Faculty Bibliography

BACKGROUND/UNASSIGNED:Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. METHODS/UNASSIGNED:We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. RESULTS/UNASSIGNED:Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. CONCLUSIONS/UNASSIGNED:DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

After discharge from the Neurological Intensive Care Unit (NICU), patients often have new functional limitations and comorbidities requiring ongoing supportive care. In this review, we discuss the current state across the care continuum and identify opportunities for improvement.

GABAergic inhibitory neurons are the principal source of inhibition in the brain. Traditionally, their role in maintaining the balance of excitation-inhibition has been emphasized. Beyond homeostatic functions, recent circuit mapping and functional manipulation studies have revealed a wide range of specific roles that GABAergic circuits play in dynamically tilting excitation-inhibition coupling across spatio-temporal scales. These span from gating of compartment- and input-specific signaling, gain modulation, shaping input-output functions and synaptic plasticity, to generating signal-to-noise contrast, defining temporal windows for integration and rate codes, as well as organizing neural assemblies, and coordinating inter-regional synchrony. GABAergic circuits are thus instrumental in controlling single-neuron computations and behaviorally-linked network activity. The activity dependent modulation of sensory and mnemonic information processing by GABAergic circuits is pivotal for the formation and maintenance of episodic memories in the hippocampus. Here, we present an overview of the local and long-range GABAergic circuits that modulate the dynamics of excitation-inhibition and disinhibition in the main output area of the hippocampus CA1, which is crucial for episodic memory. Specifically, we link recent findings pertaining to GABAergic neuron molecular markers, electrophysiological properties, and synaptic wiring with their function at the circuit level. Lastly, given that area CA1 is particularly impaired during early stages of Alzheimer's disease, we emphasize how these GABAergic circuits may contribute to and be involved in the pathophysiology.

BACKGROUND/UNASSIGNED:Although current programs exist to encourage undergraduate interest in neuroscience and neurology, few students go on to pursue a career in neurology. Thus, there is a need for more neurologists in the US. To assess undergraduate pipeline programs and their goals of garnering interest and knowledge of neurology, we systematically reviewed available literature on existing undergraduate neurology pipeline programs. METHODS/UNASSIGNED:A medical librarian conducted an electronic database search of PubMed, EMBASE, PsycINFO, Education Source, and ERIC based on a search strategy developed with a team of undergraduates and a neurologist. Of the 2,852 articles screened, 33 met the systematic review criteria and were evaluated based on the type and goal of the pipeline program, its delivery, and efficacy. RESULTS/UNASSIGNED:The 33 programs were classified into subtypes of pipeline programs, with focuses ranging from student-led projects to early clinical research opportunities. All programs were found to be successful in attracting student interest in neurology, providing exposure to relevant opportunities, and classroom enrichment. DISCUSSION/UNASSIGNED:The existing literature shows that neurology pipeline programs successfully inspire interest in a career in neurology among undergraduate students. These programs are valuable supplements to undergraduate neuroscience curricula and instrumental in introducing students to various fields.

BACKGROUND/UNASSIGNED:Extreme Lateral Lumbar Interbody Fusions (XLIF), Oblique Lateral Interbody Fusion (OLIF,) and Lateral Lumbar Interbody Fusion (LLIF) were largely developed to provide indirect lumbar decompressions for spinal stenosis, deformity, and/or instability. METHODS/UNASSIGNED:Here, we have reviewed and updated the incidence of intraoperative errors attributed to XLIF, OLIF, and LLIF. Specifically, we focused on how often these procedures caused new neurological deficits, major vessel, visceral, and other injuries, including those warranting secondary surgery. RESULTS/UNASSIGNED:Performing XLIF, OLIF, and LLIF can lead to significant intraoperative surgical errors that include varying rates of; new neurological injuries (i.e. iliopsoas motor deficits (4.3-19.7-33.6-40%), proximal hip/upper thigh sensory loss/dysesthesias (5.1% to 21.7% to 40%)), life-threatneing vascular injuries (i.e., XLIF (0% - 0.4%-1.8%), OLIF (3.2%), and LLIF (2%) involving the aorta, iliac artery, inferior vena cava, iliac vein, and segmental arteries), and bowel/viscarl injuries (0.03%-0.4%) leading to reoperations (i.e., XLIF (1.8%) vs. LLIF (3.8%) vs. XLIF/LLIF/OLIF 2.2%)). CONCLUSION/UNASSIGNED:Varying reports documented that XLIF, OLIF and LLIF caused up to a 40% incidence of new sensory/motor deficits, up to a 3.2% incidence of major vascular insults, a 0.4% frequency of visceral/bowel perforations, and a 3.8% need for reoperations. These high frequencies of intraoperative surgical errors attributed to XLIF, OLIF, and LLIF should prompt reconsideration of whether these procedures are "safe."

INTRODUCTION/UNASSIGNED:Brain metastases are the most common intracranial tumor diagnosed in adults. In patients treated with stereotactic radiosurgery, the incidence of post-treatment radionecrosis appears to be rising, which has been attributed to improved patient survival as well as novel systemic treatments. The impacts of concomitant immunotherapy and the interval between diagnosis and treatment on patient outcomes are unclear. METHODS/UNASSIGNED:This single institution, retrospective study consisted of patients who received single or multi-fraction stereotactic radiosurgery for intact brain metastases. Exclusion criteria included neurosurgical resection prior to treatment and treatment of non-malignant histologies or primary central nervous system malignancies. A univariate screen was implemented to determine which factors were associated with radionecrosis. The chi-square test or Fisher's exact test was used to compare the two groups for categorical variables, and the two-sample t-test or Mann-Whitney test was used for continuous data. Those factors that appeared to be associated with radionecrosis on univariate analyses were included in a multivariable model. Univariable and multivariable Cox proportional hazards models were used to assess potential predictors of time to local failure and time to regional failure. RESULTS/UNASSIGNED:A total of 107 evaluable patients with a total of 256 individual brain metastases were identified. The majority of metastases were non-small cell lung cancer (58.98%), followed by breast cancer (16.02%). Multivariable analyses demonstrated increased risk of radionecrosis with increasing MRI maximum axial dimension (OR 1.10, p=0.0123) and a history of previous whole brain radiation therapy (OR 3.48, p=0.0243). Receipt of stereotactic radiosurgery with concurrent immunotherapy was associated with a decreased risk of local failure (HR 0.31, p=0.0159). Time interval between diagnostic MRI and first treatment, time interval between CT simulation and first treatment, and concurrent immunotherapy had no impact on incidence of radionecrosis or regional failure. DISCUSSION/UNASSIGNED:An optimal time interval between diagnosis and treatment for intact brain metastases that minimizes radionecrosis and maximizes local and regional control could not be identified. Concurrent immunotherapy does not appear to increase the risk of radionecrosis and may improve local control. These data further support the safety and synergistic efficacy of stereotactic radiosurgery with concurrent immunotherapy.

Classic psychedelics are currently re-emerging as therapeutic agents with unique clinical benefits; however, it is also important to recognize the adverse effects of this drug class. While the risk of seizures with this drug class is known, the literature is lacking in detail. We present a case of psychedelic mushroom-induced seizures in a person with refractory right temporal lobe epilepsy implanted with a responsive neurostimulation (RNS) system. A large increase in typical seizure frequency coincided with the ingestion of a large dose of the mushrooms. This is the first reported case of electrographically confirmed seizures associated with classic psychedelic drug use. With the surge of research and movements toward the clinical application of classic psychedelic compounds, the risk for drug-induced seizures should be considered, including factors such as a history of epilepsy and drug doses and regimens.

Traumatic brain injury (TBI), Alzheimer's disease (AD), and epilepsy share proposed mechanisms of injury, including neuronal excitotoxicity, cascade signaling, and activation of protein biomarkers such as tau. Although tau is typically present intracellularly, in tauopathies, phosphorylated (p-) and hyper-phosphorylated (hp-) tau are released extracellularly, the latter leading to decreased neuronal stability and neurofibrillary tangles (NFTs). Tau cleavage at particular sites increases susceptibility to hyper-phosphorylation, NFT formation, and eventual cell death. The relationship between tau and inflammation, however, is unknown. In this review, we present evidence for an imbalanced endoplasmic reticulum (ER) stress response and inflammatory signaling pathways resulting in atypical p-tau, hp-tau and NFT formation. Further, we propose tau as a biomarker for neuronal injury severity in TBI, AD, and epilepsy. We present a hypothesis of tau phosphorylation as an initial acute neuroprotective response to seizures/TBI. However, if the underlying seizure pathology or TBI recurrence is not effectively treated, and the pathway becomes chronically activated, we propose a "tipping point" hypothesis that identifies a transition of tau phosphorylation from neuroprotective to injurious. We outline the role of amyloid beta (Aβ) as a "last ditch effort" to revert the cell to programmed death signaling, that, when fails, transitions the mechanism from injurious to neurodegenerative. Lastly, we discuss targets along these pathways for therapeutic intervention in AD, TBI, and epilepsy.

The relationship between conscious experience and brain activity has intrigued scientists and philosophers for centuries. In the last decades, several theories have suggested different accounts for these relationships. These theories have developed in parallel, with little to no cross-talk among them. To advance research on consciousness, we established an adversarial collaboration between proponents of two of the major theories in the field, Global Neuronal Workspace and Integrated Information Theory. Together, we devised and preregistered two experiments that test contrasting predictions of these theories concerning the location and timing of correlates of visual consciousness, which have been endorsed by the theories' proponents. Predicted outcomes should either support, refute, or challenge these theories. Six theory-impartial laboratories will follow the study protocol specified here, using three complementary methods: Functional Magnetic Resonance Imaging (fMRI), Magneto-Electroencephalography (M-EEG), and intracranial electroencephalography (iEEG). The study protocol will include built-in replications, both between labs and within datasets. Through this ambitious undertaking, we hope to provide decisive evidence in favor or against the two theories and clarify the footprints of conscious visual perception in the human brain, while also providing an innovative model of large-scale, collaborative, and open science practice.