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Predicting patient needs for extended care after spinal fusion remains challenging. The Risk Assessment and Prediction Tool (RAPT) was externally developed to predict discharge disposition after nonspine orthopedic surgery but remains scarcely used in neurosurgery. The present study is the first to use coarsened exact matching-which incorporated patient characteristics known to independently affect outcomes-for 1:1 matching across a large population of single-level, posterior lumbar fusions, to isolate the predictive value of preoperative RAPT score on postoperative discharge disposition.Preoperative RAPT scores were prospectively calculated for 1066 patients undergoing consecutive single-level, posterior-only lumbar fusion within a single, university healthcare system. The primary outcome was discharge disposition. Logistic regression was executed across all patients, evaluating the RAPT score as a continuous variable to predict home discharge. Subsequently, patients were retrospectively clustered into predicted risk cohorts-validated within prior orthopedic joint research-based on the RAPT score (Lowest, Intermediate, and Highest Risk). Coarsened exact matching was performed among predicted risk cohorts, and outcomes were compared between exact-matched groups.Among all patients, single-point increases in the RAPT score (i.e., decrease in predicted risk) were associated a 75% increased odds of home discharge (P0.001). Exact-matched analysis demonstrated increased odds of home discharge by 400% when comparing the Lowest versus Highest Risk cohorts (P = 0.004), by 750% when comparing the Intermediate versus Highest Risk cohorts (P0.001), and by 200% when comparing the Lowest versus Intermediate Risk cohorts (P0.001).The RAPT score, captured in preoperative evaluations, can be highly predictive of discharge disposition following single-level, posterior lumbar fusion.

SUMMARYThe human olfactory system has two discrete channels of sensory input, arising from olfactory epithelia housed in the left and right nostrils. Here, we asked whether primary olfactory cortex (piriform cortex, PC) encodes odor information arising from the two nostrils as unified or distinct stimuli. We recorded intracranial EEG signals directly from PC while human subjects participated in an odor identification task where odors were delivered to the left, right, or both nostrils. We analyzed the time-course of odor-identity coding using machine learning approaches, and found that odor inputs from the ipsilateral nostril are encoded ∼480 ms faster than odor inputs from the contralateral nostril. This temporal staggering across the nostrils gave rise to two non-overlapping epochs of odor coding within a single sniff when odors were sampled through both nostrils. These findings reveal that PC maintains distinct representations from each nostril by temporally segregating odor information, highlighting an olfactory coding scheme at the cortical level that can parse odor information across nostrils within a single sniff.HIGHLIGHTSIpsilateral odors are encoded faster than contralateral odors in piriform cortexBi-nostril odors are encoded in two non-overlapping epochs within a single sniffRobustness of odor coding correlates with improved odor identification across subjectsThe timing of odor coding determines when piriform responses inform odor identification

ObjectiveStereotactic laser amygdalohippocampotomy (SLAH) is an appealing option for patients with temporal lobe epilepsy, who often require intracranial monitoring to confirm mesial temporal seizure onset. However, given limited spatial sampling, it is possible that stereotactic electroencephalography (sEEG) may miss seizure onset elsewhere. We hypothesized that sEEG seizure onset patterns (SOPs) may differentiate between primary onset and secondary spread and predict postoperative seizure control. In this study, we characterized the two-year outcomes of patients who underwent single-probe SLAH after sEEG and evaluated whether sEEG SOPs predict postoperative seizure freedom.MethodsThis retrospective five-center study included patients with or without mesial temporal sclerosis (MTS) who underwent sEEG followed by single probe SLAH between August 2014 and January 2022. Patients with causative hippocampal lesions apart from MTS or for whom the SLAH was considered palliative were excluded. A SOP catalogue was developed based on literature review. The dominant pattern for each patient was used for survival analysis. The primary outcome was two-year Engel I classification or recurrent seizures before then, stratified by SOP category.Results58 patients were included with a mean follow-up duration of 39 ± 12 months after SLAH. Overall one-, two, and three-year Engel I seizure freedom probability was 54%, 36%, and 33% respectively. Patients with SOPs including low voltage fast activity or low frequency repetitive spiking had a 46% two-year seizure freedom probability, compared to 0% for patients with alpha or theta frequency repetitive spiking or theta or delta frequency rhythmic slowing (log rank test, p = 0.00015).SignificancePatients who underwent SLAH after sEEG had a low probability of seizure freedom at two years, but SOPs successfully predicted seizure recurrence in a subset of patients. This study provides proof of concept that SOPs distinguish between seizure onset and spread and supports using SOPs to improve selection of SLAH candidates.Key PointsWe described extended seizure outcomes in a five-center retrospective review of 58 patients.Seizure onset patterns (SOP) were categorized as putative positive vs. negative predictors of postoperative seizure freedom.Low voltage fast activity or low frequency repetitive spiking are associated with higher seizure freedom probabilityA 0% Engel I probability was found for patients whose dominant SOP was rhythmic slowing or repetitive spiking in the theta or alpha frequency bands.

Functional restoration following major peripheral nerve injury (PNI) is challenging, given slow axon growth rates and eventual regenerative pathway degradation in the absence of axons. We are developing tissue-engineered nerve grafts (TENGs) to simultaneously “bridge” missing nerve segments and “babysit” regenerative capacity by providing living axons to guide host axons and maintain the distal pathway. TENGs were biofabricated using porcine neurons and “stretch-grown” axon tracts. TENG neurons survived and elicited axon-facilitated axon regeneration to accelerate regrowth across both short (1 cm) and long (5 cm) segmental nerve defects in pigs. TENG axons also closely interacted with host Schwann cells to maintain proregenerative capacity. TENGs drove regeneration across 5-cm defects in both motor and mixed motor-sensory nerves, resulting in dense axon regeneration and electrophysiological recovery at levels similar to autograft repairs. This approach of accelerating axon regeneration while maintaining the pathway for long-distance regeneration may achieve recovery after currently unrepairable PNIs.

Parkinson’s disease is a neurodegenerative disease affecting around 10 million people worldwide. The death of dopaminergic neurons in the substantia nigra and the axonal fibers that constitute the nigrostriatal pathway leads to a loss of dopamine in the striatum that causes the motor symptoms of this disease. Traditional treatments have focused on reducing symptoms, while therapies with human fetal or stem cell-derived neurons have centered on implanting these cells in the striatum to restore its innervation. An alternative approach is pathway reconstruction, which aims to rebuild the entire structure of neurons and axonal fibers of the nigrostriatal pathway in a way that matches its anatomy and physiology. This type of repair could be more capable of reestablishing the signaling mechanisms that ensure proper dopamine release in the striatum and regulation of other motor circuit regions in the brain. In this manuscript, we conduct a review of the literature related to pathway reconstruction as a treatment for Parkinson’s disease, delve into the limitations of these studies, and propose the requisite design criteria to achieve this goal at a human scale. We then present our tissue engineering-based platform to fabricate hydrogel-encased dopaminergic axon tracts in vitro for later implantation into the brain to replace and reconstruct the pathway. These tissue-engineered nigrostriatal pathways (TE-NSPs) can be characterized and optimized for cell number and phenotype, axon growth lengths and rates, and the capacity for synaptic connectivity and dopamine release. We then show original data of advances in creating these constructs matching clinical design criteria using human iPSC-derived dopaminergic neurons and a hyaluronic acid hydrogel. We conclude with a discussion of future steps that are needed to further optimize human-scale TE-NSPs and translate them into clinical products.

Imaging detection of brain perfusion alterations after traumatic brain injury (TBI) may provide prognostic insights. In this study, we used arterial spin labeling (ASL) to quantify cross-sectional and longitudinal changes in cerebral blood flow (CBF) after TBI and correlated changes with clinical outcome. We analyzed magnetic resonance imaging scans from adult participants with TBI requiring hospitalization in the acute (2 weeks post-injury, n = 33) and chronic (6 months post-injury, n = 16) phases, with 13 participants scanned longitudinally at both time points. We also analyzed 18 age- and sex-matched healthy controls. Whole-brain CBF maps were derived using a three-dimensional pseudo-continuous arterial spin label technique. Mean CBF across tissue-based regions (whole brain, gray matter, and white matter) was compared cross-sectionally and longitudinally. In addition, individual-level clusters of abnormal perfusion were identified using voxel-based z-score analysis of relative CBF maps, and number and volume of abnormally hypo- and hyperperfused clusters were assessed cross-sectionally and longitudinally. Finally, all CBF measures were correlated with clinical outcome measures. Mean global and gray matter CBF were significantly elevated in acute and chronic TBI participants compared to controls. Participants with better outcome at 6 months post-injury tended to have higher CBF in the acute phase compared to those with poorer outcome. Acute TBI participants had a significantly greater volume of hypo- and hyperperfused brain tissue compared to controls, with these regions partially normalizing by the chronic phase. Our findings demonstrate global elevation of CBF with focal hypo- and hyperperfusion in the early post-injury period and suggest a reparative role for acute elevation in CBF post-TBI.

Parkinson’s disease (PD) affects 1–2% of people over 65, causing significant morbidity across a progressive disease course. The classic PD motor deficits are caused by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in the loss of their long-distance axonal projections that modulate striatal output. While contemporary treatments temporarily alleviate symptoms of this disconnection, there is no approach able to replace the nigrostriatal pathway. We applied microtissue engineering techniques to create a living, implantable tissue-engineered nigrostriatal pathway (TE-NSP) that mimics the architecture and function of the native pathway. TE-NSPs comprise a discrete population of dopaminergic neurons extending long, bundled axonal tracts within the lumen of hydrogel micro-columns. Neurons were isolated from the ventral mesencephalon of transgenic rats selectively expressing the green fluorescent protein in dopaminergic neurons with subsequent fluorescent-activated cell sorting to enrich a population to 60% purity. The lumen extracellular matrix and growth factors were varied to optimize cytoarchitecture and neurite length, while immunocytochemistry and fast-scan cyclic voltammetry (FSCV) revealed that TE-NSP axons released dopamine and integrated with striatal neurons in vitro. Finally, TE-NSPs were implanted to span the nigrostriatal pathway in a rat PD model with a unilateral 6-hydroxydopamine SNpc lesion. Immunohistochemistry and FSCV established that transplanted TE-NSPs survived, maintained their axonal tract projections, extended dopaminergic neurites into host tissue, and released dopamine in the striatum. This work showed proof of concept that TE-NSPs can reconstruct the nigrostriatal pathway, providing motivation for future studies evaluating potential functional benefits and long-term durability of this strategy. This pathway reconstruction strategy may ultimately replace lost neuroarchitecture and alleviate the cause of motor symptoms for PD patients.

We studied the risk of associated spinal and nonspinal injuries (NSIs) in the setting of observed thoracolumbar transverse process fracture (TPF) and examined the clinical management of TPF.Patients treated at a Level I trauma center over a 5-year period were screened for thoracolumbar TPF. Prevalence of associated spinal fractures and NSIs as well as relationship to level of TPF was explored. Clinical management and follow-up outcomes were reviewed.A total of 252 patients with thoracolumbar TPFs were identified. NSIs were commonly observed (70.6%, n = 178); however, associated spinal fractures were more rarely seen (24.6%, n = 62, P0.0001). No patients had neurological deficits attributable to TPFs, and only 3 patients with isolated TPFs were treated with orthosis. Among patients with outpatient follow-up (70.6%, n = 178), none developed delayed-onset neurological deficits or spinal instability. Thoracic TPFs (odds ratio = 3.56, 95% confidence interval = 1.20-10.56) and L1 TPFs (odds ratio = 2.48, 95% confidence interval = 1.41-4.36) were predictive of associated thoracic NSIs. L5 TPF was associated with pelvic fractures (odds ratio = 6.30, 95% confidence interval = 3.26-12.17). There was no difference in rate of NSIs between isolated TPF (70.0%) and TPF with associated clinically relevant spinal fracture (72.6%, P = 0.70).NSIs are nearly 3 times more common in patients with thoracolumbar TPFs than associated clinically relevant spinal fractures. Spine service consultation for TPF may be unnecessary unless fracture is associated with a clinically relevant spinal injury, which represents a minority of cases. However, detection of TPF should raise suspicion for high likelihood of associated NSIs.

Over the past decade, several landmark reports have demonstrated that the nervous system plays an active role in cancer initiation and progression. These studies demonstrate that ablation of specific nerve types (parasympathetic, sympathetic, or sensory) abrogates tumor growth in a tissue-specific manner. Further, many tumor types are more densely innervated than their normal tissues of origin. These striking results raise fundamental questions regarding tumor innervation, how it is initiated, and how it molecularly contributes to disease. In this review, we aim to address what is currently known about the origin of tumor-infiltrating nerves, how they may be recruited to tumors, and how their presence may give rise to aggressive disease.

Although traditional small animal and cell culture models of neurodegenerative disease have been valuable in foundational discoveries, their inherent imprecision may have biased our understanding of etiology in humans and hindered translation of therapeutics. Recent breakthroughs to generate human stem cell–derived brain organoids — including from patient-specific cell sources — provide powerful platforms to improve disease modeling accuracy. However, brain organoids do not recapitulate crucial anatomical structures such as long bundled axon tracts — a central systems-level feature of human brains — critical to neurodegenerative disease pathogenesis, including Parkinson's disease. To address this challenge, advances in tissue engineering recapitulate brain pathways with three-dimensional anatomical fidelity to discrete systems-level brain structures, such as the first tissue engineered nigrostriatal pathway. Promulgating anatomically inspired human-derived engineered microtissue may improve translational relevance, empower personalized medicine, and ultimately reduce costs compared to conventional model systems, thus proving useful for targeted development and screening of new therapeutic strategies.

OBJECTIVEMultidisciplinary treatment including medical oncology, radiation oncology, and surgical consultation is necessary to provide comprehensive therapy for patients with spinal metastases. The goal of this study was to review the use of radiation therapy and/or surgical intervention and their impact on patient outcomes.METHODSIn this retrospective series, the authors identified at their institution those patients with spinal metastases who had received radiation therapy alone or had undergone surgery with or without radiation therapy within a 6-year period. Data on patient age, chemotherapy, surgical procedure, radiation therapy, Karnofsky Performance Status (KPS), primary tumor pathology, Spinal Instability Neoplastic Score (SINS), and survival after treatment were collected from the patient electronic medical records. N − 1 chi-square testing was used for comparisons of proportions. The Student t-test was used for comparisons of means. A p value < 0.05 was considered statistically significant. A survival analysis was completed using a multivariate Cox proportional hazards model.RESULTSTwo hundred thirty patients with spinal metastases were identified, 109 of whom had undergone surgery with or without radiation therapy. Among the 104 patients for whom the surgical details were reviewed, 34 (33%) had a history of preoperative radiation to the surgical site but ultimately required surgical intervention. In this surgical group, a significantly increased frequency of death within 30 days was noted for the SINS unstable patients (23.5%) as compared to that for the SINS stable patients (2.3%; p < 0.001). The SINS was a significant predictor of time to death among surgical patients (HR 1.11, p = 0.037). Preoperative KPS was not independently associated with decreased survival (p > 0.5) on univariate analysis. One hundred twenty-six patients met the criteria for inclusion in the radiation-only analysis. Ninety-eight of these patients (78%) met the criteria for potential instability (PI) at the time of treatment, according to the SINS system. Five patients (5%) with PI in the radiation therapy group had a documented neurosurgical or orthopedic surgery consultation prior to radiation therapy.CONCLUSIONSAt the authors’ institution, patients with gross mechanical instability per the SINS system had an increased rate of 30-day postoperative mortality, which remained significant when controlling for other factors. Surgical consultation for metastatic spine patients receiving radiation oncology consultation with PI is low. The authors describe an institutional pathway to encourage multidisciplinary treatment from the initial encounter in the emergency department to expedite surgical evaluation and collaboration.

Traumatic brain injury (TBI) remains a prominent public health concern despite several decades of attempts to develop therapies for the associated neurological and cognitive deficits. Effective models of this condition are imperative for better defining its pathophysiology and testing therapeutics. Human brain organoids are stem cell–derived neural tissues that recapitulate many of the steps of normal neurodevelopment, resulting in the reproduction of a substantial degree of brain architecture. Organoids are highly relevant to clinical conditions because of their human nature and three-dimensional tissue structure, yet they are easier to manipulate and interrogate experimentally than animals. Thus, they have the potential to serve as a novel platform for studying TBI. In this article, we discuss available in vitro models of TBI, active areas of inquiry on brain organoids, and how these two concepts could be merged.

OBJECTIVEAlthough it is known that intersurgeon variability in offering elective surgery can have major consequences for patient morbidity and healthcare spending, data addressing variability within neurosurgery are scarce. The authors performed a prospective peer review study of randomly selected neurosurgery cases in order to assess the extent of consensus regarding the decision to offer elective surgery among attending neurosurgeons across one large academic institution.METHODSAll consecutive patients who had undergone standard inpatient surgical interventions of 1 of 4 types (craniotomy for tumor [CFT], nonacute redo CFT, first-time spine surgery with/without instrumentation, and nonacute redo spine surgery with/without instrumentation) during the period 2015–2017 were retrospectively enrolled (n = 9156 patient surgeries, n = 80 randomly selected individual cases, n = 20 index cases of each type randomly selected for review). The selected cases were scored by attending neurosurgeons using a need for surgery (NFS) score based on clinical data (patient demographics, preoperative notes, radiology reports, and operative notes; n = 616 independent case reviews). Attending neurosurgeon reviewers were blinded as to performing provider and surgical outcome. Aggregate NFS scores across various categories were measured. The authors employed a repeated-measures mixed ANOVA model with autoregressive variance structure to compute omnibus statistical tests across the various surgery types. Interrater reliability (IRR) was measured using Cohen’s kappa based on binary NFS scores.RESULTSOverall, the authors found that most of the neurosurgical procedures studied were rated as “indicated” by blinded attending neurosurgeons (mean NFS = 88.3, all p values < 0.001) with greater agreement among neurosurgeon raters than expected by chance (IRR = 81.78%, p = 0.016). Redo surgery had lower NFS scores and IRR scores than first-time surgery, both for craniotomy and spine surgery (ANOVA, all p values < 0.01). Spine surgeries with fusion had lower NFS scores than spine surgeries without fusion procedures (p < 0.01).CONCLUSIONSThere was general agreement among neurosurgeons in terms of indication for surgery; however, revision surgery of all types and spine surgery with fusion procedures had the lowest amount of decision consensus. These results should guide efforts aimed at reducing unnecessary variability in surgical practice with the goal of effective allocation of healthcare resources to advance the value paradigm in neurosurgery.

Human brain organoids emerged in 2013 as a technology that, unlike prior in Vitro neural models, recapitulates brain development with a high degree of spatial and temporal fidelity. As the platform matured with more accurate reproduction of cerebral architecture, brain organoids became increasingly valuable for studying both normal cortical neurogenesis and a variety of congenital human brain disorders. While the majority of research utilizing human brain organoids has been in the realm of basic science, clinical applications are forthcoming. These present and future translational efforts have the potential to make a considerable impact on the field of neurosurgery. For example, glioma organoids are already being used to study tumor biology and drug responses, and adaptation for the investigation of other neurosurgery-relevant diseases is underway. Moreover, organoids are being explored as a structured neural substrate for repairing brain circuitry. Thus, we believe it is important for our field to be aware and have an accurate understanding of this emerging technology. In this review, we describe the key characteristics of human brain organoids, review their relevant translational applications, and discuss the ethical implications of their use through a neurosurgical lens.

Approximately 20 million Americans currently experience residual deficits from traumatic peripheral nerve injury. Despite recent advancements in surgical technique, peripheral nerve repair typically results in poor functional outcomes due to prolonged periods of denervation resulting from long regenerative distances coupled with relatively slow rates of axonal regeneration. Development of novel surgical solutions requires valid preclinical models that adequately replicate the key challenges of clinical peripheral nerve injury. Our team has developed a porcine model using Yucatan minipigs that provides an opportunity to investigate peripheral nerve regeneration using different nerves tailored for a specific mechanism of interest, such as (1) nerve modality: motor, sensory, and mixed-modality; (2) injury length: short versus long gap; and (3) total regenerative distance: proximal versus distal injury. Here, we describe a comprehensive porcine model of two challenging clinically relevant procedures for repair of long segmental lesions (≥ 5 cm) – the deep peroneal nerve repaired using a sural nerve autograft and the common peroneal nerve repaired using a saphenous nerve autograft – each featuring ultra-long total regenerative distances (up to 20 cm and 27 cm, respectively) to reach distal targets. This paper includes a detailed characterization of the relevant anatomy, surgical approach/technique, functional/electrophysiological outcomes, and nerve morphometry for baseline and autograft repaired nerves. These porcine models of major peripheral nerve injury are suitable as preclinical, translatable models for evaluating the efficacy, safety, and tolerability of next-generation artificial nerve grafts prior to clinical deployment.

Previously undiagnosed obstructive sleep apnea (OSA) is a known contributor to negative postoperative outcomes. The STOP-Bang questionnaire is a screening tool for OSA that has been validated in both medical and surgical populations. The authors have previously studied this screening tool in a brain tumor population at 30 days. The present study seeks to investigate the effectiveness of this questionnaire, for predicting 90-day readmissions in a population of brain tumor patients with previously undiagnosed OSA.Included for analysis were all patients undergoing craniotomy for supratentorial neoplasm at a multihospital, single academic medical center. Data were collected from supratentorial craniotomy cases for which the patient was alive at 90 days after surgery (n = 238). Simple logistic regression analyses were used to assess the ability of the STOP-Bang questionnaire and subsequent single variables to accurately predict patient outcomes at 90 days.The sample included 238 brain tumor admissions, of which 50% were female (n = 119). The average STOP-Bang score was 1.95 ± 1.24 (range 0-7). A 1-unit higher increase in STOP-Bang score accurately predicted 90-day readmissions (odds ratio [OR] = 1.65, P = 0.001), 30- to 90-day emergency department visits (OR = 1.85, P 0.001), and 30- to 90-day reoperation (OR = 2.32, P 0.001) with fair accuracy as confirmed by the receiver operating characteristic (C-statistic = 0.65-0.76). However, the STOP-Bang questionnaire did not correlate with home discharge (P = 0.315).The results of this study suggest that undiagnosed OSA, as evaluated by the STOP-Bang questionnaire, is an effective predictor of readmission risk and health system utilization in a brain tumor craniotomy population with previously undiagnosed OSA.

Differentiation of true tumor progression (TP) from pseudoprogression (PsP) is a major unmet need in patients with glioblastoma. [18F]Fluciclovine is a synthetic amino acid PET radiotracer that is FDA-approved in biochemical recurrence in prostate cancer. The study aim was to assess the value of [18F]Fluciclovine PET in differentiation of histologically confirmed (“true”) TP and PsP in post-treatment of glioblastoma. METHODS: 23 patients with glioblastoma with new contrast-enhancing lesions or lesions showing increased enhancement ( > 25% increase) on standard MRI after completion of radiation underwent 60-minutes dynamic [18F]Fluciclovine PET imaging. Patients subsequently underwent resection of enhancing lesion and tumor percentage vs. treatment-related changes were quantified on histopathology. Patients were considered "true” TP if tumor represented ≥ 50% of the resected specimen, mixed TP-PsP if < 50% and > 10%, and PsP if tumor represented ≤ 10%. Summed 30- to 40-minute post-injection PET images were used to measure SUVpeak and SUVmax (g/mL units). RESULTS: 15 patients with “true” TP, 3 with mixed TP-PsP, and 5 with PsP were included. There was a positive correlation between SUVpeak by PET and tumor percentage by histology (Rho= 0.56, p= 0.006). Patients who demonstrated “true” TP had significantly higher SUVpeak compared to patients with histological PsP (4.8±1.6 vs 2.9± 1.0, p= 0.02, AUC= 0.91, n=20). SUVpeak cut-off of 3.3 provided 93% sensitivity, 80% specificity, and 90% accuracy for differentiation of “true” TP from PsP. Patients with “true” TP/mixed TP-PsP also had significantly higher SUVpeak than patients with PsP (4.6±1.5 vs 2.9± 1.0, p= 0.03, AUC= 0.88, n=23). SUVmax and partial volume-corrected SUVpeak and SUVmax exhibited similar performance. CONCLUSION: Our results indicated that [18F]Fluciclovine PET imaging can accurately differentiate “true” TP from PsP. Further studies are required to confirm these promising early results and determine optimal criteria for interpreting [18F]Fluciclovine PET to distinguish PsP from TP.

Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity and unique brain functions in rodents(1,2) and they are dysregulated in multiple human neurological disorders(3–5). Little is known about molecular characteristics of adult human hippocampal imGCs and even their existence is under debate(1,6–8). Here we performed single-nucleus RNA-sequencing (snRNA-seq) aided by a validated machine learning-based analytic approach to identify imGCs and quantify their abundance in the human hippocampus during infant, child, adolescent, adult, and aging stages. We identified common molecular hallmarks of human imGCs across the lifespan and discovered age-dependent transcriptional dynamics unique to human imGCs that suggest changes in cellular functionality, niche interactions, and disease relevance, in contrast to those in mice9. We also found a decreased number of imGCs with altered gene expression in Alzheimer’s disease (AD). Finally, we demonstrated the capacity for neurogenesis in the adult human hippocampus with the presence of rare dentate granule cell fate-specific proliferating neural progenitors and with cultured surgical specimens. Together, our findings suggest the presence of a significant number of imGCs in the adult human hippocampus via low frequency de novo generation and protracted maturation, and our study reveals their molecular properties across the lifespan and in AD.

Soft bioelectronic interfaces for mapping and modulating excitable networks at high resolution and at large scale can enable paradigm-shifting diagnostics, monitoring, and treatment strategies. Yet, current technologies largely rely on materials and fabrication schemes that are expensive, do not scale, and critically limit the maximum attainable resolution and coverage. Solution processing is a cost-effective manufacturing alternative, but biocompatible conductive inks matching the performance of conventional metals are lacking. Here, we introduce MXtrodes, a class of soft, high-resolution, large-scale bioelectronic interfaces enabled by Ti(3)C(2) MXene (a two-dimensional transition metal carbide nanomaterial) and scalable solution processing. We show that the electrochemical properties of MXtrodes exceed those of conventional materials, and do not require conductive gels when used in epidermal electronics. Furthermore, we validate MXtrodes in applications ranging from mapping large scale neuromuscular networks in humans to cortical neural recording and microstimulation in swine and rodent models. Finally, we demonstrate that MXtrodes are compatible with standard clinical neuroimaging modalities.

Background: We present a “Do-It-Yourself” method to build an affordable augmented reality heads-up display system (AR-HUD) capable of displaying intraoperative images. All components are commercially available products, which the surgeons may use in their own practice for educational and research purposes. Methods: Moverio BT 35-E smart glasses were connected to operating room imaging modalities (ie, fluoroscopy and 3D navigation platforms) via a high-definition multimedia interface (HDMI) converter, allowing for continuous high-definition video transmission. The addition of an HDMI transmitter-receiver makes the AR-HUD system wireless. Results: We used our AR-HUD system in 3 patients undergoing instrumented spinal fusion. AR-HUD projected fluoroscopy images onto the surgical field, eliminating shift of surgeon focus and procedure interruption, with only a 40- to 100-ms delay in transmission, which was not clinically impactful. Conclusions: An affordable AR-HUD capable of displaying real-time information into the surgeon9s view can be easily designed, built, and tested in surgical practice. As wearable heads-up display technology continues to evolve rapidly, individual components presented here may be substituted to improve its functionality and usability. Surgeons are in a unique position to conduct clinical testing in the operating room environment to optimize the augmented reality system for surgical use.

Summary Reestablishing cerebral connectivity is a critical part of restoring neuronal network integrity and brain function after trauma, stroke, and neurodegenerative diseases. Creating transplantable axon tracts in the laboratory is an unexplored strategy for overcoming the common barriers limiting axon regeneration in vivo, including growth-inhibiting factors and the limited outgrowth capacity of mature neurons in the brain. We describe the generation, phenotype, and connectivity of constrained three-dimensional human axon tracts derived from brain organoids. These centimeter-long constructs are encased in an agarose shell that permits physical manipulation and are composed of discrete cellular regions spanned by axon tracts, mirroring the separation of cerebral gray and white matter. Features of cerebral cortex also are emulated, as evidenced by the presence of neurons with different cortical layer phenotypes. This engineered neural tissue represents a first step toward potentially reconstructing brain circuits by physically replacing neuronal populations and long-range axon tracts in the brain., Graphical Abstract, Highlights • Transplantable 3D axon tracts are tissue engineered from human brain organoids • Growth of organoid axons in a hydrogel column is enhanced compared with planar culture • Organoids within engineered columns can maintain a laminar cortical architecture • Functional connectivity across the construct is demonstrated using calcium imaging, Biological Sciences; Neuroscience; Tissue Engineering

BACKGROUND As the use of bundled care payment models has become widespread in neurosurgery, there is a distinct need for improved preoperative predictive tools to identify patients who will not benefit from prolonged hospitalization, thus facilitating earlier discharge to rehabilitation or nursing facilities. OBJECTIVE To validate the use of Risk Assessment and Prediction Tool (RAPT) in patients undergoing posterior lumbar fusion for predicting discharge disposition. METHODS Patients undergoing elective posterior lumbar fusion from June 2016 to February 2017 were prospectively enrolled. RAPT scores and discharge outcomes were recorded for patients aged 50 yr or more (n = 432). Logistic regression analysis was used to assess the ability of RAPT score to predict discharge disposition. Multivariate regression was performed in a backwards stepwise logistic fashion to create a binomial model. RESULTS Escalating RAPT score predicts disposition to home (P

BACKGROUND Several studies have explored the effect of overlapping surgery on patient outcomes, but impact of surgical overlap during wound closure has not been studied. OBJECTIVE To examine the association of overlap during wound closure and suture time overlap (STO) with patient outcomes in a heterogeneous neurosurgical population. METHODS Over 4 yr (7/2013-7/2017), 1 7689 neurosurgical procedures were retrospectively reviewed at a single, multihospital academic medical center. STO was defined as all surgeries for which an overlapping surgery occurred, exclusively, during wound closure of the index case being studied. We excluded nonelective cases and overlapping surgeries that involved overlap during surgical portions of the case other than wound closure. Tests of independence and Wilcoxon tests were used for statistical analysis. RESULTS Patients with STO had a shortened length of hospital stay (100.6 vs 135.1 h; P

Freehand bedside ventriculostomy placement can result in catheter malfunction requiring a revision procedure and cause significant patient morbidity. We performed a single-center retrospective review to assess factors related to this complication.Using an administrative database and chart review, we identified 101 first-time external ventricular drain placements performed at the bedside. We collected data regarding demographics, medical comorbidities, complications, and catheter tip location. We performed univariate and multivariate statistical analyses using MATLAB. We corrected for multiple comparisons using the false discovery rate (FDR) procedure.Multivariate regression analyses revealed that revision procedures were more likely to occur after drain blockage (odds ratio [OR] 17.9) and hemorrhage (OR 10.3, FDR-corrected P values0.01, 0.05, respectively). Drain blockage was less frequent after placement in an "optimal location" (ipsilateral ventricle or near foramen of Monroe; OR 0.09, P = 0.009, FDR-corrected P0.03) but was more likely to occur after placement in third ventricle (post-hoc P values0.015). Primary diagnoses included subarachnoid hemorrhage (n = 30, 29.7%), intraparenchymal hemorrhage with intraventricular extravasation (n = 24, 23.7%), tumor (n = 20, 19.8%), and trauma (n = 17, 16.8%). Most common complications included drain blockage (n = 12, 11.8%) and hemorrhage (n = 8, 7.9%). In total, 16 patients underwent at least 1 revision procedure (15.8%).Bedside external ventricular drain placement is associated with a 15% rate of revision, that typically occurred after drain blockage and postprocedure hemorrhage. Optimal placement within the ipsilateral frontal horn or foramen of Monroe was associated with a reduced rate of drain blockage.

Brain-computer interface and neuromodulation strategies relying on penetrating non-organic electrodes/optrodes are limited by an inflammatory foreign body response that ultimately diminishes performance. A novel "biohybrid" strategy is advanced, whereby living neurons, biomaterials, and microelectrode/optical technology are used together to provide a biologically-based vehicle to probe and modulate nervous-system activity. Microtissue engineering techniques are employed to create axon-based "living electrodes", which are columnar microstructures comprised of neuronal population(s) projecting long axonal tracts within the lumen of a hydrogel designed to chaperone delivery into the brain. Upon microinjection, the axonal segment penetrates to prescribed depth for synaptic integration with local host neurons, with the perikaryal segment remaining externalized below conforming electrical-optical arrays. In this paradigm, only the biological component ultimately remains in the brain, potentially attenuating a chronic foreign-body response. Axon-based living electrodes are constructed using multiple neuronal subtypes, each with differential capacity to stimulate, inhibit, and/or modulate neural circuitry based on specificity uniquely afforded by synaptic integration, yet ultimately computer controlled by optical/electrical components on the brain surface. Current efforts are assessing the efficacy of this biohybrid interface for targeted, synaptic-based neuromodulation, and the specificity, spatial density and long-term fidelity versus conventional microelectronic or optical substrates alone.

For implantable neural interfaces, functional/clinical outcomes are challenged by limitations in specificity and stability of inorganic microelectrodes. A biological intermediary between microelectrical devices and the brain may improve specificity and longevity through (i) natural synaptic integration with deep neural circuitry, (ii) accessibility on the brain surface, and (iii) optogenetic manipulation for targeted, light-based readout/control. Accordingly, we have developed implantable "living electrodes," living cortical neurons, and axonal tracts protected within soft hydrogel cylinders, for optobiological monitoring/modulation of brain activity. Here, we demonstrate fabrication, rapid axonal outgrowth, reproducible cytoarchitecture, and simultaneous optical stimulation and recording of these tissue engineered constructs in vitro. We also present their transplantation, survival, integration, and optical recording in rat cortex as an in vivo proof of concept for this neural interface paradigm. The creation and characterization of these functional, optically controllable living electrodes are critical steps in developing a new class of optobiological tools for neural interfacing.

Innervation plays a pivotal role as a driver of tissue and organ development as well as a means for their functional control and modulation. Therefore, innervation should be carefully considered throughout the process of biofabrication of engineered tissues and organs. Unfortunately, innervation has generally been overlooked in most non-neural tissue engineering applications, in part due to the intrinsic complexity of building organs containing heterogeneous native cell types and structures. To achieve proper innervation of engineered tissues and organs, specific host axon populations typically need to be precisely driven to appropriate location(s) within the construct, often over long distances. As such, neural tissue engineering and/or axon guidance strategies should be a necessary adjunct to most organogenesis endeavors across multiple tissue and organ systems. To address this challenge, our team is actively building axon-based “living scaffolds” that may physically wire in during organ development in bioreactors and/or serve as a substrate to effectively drive targeted long-distance growth and integration of host axons after implantation. This article reviews the neuroanatomy and the role of innervation in the functional regulation of cardiac, skeletal, and smooth muscle tissue and highlights potential strategies to promote innervation of biofabricated engineered muscles, as well as the use of “living scaffolds” in this endeavor for both in vitro and in vivo applications. We assert that innervation should be included as a necessary component for tissue and organ biofabrication, and that strategies to orchestrate host axonal integration are advantageous to ensure proper function, tolerance, assimilation, and bio-regulation with the recipient post-implant.

Recombinant adeno-associated virus (rAAV), produced from a nonpathogenic parvovirus, has become an increasing popular vector for gene therapy applications in human clinical trials. However, transduction and transgene expression of rAAVs can differ acrossin vitroand ex vivo cellular transduction strategies. This study compared 11 rAAV serotypes, carrying one reporter transgene cassette containing a cytomegalovirus immediate-early enhancer (eCMV) and chicken beta actin (CBA) promoter driving the expression of an enhanced green-fluorescent protein (eGFP) gene, which was transduced into four different cell types: human iPSC, iPSC-derived RPE, iPSC-derived cortical, and dissociated embryonic day 18 rat cortical neurons. Each cell type was exposed to three multiplicity of infections (MOI: 1E4, 1E5, and 1E6 vg/cell). After 24, 48, 72, and 96 h posttransduction, GFP-expressing cells were examined and compared across dosage, time, and cell type. Retinal pigmented epithelium showed highest AAV-eGFP expression and iPSC cortical the lowest. At an MOI of 1E6 vg/cell, all serotypes show measurable levels of AAV-eGFP expression; moreover, AAV7m8 and AAV6 perform best across MOI and cell type. We conclude that serotype tropism is not only capsid dependent but also cell type plays a significant role in transgene expression dynamics.

OBJECTIVEHealthcare costs continue to escalate. Approaches to care that have comparable outcomes and complications are increasingly assessed for quality improvement and, when possible, cost containment. Efforts to identify components of care to reduce length of stay (LOS) have been ongoing. Spinal anesthesia (SA), for select lumbar spine procedures, has garnered interest as an alternative to general anesthesia (GA) that might reduce cost and in-hospital LOS and accelerate recovery. While clinical outcomes with SA or GA have been studied extensively, few authors have looked at the cost-analysis in relation to clinical outcomes. The authors’ objectives were to compare the clinical perioperative outcomes of patients who received SA and GA, as well as the direct costs associated with each modality of care, and to determine which, in a retrospective analysis, can serve as a dominant procedural approach.METHODSThe authors retrospectively analyzed a homogeneous surgical population of 550 patients who underwent hemilaminotomy for disc herniation and who received either SA (n = 91) or GA (n = 459). All clinical and billing data were obtained via each patient’s chart and the hospital’s billing database, respectively. Additionally, the authors prospectively assessed patient-reported outcome measures for a subgroup of consecutively treated patients (n = 75) and compared quality-adjusted life year (QALY) gains between the two cohorts. Furthermore, the authors performed a propensity score–matching analysis to compare the two cohorts (n = 180).RESULTSDirect hospital costs for patients receiving SA were 40% higher, in the hundreds of dollars, than for patients who received GA (p < 0.0001). Furthermore, there was a significant difference with regard to LOS (p < 0.0001), where patients receiving SA had a considerably longer hospital LOS (27.6% increase in hours). Patients undergoing SA had more comorbidities (p = 0.0053), specifically diabetes and hypertension. However, metrics of complications, including readmission (p = 0.3038) and emergency department (ED) visits at 30 days (p = 1.0), were no different. Furthermore, in a small pilot group, QALY gains were statistically no different (n = 75, p = 0.6708). Propensity score–matching analysis demonstrated similar results as the univariate analysis: there was no difference between the cohorts regarding 30-day readmission (p = 1.0000); ED within 30 days could not be analyzed as there were no patients in the SA group; and total direct costs and LOS were significantly different between the two cohorts (p < 0.0001 and p = 0.0126, respectively).CONCLUSIONSBoth SA and GA exhibit the qualities of a good anesthetic, and the utilization of these modalities for lumbar spine surgery is safe and effective. However, this work suggests that SA is associated with increased LOS and higher direct costs, although these differences may not be clinically or fiscally meaningful.

Neurogenesis in the postnatal mammalian brain is known to occur in the dentate gyrus of the hippocampus and the subventricular zone. These neurogenic niches serve as endogenous sources of neural precursor cells that could potentially replace neurons that have been lost or damaged throughout the brain. As an example, manipulation of the subventricular zone to augment neurogenesis has become a popular strategy for attempting to replace neurons that have been lost due to acute brain injury or neurodegenerative disease. In this review article, we describe current experimental strategies to enhance the regenerative potential of endogenous neural precursor cell sources by enhancing cell proliferation in neurogenic regions and/or redirecting migration, including pharmacological, biomaterial, and tissue engineering strategies. In particular, we discuss a novel replacement strategy based on exogenously biofabricated "living scaffolds" that could enhance and redirect endogenous neuroblast migration from the subventricular zone to specified regions throughout the brain. This approach utilizes the first implantable, biomimetic tissue-engineered rostral migratory stream, thereby leveraging the brain's natural mechanism for sustained neuronal replacement by replicating the structure and function of the native rostral migratory stream. Across all these strategies, we discuss several challenges that need to be overcome to successfully harness endogenous neural precursor cells to promote nervous system repair and functional restoration. With further development, the diverse and innovative tissue engineering and biomaterial strategies explored in this review have the potential to facilitate functional neuronal replacement to mitigate neurological and psychiatric symptoms caused by injury, developmental disorders, or neurodegenerative disease.

BACKGROUND AND IMPORTANCE Extracorporeal membrane oxygenation (ECMO) represents a life-saving therapy in cases of refractory hypoxia and has been utilized in patients suffering from the most severe forms of coronavirus disease 2019 (COVID-19). A strikingly high mortality rate of 94% was described in early reports of patients with COVID-19 transitioned to ECMO. Later case reports and series demonstrating successful recovery from COVID-19 after ECMO have revived interest in this therapeutic modality, including the recent approval of ECMO for COVID-19 patients by the Food and Drug Administration (FDA). Here, we present the first reports of devastating intracranial hemorrhage as a complication of veno-venous (VV) ECMO in two COVID-19 patients. CLINICAL PRESENTATION We performed a retrospective analysis of 2 cases of devastating intracranial hemorrhage in patients on VV-ECMO for the treatment of COVID-19. Collected data included clinical history, laboratory results, treatment, and review of all available imaging. Both patients demonstrated activated partial thromboplastin times (aPTT) within an appropriate therapeutic range. No risk factors that clearly predicted likelihood of this complication were identified. CONCLUSION Understanding the complications of ECMO in this cohort and developing therapeutic algorithms to aid in optimal patient selection will be critical in the limited resource setting experienced as a result of global pandemic. We propose the use of head computed tomography (CT) to identify devastating neurological complications as early as possible, aiding in the resource allocation of ECMO machines to the most appropriately selected patients.

Objectives The LACE+ index risk prediction tool has not been successfully used to predict short-term outcomes after neurosurgery. This study assessed the ability of LACE+ to predict 30-day (30D) adverse outcomes after supratentorial brain tumor surgery. Patients and methods LACE+ scores were retrospectively calculated for consecutive patients (n = 624) who received surgery for supratentorial tumors at one multi-center health system (2017–2019). Coarsened exact matching was employed to control for confounding variables. Outcomes including unplanned hospital readmission, emergency department visits, and death were compared for patients with different LACE+ score quartiles (Q1, Q2, Q3, Q4). Results 134 patients were matched between Q1 and Q4; 152 patients between Q2 and Q4; 192 patients between Q3 and Q4. LACE+ score was not found to predict readmission within 30D of discharge for Q1 vs Q4 (p = 0.239), Q2 vs Q4 (p = 0.336), or Q3 vs Q4 (p = 0.739). LACE + score also did not predict 30D risk of emergency department visits for Q1 vs Q4 (p = 0.210), Q2 vs Q4 (p = 0.839), or Q3 vs Q4 (p = 0.167). LACE + did predict death within 30D of surgery for Q3 vs Q4 (1.04 % vs 7.29 %, p = 0.039), but not for Q1 vs Q4 (p = 0.625) or Q2 vs Q4 (p = 0.125). Conclusion LACE + may not be suitable for characterizing short-term risk of certain perioperative events in a patient population undergoing supratentorial brain tumor surgery.

Brain organoids are an exciting new technology with the potential to significantly change how diseases of the brain are understood and treated. These three-dimensional neural tissues are derived from the self-organization of pluripotent stem cells, and they recapitulate the developmental process of the human brain, including progenitor zones and rudimentary cortical layers. Brain organoids have been valuable in investigating different aspects of developmental neurobiology and comparative biology. Several characteristics of organoids also make them attractive as models of brain disorders. Data generated from human organoids are more generalizable to patients because of the match in species background. Personalized organoids also can be generated from patient-derived induced pluripotent stem cells. Furthermore, the three-dimensionality of brain organoids supports cellular, mechanical, and topographical cues that are lacking in planar systems. In this review, we discuss the translational potential of brain organoids, using the examples of Zika virus, autism-spectrum disorder, and glioblastoma multiforme to consider how they could contribute to disease modeling, personalized medicine, and testing of therapeutics. We then discuss areas of improvement in organoid technology that will enhance the translational potential of brain organoids, as well as the possibility of their use as substrates for repairing cerebral circuitry after injury. Developmental Dynamics 248:53-64, 2019. © 2018 Wiley Periodicals, Inc.

The objective of this study was to assess the independent effect of complications on 30-day mortality in 32,695 patients undergoing elective craniotomy.The American College of Surgeons National Surgical Quality Improvement Program was queried for patients undergoing elective craniotomy from 2006 to 2015. Multivariate logistic regression was used to examine the effect of complications on mortality independent of preoperative risk and other postoperative complications. This effect was further assessed in risk-stratified patient subgroups using the American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator.Of 13 complications analyzed, the 5 most strongly associated with mortality independent of preoperative risk factors were unplanned intubation (odds ratio [OR], 12.1; 95% confidence interval [CI], 9.5-15.4; P0.001), stroke (OR, 11.1; 95% CI, 8.3-14.9; P0.001), ventilator requirement48 hours after surgery (OR, 9.9; 95% CI, 7.9-12.6; P0.001), and renal failure (OR, 8.5; 95% CI, 4.4-16.2; P0.001). These same complications were also the 5 most associated with mortality independent of other postoperative complications. They were also associated with mortality across all risk-stratified patient subgroups. On the contrary, venous thromboembolism (OR, 1.3; 95% CI, 0.98-1.7; P = 0.06), urinary tract infection (OR, 1.1; 95% CI, 0.76-1.6; P = 0.61), unplanned reoperation (OR, 1.1; 95% CI, 0.83-1.4; P = 0.55), and surgical site infection (OR, 0.35; 95% CI, 0.18-0.71; P = 0.004) showed no significant link with increased mortality independent of other complications.Of 13 complications analyzed, myocardial infarction, unplanned intubation, prolonged ventilator requirement, stroke, and renal failure showed the strongest association with mortality independent of preoperative risk, independent of other complications, and across all risk-stratified subgroups. These findings help identify causes of perioperative mortality after elective craniotomy. Dedicating additional resources toward preventing and treating these complications postoperatively may help reduce rates of failure-to-rescue in the neurosurgical population.

The classic motor deficits of Parkinson's disease are caused by degeneration of dopaminergic neurons in the substantia nigra pars compacta, resulting in the loss of their long-distance axonal projections that modulate the striatum. Current treatments only minimize the symptoms of this disconnection as there is no approach capable of replacing the nigrostriatal pathway. We are applying microtissue engineering techniques to create living, implantable constructs that mimic the architecture and function of the nigrostriatal pathway. These constructs consist of dopaminergic neurons with long axonal tracts encased within hydrogel microcolumns. Microcolumns were seeded with dopaminergic neuronal aggregates, while lumen extracellular matrix, growth factors, and end targets were varied to optimize cytoarchitecture. We found a 10-fold increase in axonal outgrowth from aggregates versus dissociated neurons, resulting in remarkable axonal lengths of over 6 mm by 14 days and 9 mm by 28 days in vitro. Axonal extension was also dependent upon lumen extracellular matrix, but did not depend on growth factor enrichment or neuronal end target presence. Evoked dopamine release was measured via fast scan cyclic voltammetry and synapse formation with striatal neurons was observed in vitro. Constructs were microinjected to span the nigrostriatal pathway in rats, revealing survival of implanted neurons while maintaining their axonal projections within the microcolumn. Lastly, these constructs were generated with dopaminergic neurons differentiated from human embryonic stem cells. This strategy may improve Parkinson's disease treatment by simultaneously replacing lost dopaminergic neurons in the substantia nigra and reconstructing their long-projecting axonal tracts to the striatum.

Summary: A number of mitochondrial diseases arise from single-nucleotide variant (SNV) accumulation in multiple mitochondria. Here, we present a method for identification of variants present at the single-mitochondrion level in individual mouse and human neuronal cells, allowing for extremely high-resolution study of mitochondrial mutation dynamics. We identified extensive heteroplasmy between individual mitochondrion, along with three high-confidence variants in mouse and one in human that were present in multiple mitochondria across cells. The pattern of variation revealed by single-mitochondrion data shows surprisingly pervasive levels of heteroplasmy in inbred mice. Distribution of SNV loci suggests inheritance of variants across generations, resulting in Poisson jackpot lines with large SNV load. Comparison of human and mouse variants suggests that the two species might employ distinct modes of somatic segregation. Single-mitochondrion resolution revealed mitochondria mutational dynamics that we hypothesize to affect risk probabilities for mutations reaching disease thresholds. : Morris et al. use independent sequencing of multiple individual mitochondria from mouse and human brain cells to show high pervasiveness of mutations. The mutations are heteroplasmic within single mitochondria and within and between cells. These findings suggest mechanisms by which mutations accumulate over time, resulting in mitochondrial dysfunction and disease. Keywords: single mitochondrion, single cell, human neuron, mouse neuron, single-nucleotide variation

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease, affecting 1–2% of people over 65. The classic motor symptoms of PD result from selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in a loss of their long axonal projections to the striatum. Current treatment strategies such as dopamine replacement and deep brain stimulation (DBS) can only minimize the symptoms of nigrostriatal degeneration, not directly replace the lost pathway. Regenerative medicine-based solutions are being aggressively pursued with the goal of restoring dopamine levels in the striatum, with several emerging techniques attempting to reconstruct the entire nigrostriatal pathway—a key goal to recreate feedback pathways to ensure proper dopamine regulation. Although many pharmacological, genetic, and optogenetic treatments are being developed, this article focuses on the evolution of transplant therapies for the treatment of PD, including fetal grafts, cell-based implants, and more recent tissue-engineered constructs. Attention is given to cell/tissue sources, efficacy to date, and future challenges that must be overcome to enable robust translation into clinical use. Emerging regenerative medicine therapies are being developed using neurons derived from autologous stem cells, enabling the construction of patient-specific constructs tailored to their particular extent of degeneration. In the upcoming era of restorative neurosurgery, such constructs may directly replace SNpc neurons, restore axon-based dopaminergic inputs to the striatum, and ameliorate motor deficits. These solutions may provide a transformative and scalable solution to permanently replace lost neuroanatomy and improve the lives of millions of people afflicted by PD.

Background Gunshot wound (GSW) injuries are among the leading causes of penetrating spinal column injury (pSI). Patients with pSI often have concurrent polytrauma that complicates management. Methods We retrospectively reviewed charts between January 2012 to June 2018 at an urban Level 1 trauma center and analyzed bracing and surgical indications, antibiotic and magnetic resonance imaging (MRI) use, and patient outcomes. Results We identified 100 patients with pSI with an average age of 27.2 (range, 15–58) years. Five patients had knife injuries and 95 suffered GSW. Polytrauma occurred in 90% of patients with an average of 3.39 bullets per patient (range, 1–23). Fourteen patients underwent either decompressive surgery (n = 8) or decompression and fusion (n = 6). Thirty-five patients were externally braced. A total of 43% of patients presented as American Spinal Injury Association-A compared with 26% who were intact. Although 14 patients received prophylactic antibiotics for retained bullets or durotomies, only 2 patients had postoperative wound infections and 4 had extraspinal infections from retained bullets. All inpatient mortalities (n = 5) were patients with cervical pSI. Thirteen patients with GSW obtained MRI scans without complications. Among our cohort, only 65 patients had follow-up with a median follow-up period of 1.25 (range, 1–60) months. Conclusions Management of pSI in urban trauma centers is complex, as these victims routinely have polytrauma that takes precedence. Indications for surgical intervention are narrow and secondary to surgery for polytrauma. External bracing may be overutilized. The efficacy of prophylactic antibiotics remains unclear. MRI can contribute valuable information but is limited by uncertainty regarding bullet compatibility. Lack of follow-up limits the study of this population.

Recent demonstrations of human brain organoid transplantation in rodents have accentuated ethical concerns associated with these entities, especially as they relate to potential "humanization" of host animals. Consideration of established scientific principles can help define the realistic range of expected outcomes in such transplantation studies. This practical approach suggests that augmentation of discrete brain functions in transplant hosts is a more relevant ethical question in the near term than the possibility of "conscious" chimeric animals. We hope that this framework contributes to a balanced approach for proceeding with studies involving brain organoid transplantation and other forms of human-animal brain chimeras.

Assays examining the open-chromatin landscape in single cells require isolation of the nucleus, resulting in the loss of spatial/microenvironment information. Here we describe CHEX-seq (CHromatin EXposed) for identifying single-stranded open-chromatin DNA regions in paraformaldehyde-fixed single cells. CHEX-seq uses light-activated DNA probes that binds to single-stranded DNA in open chromatin. In situ laser activation of the annealed probes’ 3’-Lightning Terminator™ in selected cells permits the probe to act as a primer for in situ enzymatic copying of single-stranded DNA that is then sequenced. CHEX-seq is benchmarked with human K562 cells and its utility is demonstrated in dispersed primary mouse and human brain cells, and immunostained cells in mouse brain sections. Further, CHEX-seq queries the openness of mitochondrial DNA in single cells. Evaluation of an individual cell’s chromatin landscape in its tissue context enables “spatial chromatin analysis”.One Sentence SummaryA new method, CHEX-seq (CHromatin eXposed), identifies the open-chromatin landscape in single fixed cells thereby allowing spatial chromatin analysis of selected cells in complex cellular environments.

IMPORTANCE: United States government personnel experienced potential exposures to uncharacterized directional phenomena while serving in Havana, Cuba, from late 2016 through May 2018. The underlying neuroanatomical findings have not been described. OBJECTIVE: To examine potential differences in brain tissue volume, microstructure, and functional connectivity in government personnel compared with individuals not exposed to directional phenomena. DESIGN, SETTING, AND PARTICIPANTS: Forty government personnel (patients) who were potentially exposed and experienced neurological symptoms underwent evaluation at a US academic medical center from August 21, 2017, to June 8, 2018, including advanced structural and functional magnetic resonance imaging analytics. Findings were compared with imaging findings of 48 demographically similar healthy controls. EXPOSURES: Potential exposure to uncharacterized directional phenomena of unknown etiology, manifesting as pressure, vibration, or sound. MAIN OUTCOMES AND MEASURES: Potential imaging-based differences between patients and controls with regard to (1) white matter and gray matter total and regional brain volumes, (2) cerebellar tissue microstructure metrics (eg, mean diffusivity), and (3) functional connectivity in the visuospatial, auditory, and executive control subnetworks. RESULTS: Imaging studies were completed for 40 patients (mean age, 40.4 years; 23 [57.5%] men; imaging performed a median of 188 [range, 4-403] days after initial exposure) and 48 controls (mean age, 37.6 years; 33 [68.8%] men). Mean whole brain white matter volume was significantly smaller in patients compared with controls (patients: 542.22 cm(3); controls: 569.61 cm(3); difference, −27.39 [95% CI, −37.93 to −16.84] cm(3); P

Cervical spine trauma (CST) may result in vertebral artery injury (VAI), increasing the risk of developing stroke. Stroke risk following CST is poorly reported.In total, 729 patients with CST were retrospectively analyzed, including rates of VAI, age at injury, cause of injury, cardiovascular history, smoking history, substance abuse history, embolization therapy, and antiplatelet or anticoagulant therapy prior or after injury. VAIs were identified and graded following the Modified Denver Criteria for Blunt Cerebrovascular Injury using magnetic resonance angiography and computed tomography angiography. Brain scans were reviewed for stroke rates and statistically significant variations.Thirty-three patients suffered penetrating trauma, whereas 696 patients experienced blunt trauma. In total, 81 patients met the criteria for analysis with confirmed VAI. VAI was more common in penetrating injury group compared with blunt injury group (64% vs. 9%, P0.0005). However, low-grade VAI (less than grade III) was more common in blunt injury group versus penetrating group (37% vs. 14%, P0.05). The frequency of posterior circulation strokes did not vary significantly between groups (26.3% vs. 13.8%, P = 0.21). Cardiovascular comorbidities were significantly more common in the blunt group (50%, P = 0.0001) compared with the penetrating group (0%).VAI occurs with a high incidence in penetrating CST. Although stroke risk following penetrating and blunt CST did not vary significantly, they resulted in serious complications in a group of patients. Further study of this patient population is required to provide high-level, evidence-based preventions for VAI complications.

Decoding laminar information across deep brain structures and cortical regions is necessary in order to understand the neuronal ensembles that represent cognition and memory. Large animal models are essential for translational research due to their gyrencephalic neuroanatomy and significant white matter composition. A lack of long-length probes with appropriate stiffness allowing penetration to deeper structures with minimal damage to the neural interface is one of the major technical limitations to applying the approaches currently utilized in lower order animals to large animals. We therefore tested the performance of multichannel silicon probes of various solutions and designs that were developed specifically for large animal electrophysiology. Neurophysiological signals from dorsal hippocampus were recorded in chronically implanted awake behaving Yucatan pigs. Single units and local field potentials were analyzed to evaluate performance of given silicon probes over time. EDGE-style probes had the highest yields during intra-hippocampal recordings in pigs, making them the most suitable for chronic implantations and awake behavioral experimentation. In addition, the cross-sectional area of silicon probes was found to be a crucial determinant of silicon probe performance over time, potentially due to reduction of damage to the neural interface. Novel 64-channel EDGE-style probes tested acutely produced an optimal single unit separation and a denser sampling of the laminar structure, identifying these research silicon probes as potential candidates for chronic implantations. This study provides an analysis of multichannel silicon probes designed for large animal electrophysiology of deep laminar brain structures, and suggests that current designs are reaching the physical thresholds necessary for long-term (∼1 month) recordings with single-unit resolution.