The laterodorsal tegmentum and seizure regulation: Revisiting the evidence.

Electrical deep brain stimulation (DBS) is now a routine treatment option for patients suffering from medically refractory epilepsy. DBS of the anterior nucleus of the thalamus (ANT) has proven to be effective but, despite its success, few patients experience complete cessation of seizure activity. However, improving the therapy is challenging because the mechanism underlying its action remains largely unknown. One angle on improving the effectiveness of ANT stimulation is to better understand the various anatomic regions that send projections to and through this area. Here, the authors utilized a connectomic atlas of the mouse brain to better understand the regions projecting to the ANT and were particularly interested by the presence of robust cholinergic projections from the laterodorsal tegmentum (LDT). A subsequent review of the literature resulted in limited studies, which presented convincing evidence supporting this region's role in seizure control present in acute rodent models of epilepsy. It is thus the purpose of this paper to encourage further research into the role of the LDT on seizure mitigation, with mechanistic effects likely stemming from its cholinergic projections to the ANT. While previous studies have laid a firm foundation supporting the role of this region in modulation of seizure activity, modern scientific methodology has yet to be applied to further elucidate the mechanisms and potential benefits associated with LDT stimulation in the epileptic population.

Evidence supporting deep brain stimulation of the medial septum in the treatment of temporal lobe epilepsy.

Electrical brain stimulation has become an essential treatment option for more than one third of epilepsy patients who are resistant to pharmacological therapy and are not candidates for surgical resection. However, currently approved stimulation paradigms achieve only moderate success, on average providing approximately 75% reduction in seizure frequency and extended periods of seizure freedom in nearly 20% of patients. Outcomes from electrical stimulation may be improved through the identification of novel anatomical targets, particularly those with significant anatomical and functional connectivity to the epileptogenic zone. Multiple studies have investigated the medial septal nucleus (i.e., medial septum) as such a target for the treatment of mesial temporal lobe epilepsy. The medial septum is a small midline nucleus that provides a critical functional role in modulating the hippocampal theta rhythm, a 4-7-Hz electrophysiological oscillation mechanistically associated with memory and higher order cognition in both rodents and humans. Elevated theta oscillations are thought to represent a seizure-resistant network activity state, suggesting that electrical neuromodulation of the medial septum and restoration of theta-rhythmic physiology may not only reduce seizure frequency, but also restore cognitive comorbidities associated with mesial temporal lobe epilepsy. Here, we review the anatomical and physiological function of the septohippocampal network, evidence for seizure-resistant effects of the theta rhythm, and the results of stimulation experiments across both rodent and human studies, to argue that deep brain stimulation of the medial septum holds potential to provide an effective neuromodulation treatment for mesial temporal lobe epilepsy. We conclude by discussing the considerations necessary for further evaluating this treatment paradigm with a clinical trial.

Clinical and radiographic characteristics of diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma: a single institution review.

PURPOSE: Genetic analyses of gliomas have identified key molecular features that impact treatment paradigms beyond conventional histomorphology. Despite at-times lower grade histopathologic appearances, IDH-wildtype infiltrating gliomas expressing certain molecular markers behave like higher-grade tumors. For IDH-wildtype infiltrating gliomas lacking traditional features of glioblastoma, these markers form the basis for the novel diagnosis of diffuse astrocytic glioma, IDH-wildtype (wt), with molecular features of glioblastoma (GBM), WHO grade-IV (DAG-G). However, given the novelty of this approach to diagnosis, literature detailing the exact clinical, radiographic, and histopathologic findings associated with these tumors remain in development. METHODS: Data for 25 patients matching the DAG-G diagnosis were obtained from our institution's retrospective database. Information regarding patient demographics, treatment regimens, radiographic imaging, and genetic pathology were analyzed to determine association with clinical outcomes. RESULTS: The initial radiographic findings, histopathology, and symptomatology of patients with DAG-G were similar to lower-grade astrocytomas (WHO grade 2/3). Overall survival (OS) and progression free survival (PFS) associated with our cohort, however, were similar to that of IDH-wt GBM, indicating a more severe clinical course than expected from other associated features (15.1 and 5.39 months respectively). CONCLUSION: Despite multiple features similar to lower-grade gliomas, patients with DAG-G experience clinical courses similar to GBM. Such findings reinforce the need for biopsy and subsequent analysis of molecular features associated with any astrocytoma regardless of presenting characteristics.

Impact of Protein Palmitoylation on the Virulence Potential of Cryptococcus neoformans.

The localization and specialized function of Ras-like proteins are largely determined by posttranslational processing events. In a highly regulated process, palmitoyl groups may be added to C-terminal cysteine residues, targeting these proteins to specific membranes. In the human fungal pathogen Cryptococcus neoformans, Ras1 protein palmitoylation is essential for growth at high temperature but is dispensable for sexual differentiation. Ras1 palmitoylation is also required for localization of this protein on the plasma membrane. Together, these results support a model in which specific Ras functions are mediated from different subcellular locations. We therefore hypothesize that proteins that activate Ras1 or mediate Ras1 localization to the plasma membrane will be important for C. neoformans pathogenesis. To further characterize the Ras1 signaling cascade mediating high-temperature growth, we have identified a family of protein S-acyltransferases (PATs), enzymes that mediate palmitoylation, in the C. neoformans genome database. Deletion strains for each candidate gene were generated by homogenous recombination, and each mutant strain was assessed for Ras1-mediated phenotypes, including high-temperature growth, morphogenesis, and sexual development. We found that full Ras1 palmitoylation and function required one particular PAT, Pfa4, and deletion of the PFA4 gene in C. neoformans resulted in altered Ras1 localization to membranes, impaired growth at 37°C, and reduced virulence.

Future Directions of MR-guided Focused Ultrasound.

MR-guided focused ultrasound (MRgFUS) allows for the incisionless treatment of intracranial lesions in an outpatient setting. While this is currently approved for the surgical treatment of essential tremor and Parkinson's disease, advancements in imaging and ultrasound technology are allowing for the expansion of treatment indications to other intracranial diseases. In addition, these advancements are also making MRgFUS treatments easier, safer, and more efficacious.

Biologically Effective Dose and Prediction of Obliteration of Arteriovenous Malformations in Pediatric Patients Treated by Gamma Knife Radiosurgery.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) represents an effective treatment for pediatric arteriovenous malformations (AVMs). Biological effective dose (BED) has shown promising results in 2 previous studies as a predictive variable for outcomes in adults, but its role has never been studied in pediatric outcomes. METHODS: Retrospective data for patients 18 years or younger treated with a single-session SRS for AVMs were collected from 1989 to 2019. BED calculations were performed using an α/ß ratio of 2.47. Kaplan-Meier analysis was used to evaluate obliteration, new hemorrhage, and radiation-induced changes (RIC). Cox-regression analysis was used for obliteration prediction using 2 models (margin dose vs BED). RESULTS: One hundred ninety-seven patients (median age = 13.1 years, IQR = 5.2) were included; 72.6% (143/197) of them presented initially with spontaneous hemorrhage. A median margin dose of 22 Gy (IQR = 4.0) with a median BED of 183.2 Gy (IQR = 70.54) was used to treat AVM with a median volume of 2.8 cm 3 (IQR = 2.9). After SRS, obliteration was confirmed in 115/197 patients (58.4%) using magnetic resonance imaging and angiography at a median follow-up of 2.85 years (IQR = 2.26). The cumulative obliteration probability was 43.6% (95% CI = 36.1-50.3), 60.5% (95% CI+ = 2.2-67.4), and 66.0% (95% CI = 56.0-73.7) at 3, 5, and 10 years, respectively. In Cox multivariate analysis, a BED >180 Gy (hazard ratio [HR] = 2.11, 95% CI = 1.30-3.40, P = .002) in model 1 and a margin dose >20 Gy (HR = 1.90, 95% CI = 1.15-3.13, P = .019) in model 2 were associated with obliteration. An AVM nidus volume >4 cm 3 was associated with lower obliteration rates in both models. The probability of symptomatic RIC at 10 years was 8.6% (95% CI = 3.5-13.4). Neither BED nor margin dose was associated with RIC occurrence, with the only predictive factor being deep AVM location (HR = 3, 95% CI = 1-9.1, P = .048). CONCLUSION: This study confirms BED as a predictor for pediatric AVM obliteration. Optimization of BED in pediatric AVM SRS planning may improve cumulative obliteration rates.

An ordinal clinical score predicts seizure freedom after minimally invasive epilepsy surgery.

OBJECTIVE: To predict one-year seizure freedom, using a combination of relevant clinical variables, following stereotactic laser amygdalohippocampotomy for mesial temporal lobe epilepsy in a series of 101 patients. METHODS: Eight predictors of seizure freedom were selected based on their association with medial temporal lobe epilepsy: (1) MRI evidence of mesial temporal sclerosis (MTS); (2) unitemporal interictal epileptiform discharges; (3) absence of generalized tonic-clonic seizures; (4) history of febrile seizures; (5) onset of epilepsy ≤16 years; (6) absence of an auditory, visual, or vertiginous aura; and (7) unitemporal ictal onset; (8) unitemporal PET hypometabolism. We compared four multivariate models: "MTS," using just evidence of MTS; "FULL," using all eight binary predictors; "AIC" using backwards selection of variables; and "SCORE," using a 0-to-8-point ordinal score awarding one point for each binary predictor. RESULTS: In univariate analysis, significant predictors for seizure freedom were evidence of mesial temporal sclerosis (p = 0.011, Fisher exact) and unitemporal interictal discharges (p = 0.005). For multivariate prediction (using leave one-out cross-validation), the ordinal SCORE model had a significantly higher area under the curve (AUC 0.70) than the other three models: MTS (AUC 0.54, p = 0.002, Delong's test), FULL (AUC 0.62, p = 0.003), or AIC (AUC 0.53, p < 0.001). INTERPRETATION: An ordinal score incorporating eight independent binary clinical variables predicted seizure freedom better on novel data than a model using MTS alone, a full multivariate model, or a backwards selected model. The ordinal score model represents a simple clinical heuristic to identify which patients should be offered minimally invasive laser surgery.

Identifying the Sources of Racial Disparity in the Treatment of Parkinson's Disease With Deep Brain Stimulation.

BACKGROUND: Deep brain stimulation (DBS) is a highly efficacious treatment for appropriately selected patients with advanced, medically refractory Parkinson's disease (PD). It is severely underutilized in Black patients-constituting a major treatment gap. The source of this disparity is unknown, but its identification and correction are necessary to provide equitable care. OBJECTIVE: To identify sources of racial disparity in DBS for PD. METHODS: We predicted the demographics of potential DBS candidates by synthesizing published data on PD and race. We retrospectively examined the clinical course of a cohort including all patients with PD evaluated for DBS at our center from 2016 to 2020, testing whether the rate of DBS use and time from evaluation to surgery differed by race. We also tested whether the geographic distribution of patient catchment was biased relative to racial demographics. RESULTS: Far fewer Black patients were evaluated for DBS than would be expected, given regional demographics. There was no significant difference in the rate at which Black patients evaluated in our clinic were treated with DBS, compared with White patients. Fewer patients were recruited from portions of the surrounding area with larger Black populations. CONCLUSION: The known underuse of DBS in Black patients with PD was replicated in this sample from a center in a racially diverse metropolitan area, but was not attributable to the presurgical workup. Future work should examine the transition from medical management to surgical evaluation where drivers of disparity are potentially situated. Surgical practices should increase outreach to physicians managing PD in underserved areas.

Comparing Cortical Bone Trajectory and Traditional Pedicle Screws in Transforaminal Lumbar Interbody Fusion: A Retrospective Cohort Study of One-Year Outcomes.

INTRODUCTION: This is a retrospective study of consecutive patients undergoing transforaminal lumbar interbody fusion (TLIF) at a single institution. The objective of this study was to compare the long-term results associated with cortical bone trajectory (CBT) and traditional pedicle screw (TPS) via posterolateral approach in TLIF. METHODS: Consecutive patients treated from November 2014 to March 2019 were included in the CBT TLIF group, while consecutive patients treated from October 2010 to August 2017 were included in the TPS TLIF group. Inclusion criteria comprised single-level or two-level TLIF for degenerative spondylolisthesis with stenosis and at least one year of clinical and radiographic follow-up. Variables of interest included pertinent preoperative, perioperative, and postoperative data. Non-parametric evaluation was performed using the Wilcoxon test. Fisher's exact test was used to assess group differences for nominal data. RESULTS: Overall, 140 patients met the inclusion criteria; 69 patients had CBT instrumentation (mean follow-up 526 days) and 71 patients underwent instrumentation placement via TPS (mean follow-up 825 days). Examination of perioperative and postoperative outcomes demonstrate comparable results between the groups with perioperative complications, length of stay, discharge destination, surgical revision rate, and fusion rates all being similar between groups (p = 0.1; p = 0.53; p = 0.091; p = 0.61; p = 0.665, respectively). CONCLUSIONS: CBT in the setting of TLIF offer equivalent outcomes to TPS with TLIF at both short- and long-term intervals of care.

Loss of efferent projections of the hippocampal formation in the mouse intrahippocampal kainic acid model.

Unilateral intrahippocampal injection of kainic acid is used as a model of medial temporal lobe epilepsy and provides a platform to study the mechanisms of epilepsy. Here, we used an AAV-9 EYFP-tagged viral vector as an anterograde tracer, injected into the dorsal and ventral hippocampus after kainic acid injection, to map out the efferent hippocampal projections after the development of spontaneous seizures in this model. The purpose of the study was to identify the extent of changes in hippocampal efferent system in several brain regions that receive significant inputs from the hippocampus. Loss of efferent hippocampal fibers was greatest in the retrosplenial cortex where neuronal loss was also observed. Loss of fibers was also observed in the fornix without any specific effect in the lateral mammillary nuclei. Although expected, these observations provide further evidence of the broader network effects as a result of hippocampal cell loss.

Artificial neural networks predict the need for permanent cerebrospinal fluid diversion following posterior fossa tumor resection.

Background: Resection of posterior fossa tumors (PFTs) can result in hydrocephalus that requires permanent cerebrospinal fluid (CSF) diversion. Our goal was to prospectively validate a machine-learning model to predict postoperative hydrocephalus after PFT surgery requiring permanent CSF diversion. Methods: We collected preoperative and postoperative variables on 518 patients that underwent PFT surgery at our center in a retrospective fashion to train several statistical classifiers to predict the need for permanent CSF diversion as a binary class. A total of 62 classifiers relevant to our data structure were surveyed, including regression models, decision trees, Bayesian models, and multilayer perceptron artificial neural networks (ANN). Models were trained using the (N = 518) retrospective data using 10-fold cross-validation to obtain accuracy metrics. Given the low incidence of our positive outcome (12%), we used the positive predictive value along with the area under the receiver operating characteristic curve (AUC) to compare models. The best performing model was then prospectively validated on a set of 90 patients. Results: Twelve percent of patients required permanent CSF diversion after PFT surgery. Of the trained models, 8 classifiers had an AUC greater than 0.5 on prospective testing. ANNs demonstrated the highest AUC of 0.902 with a positive predictive value of 83.3%. Despite comparable AUC, the remaining classifiers had a true positive rate below 35% (compared to ANN, P < .0001). The negative predictive value of the ANN model was 98.8%. Conclusions: ANN-based models can reliably predict the need for ventriculoperitoneal shunt after PFT surgery.

Trends in Academic Spine Neurosurgeon Productivity as Measured by the Relative Citation Ratio.

BACKGROUND: Publication metrics such as the author-level h-index are often used to evaluate and compare research productivity in academia. The h-index, however, is not a field-normalized statistic and has been criticized as inappropriate for comparison of authors from different fields. For example, fields such as internal medicine have a larger audience and thus afford publications a higher likelihood of increased citations compared with a perhaps equally impactful paper in a smaller field such as neurosurgery. The National Institutes of Health (NIH) has developed a new field-normalized article-level metric called the relative citation ratio (RCR) that can be used to more accurately compare author productivity between fields. Spine represents a distinct subset of neurosurgery with a designated fellowship and distinct differences in the RCR metrics. The authors look to analyze the unique results found in the academic spine neurosurgeon RCR values compared with all academic neurosurgeons. PURPOSE: The assessment of academic physicians should use field-independent publication metrics to measure the improvement of grant outcomes, promotion, and continued evaluation of research productivity. Here, we provide an analysis of RCR indices for 358 academic spine neurosurgeons in the United States, including the mean RCR of each author's total publications and the weighted RCR, which is the sum of all publication-level RCR values of an author. We further assess the impact of gender, career duration, academic rank, and Ph.D. acquisition on the RCR scores of U.S. academic spine neurosurgeons. METHODS: The mean RCR is the total citations per year of a publication divided by average citations per year received by NIH-funded papers in the same field. A value of 1 is the normal NIH-funded standard. iCite database searches were performed for all physician faculty members affiliated with accredited neurological surgery programs who have subspecialized in spine as of November 1, 2019. Gender, career duration, academic rank, additional degrees, total publications, mean RCR, and weighted RCR were collected for each individual. RCR and weighted RCR were compared between variables to assess patterns of analysis. RESULTS: A total of 358 fellowship-trained academic spine neurosurgeons from 125 institutions were included in the analysis. Exceptional research productivity was noted, with a median RCR of 1.38 (interquartile range = 0.94-1.95) and a weighted median RCR of 25.28 (interquartile range = 6.87-79.93). Overall, gender and academic rank were associated with increased mean RCR and weighted RCR values. Career duration and Ph.D. acquisition were not. All subgroups analyzed had an RCR value above 1.0, with professor-level faculty or department chair having the highest mean and weighted RCR values overall. CONCLUSIONS: Current academic spine neurosurgeons have high median RCR values relative to the NIH standard RCR value of 1.0. Relative to the field of neurological surgery overall, RCR values for the spine subspecialty are comparable. These data offer a more accurate means for self-evaluation of academic neurosurgeons as well as evaluation of faculty by institutional and departmental leaders.

A simple and cost-effective model for ventricular catheter placement training: technical note.

OBJECTIVE: External ventricular drain (EVD) placement is one of first cranial procedures neurosurgery residents are expected to perform independently. While proper training improves patient outcomes, there are few options for practicing EVD placement prior to placing the EVD in patients in a clinical setting. Proposed solutions to this include using cadaveric models and virtual simulations, but barriers exist with these as well in regard to authenticity. EVD simulators using virtual reality technologies are a promising new technique for training, but the cost of these devices poses a barrier to general/widespread accessibility among smaller programs or underserved hospitals. The authors desribe a novel, yet simple, and cost-effective technique (less than $5 per mold) for developing a brain model constructed of homemade ballistics gelatin that can be used for teaching and practicing the placement of EVD. METHODS: A brain model is made with ballistics gelatin using an anatomically correct skull model as a mold. A 3D-printed ventricular system model is used to create a mold of an anatomically correct ventricular system in the brain model. A group of medical students (n = 10) were given a basic presentation about EVD placement, including standard landmarks and placement techniques, and were also shown a demonstration of EVD placement on the brain model. They were then allowed to perform an EVD placement using the brain model. The students were surveyed on their experience with using the brain model, including usability and practicality of the model. Accuracy of EVD placement by each student was also assessed, with adequate position of catheter tip being in the ipsilateral frontal horn. RESULTS: The final product is fairly inexpensive and easy to make. It is soft enough to pass a catheter through, but it is also firm enough to maintain its shape, including a cavity representing the lateral ventricles. The dense gelatin holds the catheter in its final resting position, while the two halves are separated and inspected. All participants in the test group of medical students reported that the brain model was easy to use, helped them understand the steps and technique of EVD placement, and provided good feedback on the ideal position of ventricular catheters. All of the participants in the group had adequate positioning of their ventricular catheters after one attempt. CONCLUSIONS: The presented brain model is easy to replicate, inexpensive, anatomically accurate, and provides a medium for neurosurgeons to teach and practice ventricular catheter placement in a risk-free environment.

A case of dual three-column thoracic spinal fractures following traumatic injury.

BACKGROUND: Thoracic spine fracture-dislocations due to motor vehicle accidents (MVAs) rarely involve double- level, noncontiguous lesions. CASE DESCRIPTION: A 19-year-old male following an MVA was paraplegic; he exhibited full motor/sensory loss below the T4 level (i.e., ASIA scale Grade A). The chest X-ray, magnetic resonance, and computed tomography studies confirmed T3-T5 and T11-12 fractures, warranting T3-L3 thoracolumbar decompression and fusion. Despite surgical intervention, the patient's neurological status remained unchanged. CONCLUSION: This case illustrates the rare presentation of noncontiguous, posttraumatic thoracic spinal lesions requiring simultaneous decompression/fixation.

Targeting the endocannabinoid system: a predictive, preventive, and personalized medicine-directed approach to the management of brain pathologies.

Cannabis-inspired medical products are garnering increasing attention from the scientific community, general public, and health policy makers. A plethora of scientific literature demonstrates intricate engagement of the endocannabinoid system with human immunology, psychology, developmental processes, neuronal plasticity, signal transduction, and metabolic regulation. Despite the therapeutic potential, the adverse psychoactive effects and historical stigma, cannabinoids have limited widespread clinical application. Therefore, it is plausible to weigh carefully the beneficial effects of cannabinoids against the potential adverse impacts for every individual. This is where the concept of "personalized medicine" as a promising approach for disease prediction and prevention may take into the account. The goal of this review is to provide an outline of the endocannabinoid system, including endocannabinoid metabolizing pathways, and will progress to a more in-depth discussion of the therapeutic interventions by endocannabinoids in various neurological disorders.