathway based on these findings for other centers developing similar protocols.

Excessive activation of mTOR in microglia impairs CNS homeostasis and causes severe epilepsy. Autophagy constitutes an important part of mTOR signaling. The contribution of microglial autophagy to CNS homeostasis and epilepsy remains to be determined. Here, we report that ATG7KO mice deficient for autophagy in microglia display a marked increase of myelination markers, a higher density of mature oligodendrocytes (ODCs), and altered lengths of the nodes of Ranvier. Moreover, we found that deficiency of microglial autophagy (ATG7KO) leads to increased seizure susceptibility in three seizure models (pilocarpine, kainic acid, and amygdala kindling). We demonstrated that ATG7KO mice develop severe generalized seizures and display nearly 100% mortality to convulsions induced by pilocarpine and kainic acid. In the amygdala kindling model, we observed significant facilitation of contralateral propagation of seizures, a process underlying the development of generalized seizures. Taken together, our results reveal impaired microglial autophagy as a novel mechanism underlying altered homeostasis of ODCs and increased susceptibility to severe and fatal generalized seizures.

While tobacco use continues to be the leading cause of preventable death in the world, current pharmacological treatments fall short. The most commonly prescribed smoking cessation drug, varenicline (commonly known as Chantix) targets the high affinity α4β2 nicotinic acetylcholine receptor that is densely expressed in the mesolimbic reward pathway. As a result of limited efficacy and a vast array of negative side effects associated with varenicline, research has been focused on finding novel targets for treating this disorder. The medial habenula-interpeduncular nucleus pathway is an alternate reward pathway in the brain. Previous research has implicated this pathway as an upstream modulator of the mesolimbic reward pathway. Currently, evidence points to receptors, specifically the α3β4 nicotinic acetylcholine receptor that is near exclusively expressed in this pathway and other receptors such as the substance P receptor as new potential targets for treating nicotine addiction.

BACKGROUND:Chronic pain causes a significant burden to the US health care system, is difficult to treat, and remains a significant contributor to increased opioid use in the United States. Spinal cord stimulation (SCS) has been FDA approved for the treatment of chronic pain. OBJECTIVE:To evaluate the hypothesis that SCS reduces opioid use, and alone maintains clinical outcome measures of pain and psychosocial determinants of health. METHODS:In this prospective cohort study, we evaluated 86 patients undergoing SCS surgery for the treatment of chronic pain between September 2012 and August 2015. Preoperatively and postoperatively, patients completed the Numerical Rating Scale (NRS), McGill Pain Questionnaire (MPQ), Pain Catastrophizing Scale (PCS), Oswestry Disability Index (ODI), and Beck's Depression Inventory (BDI). VAS scores were retrospectively analyzed. RESULTS:Fifty-three patients used opioids before SCS implantation. The 33 nonusers had lower mean VAS, NRS, and ODI scores than both opioid groups at 1 yr and improved significantly at 1 yr on the VAS (P < .001), NRS (P < .001), MPQ (P = .002), PCS (P < .001), BDI (P = .04), and ODI (P = .002). After surgery, 41.5% remained opioids and 58.5% reduced/eliminated use. Discontinued (n = 29) or reduced (n = 2) use resulted in VAS, NRS, total MPQ, and ODI score reduction (P < .001, P = .002, P = .002, and P = .009 respectively). At 1 yr, survey scores in opioid users were unchanged. There was no difference between groups in revision or failure rates. CONCLUSION:Sixty-four percent of patients who were using opioids prior to SCS reduced (n = 2) or eliminated opioid use (n = 29) at 1 yr postoperatively. Patients who eliminated opioid use or never used opioids had superior clinical outcomes to those who continued use.

INTRODUCTION:Preoperative work-up for spinal cord stimulation (SCS) includes a psychological assessment; however, no one psychological factor has correlated with poor outcomes across studies. We developed a Psychological Evaluation Tool for Spinal Cord Stimulation Candidacy (PETSCSC), which includes all factors in the literature found to correlate with outcomes. In this study, we examine whether PETSCSC correlates with postoperative outcomes.METHODS:Patients undergoing SCS were prospectively enrolled in this study. PETSCSC scores were obtained preoperatively. Numeric rating scale (NRS), global impression of change (GIC), pain catastrophizing scale (PCS), McGill pain questionnaire (MPQ), Oswestry disability index (ODI), and Beck Depression Inventory were assessed preoperatively and postoperatively. Outcomes were correlated with PETSCSC scores.RESULTS:Thirty-four SCS patients had a mean follow-up of 9.88 ± 2.91 months. At latest follow-up, we observed significant improvement in NRS, PCS, MPQ, and ODI. Total PETSCSC score exhibited significant correlation with GIC (p = 0.026, r = 0.380) and improvement in PCS total (p = 0.041, r = 0.351), and MPQ affective (p = 0.002, r = 0.517) scores. The PETSCSC emotive subset significantly correlated with GIC (p = 0.020, r = 0.395). The PETSCSC depression subset significantly correlated with improvement in PCS rumination (p = 0.009, r = 0.439), PCS helplessness (p = 0.021, r = 0.393), PCS total (p = 0.021, r = 0.394), and MPQ affective (p = 0.002, r = 0.501). The PETSCSC therapy subset significantly correlated with improvement in MPQ sensory (p = 0.026, r = -0.381) and MPQ affective (p < 0.001, r = 0.583).DISCUSSION:PETSCSC scores and subscores demonstrate significant correlation with pain outcomes used in assessment of SCS efficacy. Higher PETSCSC scores correlate with greater improvement in GIC, MPQ affective, and PCS scores. Stratification of these patients based on PETSCSC total and subset scores could help with prognostication.

Objective: Pain is a prevalent and debilitating nonmotor symptom of Parkinson's disease (PD) that is often inadequately managed. Deep brain stimulation (DBS) has been shown to relieve pain in PD but an effective method of identifying which types of PD pain respond to DBS has not been established. We examine the effects of DBS on different types of PD pain using the King's Parkinson's disease pain scale (KPDPS), the only validated scale of PD pain. Methods: We prospectively followed 18 PD patients undergoing subthalamic nucleus (STN) or Globus pallidus interna (GPi) DBS. Subjects completed the KPDPS, low back disability index (LBDI), and McGill pain questionnaire (MPQ), preoperatively and at six months postoperatively. Subjects underwent the unified Parkinson's disease rating scale-III (UPDRS-III) with preoperative scores ON medication and postoperative scores ON medication/DBS stimulation. Results: Of the 18 patients, a total of 12 subjects had STN DBS and 6 had GPi DBS. As a group, subjects showed improvement in total KPDPS score at six-month postoperative follow-up (p = 0.004). Fluctuation and nocturnal pain were most significantly improved (p = 0.006, 0.01, respectively). Significant improvements were found in fluctuation-related pain domain following GPi DBS. Conclusions: In this pilot study, we are the first group to employ KPDPS to monitor pain relief following DBS in PD patients. We demonstrate that fluctuation-related pain and nocturnal pain significantly improve with DBS. Use of the KPDPS in the future will allow better understanding of how STN and GPi DBS treat PD pain over time.

This article was migrated. The article was marked as recommended. IntroductionMultiple mini-interview (MMI) comments can help to reveal an underlying personality or behavioral flaw that the numerical scores are not designed to illustrate. The importance of the comments provided by interviewers has not been documented in the literature. This study sought to examine whether MMI comments influenced admission committee decision-making. MethodsFive thousand de-identified interview comments from a subset of 625 medical school applicants were reviewed by study raters who followed a rubric that outlined scoring assignments based upon the number of positive and negative statements made by MMI interviewers. The presence of extremely negative MMI comments was also evaluated.ResultsMMI score strongly correlated with MMI comment score assigned by the raters and contributed to overall committee score and decision for acceptance or rejection to medical school. The presence of one negative outlier comment score alone did not impact committee score or acceptance; however, when extremely negative attributes were identified by study raters within an outlier comment, this was associated with a reduction of final committee score and higher incidence of rejection.ConclusionsA strong correlation existed between the MMI comments and overall MMI score. Both MMI comments and MMI scores predict acceptance to medical school. The additional value of the MMI comments lies in the extremely negative outlier comments.

Objectives: Spinal Cord Stimulation (SCS) is an effective treatment for chronic pain. How often pain remission follows SCS has not been evaluated. This is a retrospective analysis of patients who underwent an implantation of spinal cord stimulators for various chronic pain conditions. The objective of the study was to elucidate characteristics and features of patients with pain relief greater than 80% after one year of treatment. Methods: A total of 86 patients with thoracic SCS and 12-month follow-up data were identified. Patients were divided into a remission group (>80% improvement in Numeric Pain Rating Scale [NRS] pain scale), average responders (20-80% improvement) and a non-responder group (less than 20% improvement). These patient groups were compared via the following outcome measures: NRS, Oswestry Disability Index (ODI), Pain Catastrophizing Scale (PCS), McGill Pain Questionnaire (MPQ), and Insomnia Severity Index (ISI). Correlations with age, body mass index (BMI), tobacco and alcohol usage, patient satisfaction with SCS, disability status, and opioid usage were assessed. Results: Nineteen of 86 patients (22%) were remitters at one year follow-up, including 17 patients who had an NRS50 at that time. Upon analyzing the three patient groups (non-responders, average responders, and remitters), remitter patients showed the greatest change over the one-year post-operative period in ODI (F(2) 58.101, p<0.01) and PCS (F(2) = 7.607, p<0.01). Moreover, remission was less likely when the patients were on disability prior to implant (chi(2) (2) = 6.469, p<0.05) and on opioids pre-operatively (chi(2) (2) = 17.688, p < 0.01). Conclusions: Our study demonstrates a remission rate of 22% with SCS at one-year follow with a total of 19.8% of our total patient cohort having an NRS of 0. Greater decreases in PCS and ODI correlate with remission. Further, pre-operative disability and opioid use correlate with lower likelihood of remission.

ObjectiveWe assess the safety of performing the epidural placement or revision of spinal cord stimulation (SCS) in patients whose anticoagulation has been held (termed "anticoagulant-suspended" patients) in accordance with the 2017 Neurostimulation Appropriateness Consensus Committee (NACC) guidelines.SubjectsPatients undergoing SCS were included in this institutional review board-approved study.DesignA retrospective analysis of a prospectively collected database was performed. Any adverse event occurring within 90 days after SCS lead placement/revision was included.ResultsA total of 225 patients who had a total of 239 surgeries including lead placement or lead revision were included; 182 patients were not on anticoagulants, 37 patients used one anticoagulant, and six patients used two or more anticoagulants. There were 13 adverse events. Anticoagulant use as a whole had no significant relationship to operative or postoperative adverse effects (χ2(1) = 1.613, P > 0.05). No anticoagulant on its own contributed significantly to adverse events; however, a small set of surgical cases showed a significantly greater incidence of adverse events for patients on enoxaparin used in combination with other anticoagulants (P < 0.05, N = 4).ConclusionsThis study is the first to demonstrate that anticoagulant-suspended patients have no increased risk of perioperative hemorrhagic or thromboembolic adverse effects following SCS surgery compared with nonanticoagulated patients. The findings of this study validate the safety of neuromodulation in anticoagulation-suspended patients, concurring with the findings of previously described case studies, which anecdotally described neuromodulation outcomes in patients whose anticoagulation regimen had been temporarily held.

Spinal cord stimulation (SCS) is an efficacious therapy used to treat chronic pain. The type of SCS programming is important in improving patients' quality of life and overall satisfaction. In this study, 19 patients who underwent SCS with traditional devices were given between 4 and 6 programs including programs with stimulation below sensory threshold and above sensory threshold. Usage patterns and preferences were assessed.

ObjectiveInfants born at less than 34 weeks' gestational age are at higher risk for morbidity and mortality. Data are limited on the impact of maternal obesity on the very preterm infant. This study reviewed whether maternal obesity further increases the intensive care needs of very preterm infants of less than 34 weeks' gestation.MethodsMaternal and neonatal data for live‐born singleton births of 23 0/7 to 33 6/7 weeks' gestation delivering in upstate New York were reviewed. BMI categorization followed the National Institutes of Health BMI classification that subdivides obesity into three ascending BMI groups.ResultsRecords were obtained on 1,224 women, of whom 31.6% were classified with obesity. Despite similar mean gestational age (31 to 31.6 weeks, P = 0.57) and birth weight (1,488 to 1,569 g, P = 0.51) of the infants in the BMI categories, delivery room (DR) resuscitation was more common for infants of women with level III obesity (63.2%, P = 0.04) with a trend toward the continued need for assisted ventilation (54.7%, P = 0.06).ConclusionsPreterm infants of women with level III obesity were more likely to require DR resuscitation with a trend to continued need for ventilatory support beyond 6 hours of age. This could impact utilization of DR resources at delivering hospitals.

The medial habenula-interpeduncular nucleus (MHb-IPN) pathway has recently been shown to modulate multiple effects nicotine in vivo, however it remains unclear which receptor subtypes in this pathway are critical for mediating these responses. To identify MHb and IPN receptors that play a role in nicotine reward, we studied receptors prevalent in these nuclei, including nicotinic acetylcholine receptors (nAChRs) and the receptor for substance P (neuokinin-1; NK1 receptor) using a model of behavioral and neurochemical sensitization to nicotine. Our results show that blockade of the α3β4 nAChR in the MHb, but not the IPN prevented increases in locomotor responding as well as increases in accumbal dopamine overflow in sensitized animals. Additionally, when NK1 receptors were blocked in the IPN, but not the MHb, a similar effect on sensitized responding was seen. Together, these results suggest that the MHb and IPN differentially modulate nicotine sensitization. Because the neurotransmission within these brain regions is primarily cholinergic and substance P ergic and these receptors are expressed in high density in both nuclei, these results could suggest a different neurophysiological signaling role or different neuroanatomical location of these receptors in this pathway. Furthermore, while α3β4 nAChRs have been suggested as a possible pharmacological target for nicotine addiction, this is the first evidence that substance P also plays a role in mediating responding to nicotine.

Systemic 18-methoxycoronaridine, an alpha3beta4 nicotinic antagonist, slows the rate of induction of behavioral sensitization to nicotine (Glick et al., 1996; 2011). The primary mechanism of action of 18-MC is believed to be the inhibition of α3β4 nicotinic acetylcholine receptors which are densely expressed in the medial habenula and interpeduncular nucleus (Pace et al., 2004; Glick et al., 2012). Recently, these habenular nicotinic receptors and their multiple roles in nicotine aversion and withdrawal have been increasingly emphasized (Antolin-Fontes et al., 2015). Here, we investigated the effects of 18-MC on both behavioral and neurochemical sensitization to nicotine. Daily systemic administration of 18-MC slowed the rate of induction of behavioral sensitization to nicotine but failed to block the expression of a sensitized locomotor response when absent. In contrast, in nicotine sensitized animals, systemic 18-MC significantly reduced the expression of behavioral sensitization. Results from intra-habenular administration of 18-MC paralleled these findings in that the expression of behavioral sensitization was also reduced in sensitized animals. Consistent with its effects on behavioral sensitization, intra-MHb treatment with 18-MC completely abolished sensitized dopamine responses in the nucleus accumbens in nicotine sensitized animals. These results show that α3β4 nicotinic receptors in the MHb contribute to nicotine sensitization, a phenomenon associated with drug craving and relapse.

Nicotine metabolism is believed to affect not only nicotine's pharmacological effects but also nicotine addiction. As a key step toward testing this hypothesis, we have studied nicotine metabolism and nicotine's pharmacological and behavioral effects in a novel knockout mouse model [named Cyp2a(4/5)bgs-null] lacking a number of cytochrome P450 genes known to be or possibly involved in nicotine metabolism, including two Cyp2a and all Cyp2b genes. We found that, compared with wild-type mice, the Cyp2a(4/5)bgs-null mice showed >90% decreases in hepatic microsomal nicotine oxidase activity in vitro, and in rates of systemic nicotine clearance in vivo. Further comparisons of nicotine metabolism between Cyp2a(4/5)bgs-null and Cyp2a5-null mice revealed significant roles of both CYP2A5 and CYP2B enzymes in nicotine clearance. Compared with the behavioral responses in wild-type mice, the decreases in nicotine metabolism in the Cyp2a(4/5)bgs-null mice led to prolonged nicotine-induced acute pharmacological effects, in that null mice showed enhanced nicotine hypothermia and antinociception. Furthermore, we found that the Cyp2a(4/5)bgs-null mice developed a preference for nicotine in a conditioned place preference test, a commonly used test of nicotine's rewarding effects, at a nicotine dose that was 4-fold lower than what was required by wild-type mice. Thus, CYP2A/2B-catalyzed nicotine clearance affects nicotine's behavioral response as well as its acute pharmacological effects in mice. This result provides direct experimental support of the findings of pharmacogenetic studies that suggest linkage between rates of nicotine metabolism and smoking behavior in humans.

Habenulo-interpeduncular nicotinic receptors, particularly those containing α3, β4 and α5 subunits, have recently been implicated in the reinforcing effects of nicotine. Our laboratory has shown that injection of α3β4 nicotinic receptor antagonists into the medial habenula (MHb) decreases self-administration of multiple abused drugs, including nicotine (Glick et al., 2006, 2008; 2011). However, it is unclear whether blockade of MHb nicotinic receptors has a direct effect on mesolimbic dopamine. Here, we performed in vivo microdialysis in female rats. Microdialysis probes were implanted into the nucleus accumbens (NAcc) and α3β4 nicotinic receptor antagonists (18-methoxycoronaridine; 18-MC or α-conotoxin AuIB; AuIB), were injected into the ipsilateral MHb, just prior to systemic nicotine (0.4 mg/kg, s.c.). Dialysate samples were collected before and after drug administration and levels of extracellular dopamine and its metabolites were measured using HPLC. Acute nicotine administration increased levels of extracellular dopamine and its metabolites in the NAcc. Pre-treatment with intra-habenular AuIB or 18-MC prevented nicotine-induced increases in accumbal dopamine. Neither drug had an effect on nicotine-induced increases in dopamine metabolites, suggesting that α3β4 receptors do not play a role in dopamine metabolism. The effect of intra-habenular blockade of α3β4 receptors on NAcc dopamine was selective for acute nicotine: neither AuIB nor 18-MC prevented increases in NAcc dopamine stimulated by acute d-amphetamine or morphine. These results suggest the mesolimbic response to acute nicotine, but not to acute administration of other drugs of abuse, is directly modulated by α3β4 nicotinic receptors in the MHb, and emphasize a critical role for habenular nicotinic receptors in nicotine's reinforcing effects.

18-Methoxycoronaridine (18-MC), a selective antagonist of α3β4 nicotinic receptors, has been previously shown, in rats, to reduce the self-administration of several drugs of abuse, reduce operant responding for sucrose, and prevent the development of sucrose-induced obesity. It has become increasingly apparent that there is a significant overlap between the systems regulating drug reward and food intake, therefore, we investigated whether 18-MC might modulate the effects of ghrelin, one of several orexigenic peptides recently implicated in both feeding and drug reward.

The iboga alkaloid congener, 18-methoxycoronaridine (18-MC), decreases self-administration of multiple drugs of abuse. Here, in a biased procedure, we investigated whether 18-MC would have a similar effect on the acquisition, expression and reinstatement of a cocaine conditioned place preference (CPP) in male Sprague-Dawley rats. While 18-MC attenuated acquisition of a cocaine CPP, it had no effect on CPP expression, and enhanced the reinstatement of cocaine CPP following extinction. Our results are consistent with those obtained using ibogaine, but reinforce the notion that acquisition, expression and reinstatement of a CPP likely involve separate mechanisms.

Cannabinoids have been used for medicinal purposes for millennia, functioning as analgesics and anxiolytics but also treating disorders ranging from constipation and digestive ailments to arthritis and malaria. For this reason, it is quite understandable that since their discovery 15 years ago, researchers have explored the uses of endogenous cannabinoids (eCBs) in the same manner. eCBs, lipophilic signaling molecules, affect the signaling of many neurotransmitter systems, and their modulation of dopamine neurotransmission, in particular, has relevance for treating conditions ranging from addiction to movement disorders such as Huntington’s and Parkinson’s diseases. In the following chapter, we will characterize the relationship between eCBs and dopamine in the nigrostriatal pathway, detailing both dopaminergic modulation of eCBs and the effect of eCBs and CB1 receptor ligands on dopaminergic transmission. The efficacy of CB1 receptor modulating drugs for the treatment of Parkinson’s disease has been examined in several animal models of the disease. However, to date, it remains undetermined whether eCBs serve as neuroprotective agents or rather, potentiate dopaminergic loss associated with Parkinson’s disease (PD). We will discuss interactions between eCBs and dopamine neurons, and propose, based on compelling evidence of eCB modulation of dopaminergic transmission, that CB1 receptor antagonists are better suited for the treatment of PD.