Responsive deep brain stimulation guided by ventral striatal electrophysiology of obsession durably ameliorates compulsion.

Treatment-resistant obsessive-compulsive disorder (OCD) occurs in approximately one-third of OCD patients. Obsessions may fluctuate over time but often occur or worsen in the presence of internal (emotional state and thoughts) and external (visual and tactile) triggering stimuli. Obsessive thoughts and related compulsive urges fluctuate (are episodic) and so may respond well to a time-locked brain stimulation strategy sensitive and responsive to these symptom fluctuations. Early evidence suggests that neural activity can be captured from ventral striatal regions implicated in OCD to guide such a closed-loop approach. Here, we report on a first-in-human application of responsive deep brain stimulation (rDBS) of the ventral striatum for a treatment-refractory OCD individual who also had comorbid epilepsy. Self-reported obsessive symptoms and provoked OCD-related distress correlated with ventral striatal electrophysiology. rDBS detected the time-domain area-based feature from invasive electroencephalography low-frequency oscillatory power fluctuations that triggered bursts of stimulation to ameliorate OCD symptoms in a closed-loop fashion. rDBS provided rapid, robust, and durable improvement in obsessions and compulsions. These results provide proof of concept for a personalized, physiologically guided DBS strategy for OCD.

Impact of Cochlear Dose on Hearing Preservation Following Stereotactic Radiosurgery in Treatment of Vestibular Schwannomas: A Multi-Center Study.

OBJECTIVE: Stereotactic radiosurgery (SRS) is a well-established treatment for vestibular schwannomas (VS). Hearing loss remains a main morbidity of VS and its treatments, including SRS. The effects of radiation parameters of SRS on hearing remain unknown. The goal of this study is to determine the effect of tumor volume, patient demographics, pretreatment hearing status, cochlear radiation dose, total tumor radiation dose, fractionation, and other radiotherapy parameters on hearing deterioration. METHODS: Multicenter retrospective analysis of 611 patients who underwent SRS for VS from 1990-2020 and had pre- and post-treatment audiograms. RESULTS: Pure tone averages (PTAs) increased and word recognition scores (WRSs) decreased in treated ears at 12-60 months while remaining stable in untreated ears. Higher baseline PTA, higher tumor radiation dose, higher maximum cochlear dose, and usage of single fraction resulted in higher post radiation PTA; WRS was only predicted by baseline WRS and age. Higher baseline PTA, single fraction treatment, higher tumor radiation dose, and higher maximum cochlear dose resulted in a faster deterioration in PTA. Below a maximum cochlear dose of 3 Gy, there were no statistically significant changes in PTA or WRS. CONCLUSIONS: Decline of hearing at one year in VS patients after SRS is directly related to maximum cochlear dose, single versus 3-fraction treatment, total tumor radiation dose, and baseline hearing level. The maximum safe cochlear dose for hearingtbrowd preservation at one year is 3 Gy, and the use of 3 fractions instead of one fraction was better at preserving hearing.

Myeloid-derived itaconate suppresses cytotoxic CD8+ T cells and promotes tumour growth.

The tumour microenvironment possesses mechanisms that suppress anti-tumour immunity. Itaconate is a metabolite produced from the Krebs cycle intermediate cis-aconitate by the activity of immune-responsive gene 1 (IRG1). While it is known to be immune modulatory, the role of itaconate in anti-tumour immunity is unclear. Here, we demonstrate that myeloid-derived suppressor cells (MDSCs) secrete itaconate that can be taken up by CD8+ T cells and suppress their proliferation, cytokine production and cytolytic activity. Metabolite profiling, stable-isotope tracing and metabolite supplementation studies indicated that itaconate suppressed the biosynthesis of aspartate and serine/glycine in CD8+ T cells to attenuate their proliferation and function. Host deletion of Irg1 in female mice bearing allografted tumours resulted in decreased tumour growth, inhibited the immune-suppressive activities of MDSCs, promoted anti-tumour immunity of CD8+ T cells and enhanced the anti-tumour activity of anti-PD-1 antibody treatment. Furthermore, we found a significant negative correlation between IRG1 expression and response to PD-1 immune checkpoint blockade in patients with melanoma. Our findings not only reveal a previously unknown role of itaconate as an immune checkpoint metabolite secreted from MDSCs to suppress CD8+ T cells, but also establish IRG1 as a myeloid-selective target in immunometabolism whose inhibition promotes anti-tumour immunity and enhances the efficacy of immune checkpoint protein blockade.

Palmitoylation of A-kinase anchoring protein 79/150 modulates its nanoscale organization, trafficking, and mobility in postsynaptic spines.

A-kinase anchoring protein 79-human/150-rodent (AKAP79/150) organizes signaling proteins to control synaptic plasticity. AKAP79/150 associates with the plasma membrane and endosomes through its N-terminal domain that contains three polybasic regions and two Cys residues that are reversibly palmitoylated. Mutations abolishing palmitoylation (AKAP79/150 CS) reduce its endosomal localization and association with the postsynaptic density (PSD). Here we combined advanced light and electron microscopy (EM) to characterize the effects of AKAP79/150 palmitoylation on its postsynaptic nanoscale organization, trafficking, and mobility in hippocampal neurons. Immunogold EM revealed prominent extrasynaptic membrane AKAP150 labeling with less labeling at the PSD. The label was at greater distances from the spine membrane for AKAP150 CS than WT in the PSD but not in extra-synaptic locations. Immunogold EM of GFP-tagged AKAP79 WT showed that AKAP79 adopts a vertical, extended conformation at the PSD with its N-terminus at the membrane, in contrast to extrasynaptic locations where it adopts a compact or open configurations of its N- and C-termini with parallel orientation to the membrane. In contrast, GFP-tagged AKAP79 CS was displaced from the PSD coincident with disruption of its vertical orientation, while proximity and orientation with respect to the extra-synaptic membrane was less impacted. Single-molecule localization microscopy (SMLM) revealed a heterogeneous distribution of AKAP150 with distinct high-density, nano-scale regions (HDRs) overlapping the PSD but more prominently located in the extrasynaptic membrane for WT and the CS mutant. Thick section scanning transmission electron microscopy (STEM) tomography revealed AKAP150 immunogold clusters similar in size to HDRs seen by SMLM and more AKAP150 labeled endosomes in spines for WT than for CS, consistent with the requirement for AKAP palmitoylation in endosomal trafficking. Hidden Markov modeling of single molecule tracking data revealed a bound/immobile fraction and two mobile fractions for AKAP79 in spines, with the CS mutant having shorter dwell times and faster transition rates between states than WT, suggesting that palmitoylation stabilizes individual AKAP molecules in various spine subpopulations. These data demonstrate that palmitoylation fine tunes the nanoscale localization, mobility, and trafficking of AKAP79/150 in dendritic spines, which might have profound effects on its regulation of synaptic plasticity.

Pilot study of responsive nucleus accumbens deep brain stimulation for loss-of-control eating.

Cravings that precede loss of control (LOC) over food consumption present an opportunity for intervention in patients with the binge eating disorder (BED). In this pilot study, we used responsive deep brain stimulation (DBS) to record nucleus accumbens (NAc) electrophysiology during food cravings preceding LOC eating in two patients with BED and severe obesity (trial registration no. NCT03868670). Increased NAc low-frequency oscillations, prominent during food cravings, were used to guide DBS delivery. Over 6 months, we observed improved self-control of food intake and weight loss. These findings provide early support for restoring inhibitory control with electrophysiologically-guided NAc DBS. Further work with increased sample sizes is required to determine the scalability of this approach.

Prediction of Discharge Status and Readmissions after Resection of Intradural Spinal Tumors.

OBJECTIVE: Intradural spinal tumors are uncommon and while associations between clinical characteristics and surgical outcomes have been explored, there remains a paucity of literature unifying diverse predictors into an integrated risk model. To predict postresection outcomes for patients with spinal tumors. METHODS: IBM MarketScan Claims Database was queried for adult patients receiving surgery for intradural tumors between 2007 and 2016. Primary outcomes-of-interest were nonhome discharge and 90-day postdischarge readmissions. Secondary outcomes included hospitalization duration and postoperative complications. Risk modeling was developed using a regularized logistic regression framework (LASSO, least absolute shrinkage and selection operator) and validated in a withheld subset. RESULTS: A total of 5,060 adult patients were included. Most surgeries utilized a posterior approach (n = 5,023, 99.3%) and tumors were most commonly found in the thoracic region (n = 1,941, 38.4%), followed by the lumbar (n = 1,781, 35.2%) and cervical (n = 1,294, 25.6%) regions. Compared to models using only tumor-specific or patient-specific features, our integrated models demonstrated better discrimination (area under the curve [AUC] [nonhome discharge] = 0.786; AUC [90-day readmissions] = 0.693) and accuracy (Brier score [nonhome discharge] = 0.155; Brier score [90-day readmissions] = 0.093). Compared to those predicted to be lowest risk, patients predicted to be highest-risk for nonhome discharge required continued care 16.3 times more frequently (64.5% vs. 3.9%). Similarly, patients predicted to be at highest risk for postdischarge readmissions were readmitted 7.3 times as often as those predicted to be at lowest risk (32.6% vs. 4.4%). CONCLUSION: Using a diverse set of clinical characteristics spanning tumor-, patient-, and hospitalization-derived data, we developed and validated risk models integrating diverse clinical data for predicting nonhome discharge and postdischarge readmissions.

STAG2 regulates interferon signaling in melanoma via enhancer loop reprogramming.

The cohesin complex participates in the organization of 3D genome through generating and maintaining DNA loops. Stromal antigen 2 (STAG2), a core subunit of the cohesin complex, is frequently mutated in various cancers. However, the impact of STAG2 inactivation on 3D genome organization, especially the long-range enhancer-promoter contacts and subsequent gene expression control in cancer, remains poorly understood. Here we show that depletion of STAG2 in melanoma cells leads to expansion of topologically associating domains (TADs) and enhances the formation of acetylated histone H3 lysine 27 (H3K27ac)-associated DNA loops at sites where binding of STAG2 is switched to its paralog STAG1. We further identify Interferon Regulatory Factor 9 (IRF9) as a major direct target of STAG2 in melanoma cells via integrated RNA-seq, STAG2 ChIP-seq and H3K27ac HiChIP analyses. We demonstrate that loss of STAG2 activates IRF9 through modulating the 3D genome organization, which in turn enhances type I interferon signaling and increases the expression of PD-L1. Our findings not only establish a previously unknown role of the STAG2 to STAG1 switch in 3D genome organization, but also reveal a functional link between STAG2 and interferon signaling in cancer cells, which may enhance the immune evasion potential in STAG2-mutant cancer.

Hemorrhage risk of direct oral anticoagulants in real-world venous thromboembolism patients.

INTRODUCTION: Venous thromboembolism (VTE) management increasingly involves anticoagulation with direct oral anticoagulants (DOACs). Few studies have used competing-risks analyses to ascertain the mortality-adjusted hemorrhage and recurrent VTE (rVTE) risk of individual DOACs. Furthermore, hemorrhage risk factors in patients treated with apixaban remain underexplored. MATERIALS AND METHODS: Patients diagnosed with VTE receiving anticoagulation were identified from the Optum Clinformatics Data Mart (2003-2019). Study endpoints included readmissions for intracranial hemorrhage (ICH), non-intracranial hemorrhage (non-ICH hemorrhage), and rVTE. Coarsened exact matching was used to balance baseline clinical characteristics. Complication incidence was evaluated using a competing-risks framework. We additionally modeled hemorrhage risk in apixaban-treated patients. RESULTS: Overall, 225,559 patients were included, of whom 34,201 received apixaban and 46,007 received rivaroxaban. Compared to rivaroxaban, apixaban was associated with decreased non-ICH hemorrhage (sHR = 0.560, 95%CI = 0.423-0.741), but not ICH, and rVTE (sHR = 0.802, 95%CI = 0.651-0.988) risk. This was primarily in emergent readmissions (sHR[emergent hemorrhage] = 0.515, 95%CI = 0.372-0.711; sHR[emergent rVTE] = 0.636, 95%CI = 0.488-0.830). Contributors to emergent hemorrhage in apixaban-treated patients include older age (sHR = 1.025, 95%CI = 1.011-1.039), female sex (sHR = 1.662, 95%CI = 1.252-2.207), prior prescription antiplatelet therapy (sHR = 1.591, 95%CI = 1.130-2.241), and complicated hypertension (sHR = 1.936, 95%CI = 1.134-3.307). Patients anticipated to be "high-risk" experienced elevated ICH (sHR = 3.396, 95%CI = 1.375-8.388) and non-ICH hemorrhage (sHR = 3.683, 95%CI = 2.957-4.588) incidence. CONCLUSIONS: In patients with VTE receiving anticoagulation, apixaban was associated with reduced non-ICH hemorrhage and rVTE risk, compared to rivaroxaban. Risk reduction was restricted to emergent readmissions. We present a risk-stratification approach to predict hemorrhage in patients receiving apixaban, potentially guiding future clinical decision-making.

Neurology trial registrations on ClinicalTrials.gov between 2007 and 2018: A cross-sectional analysis of characteristics, early discontinuation, and results reporting.

BACKGROUND: Increasing neurological disease burden and advancing treatment options require clinical trials to expand the evidence base of clinical care. We aimed to characterize neurology clinical trials registered between October 2007 and April 2018 and identify features associated with early discontinuation and results reporting. METHODS: We compared 16,994 neurology (9.4%) and 163,714 non-neurology comparison trials registered to ClinicalTrials.gov. Trials therapeutic focus within neurology was assigned via combination programmatic and manual review. We performed descriptive analyses of trial characteristics, cox regression of early discontinuation, and multivariable logistic regression for results reporting within 3 years of completion. RESULTS: Most neurology trials were academic-funded (58.5%) followed by industry (31.9%) and US-government (9.6%). Neurology trials focused more on treatment than prevention compared to non-neurology studies. Of neurology trials, 11.3% discontinued early, and 32.2% of completed trials reported results by April 30, 2018. In multivariable analysis accounting for time-to-event, neurology trials were at lower risk of discontinuation than non-neurology trials (adjusted hazard 0.83, p < 0.0001). Both academic and government-funded trials had greater risk of discontinuation than industry (adjusted hazard 0.57 and 0.46, respectively). Among completed trials, government-funded studies (adjusted odds ratio 2.12, p < 0.0001) had highest odds of results reporting while academic trials reported less (adjusted odds ratio 0.51, p < 0.0001). CONCLUSIONS: Funding source is associated with trial characteristics and outcomes in neurology. Improvements in trial completion and timely dissemination of results remain urgent goals for the field.

The insulo-opercular cortex encodes food-specific content under controlled and naturalistic conditions.

The insulo-opercular network functions critically not only in encoding taste, but also in guiding behavior based on anticipated food availability. However, there remains no direct measurement of insulo-opercular activity when humans anticipate taste. Here, we collect direct, intracranial recordings during a food task that elicits anticipatory and consummatory taste responses, and during ad libitum consumption of meals. While cue-specific high-frequency broadband (70-170 Hz) activity predominant in the left posterior insula is selective for taste-neutral cues, sparse cue-specific regions in the anterior insula are selective for palatable cues. Latency analysis reveals this insular activity is preceded by non-discriminatory activity in the frontal operculum. During ad libitum meal consumption, time-locked high-frequency broadband activity at the time of food intake discriminates food types and is associated with cue-specific activity during the task. These findings reveal spatiotemporally-specific activity in the human insulo-opercular cortex that underlies anticipatory evaluation of food across both controlled and naturalistic settings.

Is Uncontrolled Diabetes Mellitus Associated with Incidence of Complications After Posterior Instrumented Lumbar Fusion? A National Claims Database Analysis.

BACKGROUND: Previous research has shown that diabetes mellitus (DM) is associated with postoperative complications, including surgical site infections (SSIs). However, evidence for the association between diabetes control and postoperative complications in patients with DM is mixed. Prior studies relied on a single metric for defining uncontrolled DM, which does not account for glycemic variability, and it is unknown whether a more comprehensive assessment of diabetes control is associated with postoperative complications. QUESTIONS/PURPOSES: (1) Is there a difference in the incidence of SSI after lumbar spine fusion in patients with uncontrolled DM, defined with a comprehensive assessment of glycemic control, compared with patients with controlled DM? (2) Is there a difference in the incidence of other select postoperative complications after lumbar spine fusion in patients with uncontrolled DM compared with patients with controlled DM? (3) Is there a difference in total reimbursements between these groups? METHODS: We used the PearlDiver Patient Records Database, a national administrative claims database that provides access to the full continuum of perioperative care. We included 46,490 patients with DM undergoing posterior lumbar fusion with instrumentation. Patients were required to be continuously enrolled in the database for at least 1 year before and 90 days after the index procedure. Patients were divided into uncontrolled and controlled DM cohorts, as defined by ICD-9 diagnostic codes. These are based on a comprehensive assessment of glycemic control, including consideration of patient self-monitoring of blood glucose levels, hemoglobin A1c, and the presence/severity of diabetes-related comorbidities. The cohorts differed only by age, insurance type, and Elixhauser comorbidity score. The primary outcome was the incidence of SSI, divided into superficial and deep, within 90 days postoperatively. Secondary complications included the incidence of cerebrovascular events, acute kidney injury, pulmonary embolism, pneumonia, urinary tract infection, blood transfusion, and total reimbursements. These are the sum of reimbursements occurring within 90 days of surgery, which capture the total professional and facility cost burden to the health payer (such as the insurer). We constructed multivariable logistic regression models to adjust for the effects of age, insurance type, and comorbidities. RESULTS: After adjusting for potentially confounding variables including age, insurance type, and comorbidities, we found that patients with uncontrolled DM had an odds ratio for deep SSI of 1.52 (95% confidence interval 1.16 to 1.95; p = 0.002). Similarly, patients with uncontrolled DM had adjusted odds ratios of 1.25 (95% CI 1.01 to 1.53; p = 0.03) for cerebrovascular events, 1.36 (95% CI 1.18 to 1.57; p < 0.001) for acute kidney injury, 1.55 (95% CI 1.16 to 2.04; p = 0.002) for pulmonary embolism, 1.30 (95% CI 1.08 to 1.54; p = 0.004) for pneumonia, 1.33 (95% CI 1.19 to 1.49; p < 0.001) for urinary tract infection, and 1.27 (95% CI 1.04 to 1.53; p = 0.02) for perioperative transfusion. Patients with uncontrolled DM had higher median 90-day total reimbursements than patients with controlled DM: USD 27,915 (interquartile range 5472 to 63,400) versus USD 10,263 (IQR 4101 to 49,748; p < 0.001). CONCLUSION: Our findings encourage surgeons to take a full diabetic history beyond the HbA1c value, including any self-monitoring of glucose measurements, time in acceptable range for continuous glucose monitors, and/or consideration of the presence/severity of diabetes-related complications before lumbar spine fusion, as HbA1c does not fully capture glycemic control or variability. We emphasize that uncontrolled DM is a clinical, rather than laboratory, diagnosis. Comprehensive diabetes histories should be incorporated into existing preoperative diabetes care pathways and elective surgery could be deferred to improve glycemic control. Future development of an index measure incorporating multidimensional measures of diabetes control (such as continuous or self-glucose monitoring, diabetes-related comorbidities) is warranted. LEVEL OF EVIDENCE: Level III, therapeutic study.

Defining and describing treatment heterogeneity in new-onset idiopathic lower back and extremity pain through reconstruction of longitudinal care sequences.

BACKGROUND CONTEXT: Despite established guidelines, long-term management of surgically-treated low back pain (LBP) and lower extremity pain (LEP) remains heterogeneous. Understanding care heterogeneity could inform future approaches for standardization of practices. PURPOSE: To describe treatment heterogeneity in surgically-managed LBP and LEP. STUDY DESIGN/SETTING: Retrospective study of a nationwide commercial database spanning inpatient and outpatient encounters for enrollees of eligible employer-supplied healthcare plans (2007-2016). PATIENT SAMPLE: A population-based sample of opioid-naïve adult patients with newly-diagnosed LBP or LEP were identified. Inclusion required at least 12-months of pre-diagnosis and post-diagnosis continuous follow-up. EXPOSURE: Included treatments/evaluations include conservative management (chiropractic manipulative therapy, physical therapy, epidural steroid injections), imaging (x-ray, MRI, CT), pharmaceuticals (opioids, benzodiazepines), and spine surgery (decompression, fusion). OUTCOME MEASURES: Primary outcomes-of-interest were 12-month net healthcare expenditures (inpatient and outpatient) and 12-month opioid usage. METHODS: Analyses include interrogation of care sequence heterogeneity and temporal trends in sequence-initiating services. Comparisons were conducted in the framework of sequence-specific treatment sequences, which reflect the personalized order of healthcare services pursued by each patient. Outlier sequences characterized by high opioid use and costs were identified from frequently observed surgical treatment sequences using Mahalanobis distance. RESULTS: A total of 2,496,908 opioid-naïve adult patients with newly-diagnosed LBP or LEP were included (29,519 surgical). In the matched setting, increased care sequence heterogeneity was observed in surgical patients (0.51 vs. 0.12 previously-unused interventions/studies pursued per month). Early opioid and MRI use has decreased between 2008 and 2015 but is matched by increases in early benzodiazepine and x-ray use. Outlier sequences, characterized by increased opioid use and costs, were found in 5.8% of surgical patients. Use of imaging prior to conservative management was common in patients pursuing outlier sequences compared to non-outlier sequences (96.5% vs. 63.8%, p<.001). Non-outlier sequences were more frequently characterized by early conservative interventions (31.9% vs. 7.4%, p<.001). CONCLUSIONS: Surgically-managed LBP and LEP care sequences demonstrate high heterogeneity despite established practice guidelines. Outlier sequences associated with high opioid usage and costs can be identified and are characterized by increased early imaging and decreased early conservative management. Elements that may portend suboptimal longitudinal management could provide opportunities for standardization of patient care.

Intraoperative Neuromonitoring for Cerebral Arteriovenous Malformation Embolization: A Propensity-Score Matched Retrospective Database Study.

Introduction The treatment of cerebral arteriovenous malformations (AVMs) may result in neurologic morbidity, particularly when an AVM is located in or adjacent to eloquent brain regions. Intraoperative neurophysiologic monitoring (IONM) may be utilized to reduce the risk of iatrogenic injury during endovascular AVM embolization; however, IONM for endovascular AVM embolization is not ubiquitously the standard of care. Methods Admissions for AVM embolization were assessed from the IBM MarketScan® Commercial and Medicare Supplemental databases (IBM Watson Health, Somers, NY). Inclusion criterion for patients was continuous enrollment six months before and after the index encounter. The use of IONM and presence of intracranial hemorrhage (ICH) were noted. Propensity-score matched cohorts with and without IONM were generated to minimize bias between treatment groups (adjusting for age, sex, and comorbidities). Results From 2007 to 2016, there were 16,279 patients diagnosed with cerebral AVM in the MarketScan database. Embolized patients were stratified into IONM and non-IONM cohorts; there were 357 patients in the IONM cohort and 1775 patients in the non-IONM cohort. Provider types were significantly different between cohorts (p<0.005). Unruptured AVMs were significantly more likely to be embolized with adjunctive IONM (17.7%) compared to ruptured AVMs (7.9%) (p<0.005). After balancing for baseline comorbidities, there were 266 patients in the IONM cohort, and 1347 patients in the non-IONM cohort. Among unruptured AVM patients, IONM was linked to a significantly shorter length of stay (2.72 versus 4.92 days; p<0.005), significantly lower rates of complications within 30 days of discharge (0.00% versus 1.88%; p=0.038), and significantly lower total payment ($40,179 versus $50,844; p<0.0001). Conclusion Endovascular embolization for unruptured AVMs performed with adjunctive IONM was associated with shorter length of stay, lower complication rates, and hospitalization costs.

Anticipatory human subthalamic area beta-band power responses to dissociable tastes correlate with weight gain.

The availability of enticing sweet, fatty tastes is prevalent in the modern diet and contribute to overeating and obesity. In animal models, the subthalamic area plays a role in mediating appetitive and consummatory feeding behaviors, however, its role in human feeding is unknown. We used intraoperative, subthalamic field potential recordings while participants (n = 5) engaged in a task designed to provoke responses of taste anticipation and receipt. Decreased subthalamic beta-band (15-30 Hz) power responses were observed for both sweet-fat and neutral tastes. Anticipatory responses to taste-neutral cues started with an immediate decrease in beta-band power from baseline followed by an early beta-band rebound above baseline. On the contrary, anticipatory responses to sweet-fat were characterized by a greater and sustained decrease in beta-band power. These activity patterns were topographically specific to the subthalamic nucleus and substantia nigra. Further, a neural network trained on this beta-band power signal accurately predicted (AUC ≥ 74%) single trials corresponding to either taste. Finally, the magnitude of the beta-band rebound for a neutral taste was associated with increased body mass index after starting deep brain stimulation therapy. We provide preliminary evidence of discriminatory taste encoding within the subthalamic area associated with control mechanisms that mediate appetitive and consummatory behaviors.

Accumbens coordinated reset stimulation in mice exhibits ameliorating aftereffects on binge alcohol drinking.

BACKGROUND: Alcohol use disorder (AUD) affects nearly 5% of the world's adult population. Despite treatment, AUD often manifests with relapse to binge drinking, which has been associated with corticostriatal hypersynchrony involving the nucleus accumbens (NAc). METHODS: A modified "Drinking in the Dark" protocol was used to provoke binge-like alcohol drinking. We implemented Coordinated Reset Stimulation (CRS), a computationally designed, spatio-temporal stimulation algorithm, to desynchronize abnormal neuronal activity via a deep brain stimulation (DBS) electrode in the NAc of mice exhibiting binge-like alcohol drinking. Integral CRS charge injected would be 2.5% of that of conventional high-frequency DBS. RESULTS: NAc CRS delivery during only the initial phase of exposure to alcohol and prior to the exposure (but not during) significantly reduced binge-like drinking without interfering with social behavior or locomotor activity. CONCLUSIONS: NAc CRS ameliorates binge-like alcohol drinking and preliminarily exhibits sustained aftereffects that are suggestive of an unlearning of hypersynchrony.

Stereotactic Radiosurgery for Vestibular Schwannoma Outcomes in Patients With Perfect Word Recognition-A Retrospective Cohort Study.

OBJECTIVES: To investigate tumor control rate and hearing outcomes following stereotactic radiosurgery (SRS) for vestibular schwannoma (VS) cases with perfect (100%) word recognition score (WRS). STUDY DESIGN: A retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: Inclusion criteria were receiving primary SRS, a pretreatment WRS of 100%, and availability of both pre- and posttreatment audiometric data for evaluation. INTERVENTION: SRS delivered by Cyberknife. MAIN OUTCOME MEASURES: Tumor growth rates and audiological outcomes after SRS. RESULTS: The cohort consisted of 139 patients, with more than 1-year follow-up (mean 6.1 yrs). SRS tumor control rate was 87% for the whole cohort. Growth before SRS was documented in 24% (n = 34 of 139). The proportion of sporadic VS cases who maintained hearing (decline <10 dB of pure-tone audiometry or <20% of WRS) at 3 years was 50%, at 5 years was 45%, and at 10 years was 42%. In multivariate analysis, increased age was found to be predictive of increased hearing loss (p = 0.03), while the following factors were shown not to be significant: sex (p = 0.5), tumor size (p = 0.2), pre-SRS tumor growth (p = 0.5), and target volume (p = 0.42). CONCLUSIONS: Among patients with VS who had perfect WRS and underwent SRS, the overall tumor control rate was 87% comparable to observation. Hearing maintenance and preservation of "serviceable" hearing rates after 5 years in VS patients with perfect WRS treated by SRS is less than that when comparing to similar observation cohorts. Given this finding we do not advocate using SRS to preserve hearing, over observation, in tumors with perfect WRS.

An Analysis of Public Interest in Elective Neurosurgical Procedures During the COVID-19 Pandemic Through Online Search Engine Trends.

OBJECTIVE: In the wake of the COVID-19 pandemic, the Centers for Medicare & Medicaid Services (CMS) has recommended the temporary cessation of all elective surgeries. The effects on patients' interest of elective neurosurgical procedures are currently unexplored. METHODS: Using Google Trends, search terms of 7 different neurosurgical procedure categories (trauma, spine, tumor, movement disorder, epilepsy, endovascular, and miscellaneous) were assessed in terms of relative search volume (RSV) between January 2015 and September 2020. Analyses of search terms were performed for over the short term (February 18, 2020, to April 18, 2020), intermediate term (January 1, 2020, to May 31, 2020), and long term (January 2015 to September 2020). State-level interest during phase I reopening (April 28, 2020, to May 31, 2020) was also evaluated. RESULTS: In the short term, RSVs of 4 categories (epilepsy, movement disorder, spine, and tumor) were significantly lower in the post-CMS announcement period. In the intermediate term, RSVs of 5 categories (miscellaneous, epilepsy, movement disorder, spine, and tumor) were significantly lower in the post-CMS announcement period. In the long term, RSVs of nearly all categories (endovascular, epilepsy, miscellaneous, movement disorder, spine, and tumor) were significantly lower in the post-CMS announcement period. Only the movement disorder procedure category had significantly higher RSV in states that reopened early. CONCLUSIONS: With the recommendation for cessation of elective surgeries, patient interests in overall elective neurosurgical procedures have dropped significantly. With gradual reopening, there has been a resurgence in some procedure types. Google Trends has proven to be a useful tracker of patient interest and may be used by neurosurgical departments to facilitate outreach strategies.

Predictive modeling of long-term opioid and benzodiazepine use after intradural tumor resection.

BACKGROUND CONTEXT: Despite increased awareness of the ongoing opioid epidemic, opioid and benzodiazepine use remain high after spine surgery. In particular, long-term co-prescription of opioids and benzodiazepines have been linked to high risk of overdose-associated death. Tumor patients represent a unique subset of spine surgery patients and few studies have attempted to develop predictive models to anticipate long-term opioid and benzodiazepine use after spinal tumor resection. METHODS: The IBM Watson Health MarketScan Database and Medicare Supplement were assessed to identify admissions for intradural tumor resection between 2007 and 2015. Adult patients were required to have at least 6 months of continuous preadmission baseline data and 12 months of continuous postdischarge follow-up. Primary outcomes were long-term opioid and benzodiazepine use, defined as at least 6 prescriptions within 12 months. Secondary outcomes were durations of opioid and benzodiazepine prescribing. Logistic regression models, with and without regularization, were trained on an 80% training sample and validated on the withheld 20%. RESULTS: A total of 1,942 patients were identified. The majority of tumors were extramedullary (74.8%) and benign (62.5%). A minority of patients received arthrodesis (9.2%) and most patients were discharged to home (79.1%). Factors associated with postdischarge opioid use duration include tumor malignancy (vs benign, B=19.8 prescribed-days/year, 95% confidence interval [CI] 1.1-38.5) and intramedullary compartment (vs extramedullary, B=18.1 prescribed-days/year, 95% CI 3.3-32.9). Pre- and perioperative use of prescribed nonsteroidal anti-inflammatory drugs and gabapentin/pregabalin were associated with shorter and longer duration opioid use, respectively. History of opioid and history of benzodiazepine use were both associated with increased postdischarge opioid and benzodiazepine use. Intramedullary location was associated with longer duration postdischarge benzodiazepine use (B=10.3 prescribed-days/year, 95% CI 1.5-19.1). Among assessed models, elastic net regularization demonstrated best predictive performance in the withheld validation cohort when assessing both long-term opioid use (area under curve [AUC]=0.748) and long-term benzodiazepine use (AUC=0.704). Applying our model to the validation set, patients scored as low-risk demonstrated a 4.8% and 2.4% risk of long-term opioid and benzodiazepine use, respectively, compared to 35.2% and 11.1% of high-risk patients. CONCLUSIONS: We developed and validated a parsimonious, predictive model to anticipate long-term opioid and benzodiazepine use early after intradural tumor resection, providing physicians opportunities to consider alternative pain management strategies.

Dual antiplatelet therapy after carotid artery stenting: trends and outcomes in a large national database.

BACKGROUND: While dual antiplatelet therapy (dAPT) is standard of care following carotid artery stenting (CAS), the optimal dAPT regimen and duration has not been established. METHODS: We canvassed a large national database (IBM MarketScan) to identify patients receiving carotid endarterectomy (CEA) or CAS for treatment of ischemic stroke or carotid artery stenosis from 2007 to 2016. We performed univariable and multivariable regression methods to evaluate the impact of covariates on post-CAS stroke-free survival, including post-discharge antiplatelet therapy. RESULTS: A total of 79 084 patients diagnosed with ischemic stroke or carotid stenosis received CEA (71 178; 90.0%) or CAS (7906; 10.0%). After adjusting for covariates, <180 days prescribed post-CAS P2Y12-inhibition was associated with increased risk for stroke (<90 prescribed days HR=1.421, 95% CI 1.038 to 1.946; 90-179 prescribed days HR=1.484, 95% CI 1.045 to 2.106). The incidence of hemorrhagic complications was higher during the period of prescribed P2Y12-inhibition (1.16% per person-month vs 0.49% per person-month after discontinuation, P<0.001). The rate of extracranial hemorrhage was nearly six-fold higher while on dAPT (6.50% per patient-month vs 1.16% per patient-month, P<0.001), and there was a trend towards higher rate of intracranial hemorrhage that did not reach statistical significance (5.09% per patient-month vs 3.69% per patient-month, P=0.0556). Later hemorrhagic events beyond 30 days post-CAS were significantly more likely to be extracranial (P=0.028). CONCLUSIONS: Increased duration of post-CAS dAPT is associated with lower rates of readmissions for stroke, and with increased risk of hemorrhagic complications, particularly extracranial hemorrhage. The potential benefit of prolonging dAPT with regard to ischemic complications must be balanced with the corresponding increased risk of predominantly extracranial hemorrhagic complications.