An evolutionarily acquired microRNA shapes development of mammalian cortical projections.

The corticospinal tract is unique to mammals and the corpus callosum is unique to placental mammals (eutherians). The emergence of these structures is thought to underpin the evolutionary acquisition of complex motor and cognitive skills. Corticospinal motor neurons (CSMN) and callosal projection neurons (CPN) are the archetypal projection neurons of the corticospinal tract and corpus callosum, respectively. Although a number of conserved transcriptional regulators of CSMN and CPN development have been identified in vertebrates, none are unique to mammals and most are coexpressed across multiple projection neuron subtypes. Here, we discover 17 CSMN-enriched microRNAs (miRNAs), 15 of which map to a single genomic cluster that is exclusive to eutherians. One of these, miR-409-3p, promotes CSMN subtype identity in part via repression of LMO4, a key transcriptional regulator of CPN development. In vivo, miR-409-3p is sufficient to convert deep-layer CPN into CSMN. This is a demonstration of an evolutionarily acquired miRNA in eutherians that refines cortical projection neuron subtype development. Our findings implicate miRNAs in the eutherians' increase in neuronal subtype and projection diversity, the anatomic underpinnings of their complex behavior.

Epigenetic regulation of nervous system development and function.

Building a brain is complicated but maintaining one may be an even greater challenge. Epigenetic mechanisms, including DNA methylation, histone and chromatin modifications, and the actions of non-coding RNAs, play an indispensable role in both. They orchestrate long-term changes in gene expression that underpin establishment of cellular identity as well as the distinct functionality of each cell type, while providing the needed plasticity for the brain to respond to a changing environment. The rapid expansion of studies on these epigenetic mechanisms over the last few decades has brought an evolving definition of the term epigenetics, including in the specialized context of the nervous system. The goal of this special issue is thus not only to bring a greater understanding of the myriad ways in which epigenetic mechanisms regulate nervous system development and function, but also to provide a platform for discussion of what is and what is not epigenetics. To this end, the editors have compiled a collection of review articles highlighting some of the remarkable breadth of epigenetic mechanisms that act at all stages of neuronal development and function, spanning from neurodevelopment, through learning and memory, and neurodegeneration.

Spinal cord injury: a study protocol for a systematic review and meta-analysis of microRNA alterations.

BACKGROUND: Spinal cord injury (SCI) is a devastating condition with no current neurorestorative treatments. Clinical trials have been hampered by a lack of meaningful diagnostic and prognostic markers of injury severity and neurologic recovery. Objective biomarkers and novel therapies for SCI represent urgent unmet clinical needs. Biomarkers of SCI that objectively stratify the severity of cord damage could expand the depth and scope of clinical trials and represent targets for the development of novel therapies for acute SCI. MicroRNAs (miRNAs) represent promising candidates both as informative molecules of injury severity and recovery, and as therapeutic targets. miRNAs are small, regulatory RNA molecules that are tissue-specific and evolutionarily conserved across species. miRNAs have been shown to represent powerful predictors of pathology, particularly with respect to neurologic disorders. METHODS: Studies investigating miRNA alterations in all species of animal models and human studies of acute, traumatic SCI will be identified from PubMed, Embase, and Scopus. We aim to identify whether SCI is associated with a specific pattern of miRNA expression that is conserved across species, and whether SCI is associated with a tissue- or cell type-specific pattern of miRNA expression. The inclusion criteria for this study will include (1) studies published anytime, (2) including all species, and sexes with acute, traumatic SCI, (3) relating to the alteration of miRNA after SCI, using molecular-based detection platforms including qRT-PCR, microarray, and RNA-sequencing, (4) including statistically significant miRNA alterations in tissues, such as spinal cord, serum/plasma, and/or CSF, and (5) studies with a SHAM surgery group. Articles included in the review will have their titles, abstracts, and full texts reviewed by two independent authors. Random effects meta-regression will be performed, which allows for within-study and between-study variability, on the miRNA expression after SCI or SHAM surgery. We will analyze both the cumulative pooled dataset, as well as datasets stratified by species, tissue type, and timepoint to identify miRNA alterations that are specifically related to the injured spinal cord. We aim to identify SCI-related miRNA that are specifically altered both within a species, and those that are evolutionarily conserved across species, including humans. The analyses will provide a description of the evolutionarily conserved miRNA signature of the pathophysiological response to SCI. DISCUSSION: Here, we present a protocol to perform a systematic review and meta-analysis to investigate the conserved inter- and intra-species miRNA changes that occur due to acute, traumatic SCI. This review seeks to serve as a valuable resource for the SCI community by establishing a rigorous and unbiased description of miRNA changes after SCI for the next generation of SCI biomarkers and therapeutic interventions. TRIAL REGISTRATION: The protocol for the systematic review and meta-analysis has been registered through PROSPERO: CRD42021222552 .

miR-409-3p represses Cited2 to refine neocortical layer V projection neuron identity.

The evolutionary emergence of the corticospinal tract and corpus callosum are thought to underpin the expansion of complex motor and cognitive abilities in mammals. Molecular mechanisms regulating development of the neurons whose axons comprise these tracts, the corticospinal and callosal projection neurons, remain incompletely understood. Our previous work identified a genomic cluster of microRNAs (miRNAs), Mirg/12qF1, that is unique to placental mammals and specifically expressed by corticospinal neurons, and excluded from callosal projection neurons, during development. We found that one of these, miR-409-3p, can convert layer V callosal into corticospinal projection neurons, acting in part through repression of the transcriptional regulator Lmo4. Here we show that miR-409-3p also directly represses the transcriptional co-regulator Cited2, which is highly expressed by callosal projection neurons from the earliest stages of neurogenesis. Cited2 is highly expressed by intermediate progenitor cells (IPCs) in the embryonic neocortex while Mirg, which encodes miR-409-3p, is excluded from these progenitors. miR-409-3p gain-of-function (GOF) in IPCs results in a phenocopy of established Cited2 loss-of-function (LOF). At later developmental stages, both miR-409-3p GOF and Cited2 LOF promote the expression of corticospinal at the expense of callosal projection neuron markers in layer V. Taken together, this work identifies previously undescribed roles for miR-409-3p in controlling IPC numbers and for Cited2 in controlling callosal fate. Thus, miR-409-3p, possibly in cooperation with other Mirg/12qF1 miRNAs, represses Cited2 as part of the multifaceted regulation of the refinement of neuronal cell fate within layer V, combining molecular regulation at multiple levels in both progenitors and post-mitotic neurons.

Resection of hip heterotrophic ossification leads to resolution of autonomic nervous system dysfunction in a patient with spinal Charcot arthropathy: a case report.

INTRODUCTION: Patients with complete spinal cord injury (SCI) may develop concurrent sequalae that interact and share symptoms; thus, a careful approach to diagnosis and management of new symptoms is crucial. CASE PRESENTATION: A patient with prior T4 complete SCI presented with progressive autonomic nervous system (ANS) dysfunction. The initial differential diagnosis included syringomyelia and lumbar Charcot arthropathy. He had comorbid heterotopic ossification (HO) of the left hip. Surprisingly, his autonomic symptoms resolved following resection of the HO. In hindsight, loss of motion through the hip caused by HO may have led to hinging through a previously asymptomatic lumbar Charcot joint, causing dysautonomia. DISCUSSION: ANS dysfunction is a disabling sequela of complete SCI and has a broad differential diagnosis. Hip immobility may be an indirect and overlooked cause due to the mechanical relationship between the hip and the lumbar spine.

Implementation of a patient-specific tapering protocol at discharge decreases total opioid dose prescribed for 6 weeks after elective primary spine surgery.

BACKGROUND AND OBJECTIVES: At our institution, we developed an individualized discharge opioid prescribing and tapering protocol for joint replacement patients and implemented the same protocol for neurosurgical spine patients. We then tested the hypothesis that this protocol will decrease the oral morphine milligram equivalent (MME) dose of opioid prescribed postdischarge after elective primary spine surgery. METHODS: In this retrospective cohort study, we identified all consecutive elective primary spine surgery cases 1 year before and after introduction of the protocol. This protocol used the patient's prior 24-hour inpatient opioid consumption to determine discharge opioid pill count and tapering schedule. The primary outcome was total opioid dose prescribed in oral MME from discharge through 6 weeks. Secondary outcomes included in-hospital opioid consumption in MME, hospital length of stay, MME prescribed at discharge, opioid refills, and rates of minor and major adverse events. RESULTS: Eighty-three cases comprised the final sample (45 preintervention and 38 postintervention). There were no differences in baseline characteristics. The total oral MME (median (IQR)) from discharge through 6 weeks postoperatively was 900 (420-1440) preintervention compared with 300 (112-806) postintervention (p<0.01, Mann-Whitney U test), and opioid refill rates were not different between groups. There were no differences in other outcomes. CONCLUSIONS: This patient-specific prescribing and tapering protocol effectively decreases the total opioid dose prescribed for 6 weeks postdischarge after elective primary spine surgery. Our experience also demonstrates the potential generalizability of this protocol, which was originally designed for joint replacement patients, to other surgical populations.

Image-guided Percutaneous Polymethylmethacrylate-augmented Spondylodesis for Painful Metastasis in the Veteran Population.

The treatment of painful spinal metastases in patients with limited life-expectancy, significant perioperative risks, and poor bone quality poses a surgical challenge. Recent advances in minimal-access spine surgery allow for the surgical treatment of patients previously considered not to be operative candidates. The addition of fenestrated screws for cement augmentation to existing image-guided percutaneous pedicle screw fixation can enhance efficiency, decrease risk of hardware complications, and improve back pain in this patient population. The patient is a 70-year-old man with severe axial back pain due to metastatic prostate cancer and L5 pathologic fractures not amenable to kyphoplasty. In the setting of a 6-12-month life-expectancy, the primary goal of surgery was relief of back pain associated with instability with minimal operative morbidity and post-operative recovery time. This was achieved with an internal fixation construct including percutaneously placed cement-augmented fenestrated pedicle screws at L4 and S1. The patient was discharged to home on post-operative day 1 with substantial improvement of his low back pain. Image-guided, percutaneous placement of fenestrated, cement-augmented pedicle screws is an emerging treatment for back pain associated with metastasis. Fenestrated screws allow for integrated cement augmentation. The minimal associated blood loss and recovery time make this approach an option even for patients with limited life-expectancy. This is the first report of utilization of this technique for the veteran population.

Patient Satisfaction and Press Ganey Scores for Spine Versus Nonspine Neurosurgery Clinics.

STUDY DESIGN: Retrospective survey review. OBJECTIVE: We seek to evaluate satisfaction scores in patients seen in neurosurgical spine versus neurosurgical nonspine clinics. SUMMARY OF BACKGROUND DATA: The Press Ganey survey is a well-established metric for measuring hospital performance and patient satisfaction. These measures have important implications in setting hospital policy and guiding interventions to improve patient perceptions of care. METHODS: Retrospective Press Ganey survey review was performed to identify patient demographics and patient visit characteristics from January 1st, 2012 to October 10th, 2017 at Stanford Medical Center. A total of 40 questions from the Press Ganey survey were investigated and grouped in categories addressing physician and nursing care, personal concerns, admission, room, meal, operating room, treatment and discharge conditions, visitor accommodations and overall clinic assessment. Raw ordinal scores were converted to continuous scores of 100 for unpaired student t test analysis. We identified 578 neurosurgical spine clinic patients and 1048 neurosurgical nonspine clinic patients. RESULTS: Spine clinic patients reported lower satisfaction scores in aggregate (88.2 vs. 90.1; P=0.0014), physician (89.5 vs. 92.6; P=0.0002) and nurse care (91.3 vs. 93.4; P=0.0038), personal concerns (88.2 vs. 90.9; P=0.0009), room (81.0 vs. 83.1; P=0.0164), admission (90.8 vs. 92.6; P=0.0154) and visitor conditions (87.0 vs. 89.2; P=0.0148), and overall clinic assessment (92.9 vs. 95.5; P=0.005). CONCLUSIONS: This study is the first to evaluate the relationship between neurosurgical spine versus nonspine clinic with regards to patient satisfaction. The spine clinic cohort reported less satisfaction than the nonspine cohort in all significant questions on the Press Ganey survey. Our findings suggest that efforts should be made to further study and improve patient satisfaction in spine clinics. LEVEL OF EVIDENCE: Level III.

Newly diagnosed glioblastoma: adverse socioeconomic factors correlate with delay in radiotherapy initiation and worse overall survival.

The optimal time for starting radiation in patients with glioblastoma (GBM) is controversial. We aimed to evaluate postoperative radiotherapy treatment patterns and the impact of timing of radiotherapy on survival outcomes in patients with GBM using a large, national hospital-based registry in the era of Stupp chemoradiation. We performed a retrospective cohort study using the National Cancer Data Base and identified adults with GBM diagnosed between 2010 and 2013 and treated with chemoradiation. We classified time from surgery/biopsy to radiation start into the following categories: <15 days, 15-21 days, 22-28 days, 29-35 days, 36-42 days and >42 days. We assessed the relation between time to radiation start and survival using Cox proportional hazards modeling adjusting for clinically relevant variables that were selected a priori. We used multivariate logistic modeling to determine factors independently associated with receipt of delayed radiation treatment. A total of 12 738 patients met our inclusion criteria after our cohort selection process. The majority of patients underwent either gross total (n = 5270, 41%) or subtotal (n = 4700, 37%) resection, while 2768 patients (22%) underwent biopsy only. Median time from definitive surgery or biopsy to initiation of radiation was 29 days (interquartile range 24-36 days). For patients who had biopsy or subtotal resection, earlier initiation of radiation did not appear to be associated with improved survival. However, among patients who underwent gross total resection, there appeared to be improved survival with early initiation of radiation. Patients who initiated radiation within 15-21 days of gross total resection had improved survival (hazard ratio 0.82, 95% confidence interval 0.69-0.98, P = 0.03) compared with patients who had delayed (>42 days after surgery) radiation. There was also a trend (P = 0.07 to 0.12) for improved survival for patients who initiated radiation within 22-35 days of gross total resection compared with patients who had delayed radiation. Patients who were black, had Medicaid or other government insurance or were not insured, and who lived in metropolitan areas or further away from the treating facility had higher odds of receiving radiation >35 days after gross total resection. Patients who lived in higher income areas had higher odds of receiving radiation within 35 days of a gross total resection. In a large cohort of patients with GBM treated with chemoradiation, our data suggest a survival benefit in initiating radiotherapy within 35 days after gross total resection. Further research is warranted to understand barriers to timely access to optimal therapy.

Evidence for Use of Teriparatide in Spinal Fusion Surgery in Osteoporotic Patients.

BACKGROUND: Osteoporosis is defined as bone mineral density. METHODS: A PubMed literature review was performed to review preclinical and clinical evidence for the use of teriparatide in osteoporotic patients undergoing spine fusion surgery. RESULTS: Preclinical studies in animal models show that teriparatide increases spinal fusion rates. Early clinical studies show that teriparatide both increases spinal fusion rates and decreases hardware loosening in the setting of postmenopausal osteoporosis. CONCLUSION: Ongoing additional trials will help formulate preoperative screening recommendations, determine the optimal duration of preoperative and postoperative teriparatide treatment, and investigate its utility in men.

Surgical timing for cervical and upper thoracic injuries in patients with polytrauma.

OBJECTIVE Few studies have investigated the advantages of early spinal stabilization in the patient with polytrauma in terms of reduction of morbidity and mortality. Previous analyses have shown that early stabilization may reduce ICU stay, with no effect on complication rates. METHODS The authors prospectively observed 340 polytrauma patients with an Injury Severity Score (ISS) of greater than 16 at a single Level 1 trauma center who were treated in accordance with a protocol termed "early appropriate care," which emphasizes operative treatment of various fractures within 36 hours of injury. Of these patients, 46 had upper thoracic and/or cervical spine injuries. The authors retrospectively compared patients treated according to protocol versus those who were not. Continuous variables were compared using independent t-tests and categorical variables using Fisher's exact test. Logistic regression analysis was performed to account for baseline confounding factors. RESULTS Fourteen of 46 patients (30%) did not undergo surgery within 36 hours. These patients were significantly more likely to be older than those in the protocol group (53 vs 38 years, p = 0.008) and have greater body mass index (BMI; 33 vs 27, p = 0.02), and they were less likely to have a spinal cord injury (SCI) (82% did not have an SCI vs 44% in the protocol group, p = 0.04). In terms of outcomes, patients in the protocol-breach group had significantly more total ventilator days (13 vs 6 days, p = 0.02) and total ICU days (16 vs 9 days, p = 0.03). Infection rates were 14% in the protocol-breach group and 3% in the protocol group (p = 0.2) Total complications trended toward being statistically significantly more common in the protocol-breach group (57% vs 31%). After controlling for potential confounding variables by logistic regression (including age, sex, BMI, race, and SCI), total complications were significantly (p < 0.05) greater in the protocol-breach group (OR 29, 95% CI 1.9-1828). This indicates that the odds of developing "any complication" were 29 times greater if treatment was delayed more than 36 hours. CONCLUSIONS Early surgical stabilization in the polytrauma patient with a cervical or upper thoracic spine injury is associated with fewer complications and improved outcomes. Hospitals may consider the benefit of protocols that promote early stabilization in this patient population.

Symptomatic Anterior Cervical Osteophyte Causing Dysphagia: Case Report, Imaging, and Review of the Literature.

Anterior cervical osteophytes are found in 20-30% of elderly patients. Rarely, severe osteophytes can cause dysphagia, dysphonia, and dyspnea. Here, we illustrate a case of severe dysphagia caused by a large post-traumatic osteophyte with oropharyngeal swallow study showing a significant mass effect on the pharynx and resolution following osteophytectomy. We also review the literature regarding the etiology, diagnosis, and treatment of symptomatic anterior cervical osteophytes.

Cervical Spondylotic Myelopathy.

Cervical spondylotic myelopathy (CSM) is a degenerative disease that represents the most common spinal cord disorder in adults. The natural history of the disease can be insidious, and patients often develop debilitating spasticity and weakness. Diagnosis includes a combination of physical examination and various imaging modalities. There are various surgical options for CSM, consisting of anterior and posterior procedures. This article summarizes the literature regarding the pathophysiology, natural history, and diagnosis of CSM, as well as the various treatment options and their associated risks and indications.

Anterolateral approach to the upper cervical spine: Case report and operative technique.

BACKGROUND: Transcervical approaches to the upper cervical spine are challenging because several upper anterior neurovascular structures need to be displaced to provide access. Although various techniques have been described, the anterolateral approach is one of the safest and most effective methods available to access the anterior C2-C3 disc space. Despite the approach's efficacy, however, it can cause postoperative complications because of, at least partly, the inter-surgeon differences in the methods by which the larynx and hypopharynx are displaced medially. METHODS AND RESULTS: We present a case report of a patient treated with a modified anterolateral approach to C2-C3. The approach provided excellent visualization while protecting vital structures. The patient recovered without any postoperative dysphagia or other surgical complications. CONCLUSION: The anterolateral approach to C2-C3 described herein safely protects the contents of the submandibular triangle while providing a wide exposure for direct access to the C2-C3 disc space.

Lumbar microdiscectomy and lumbar decompression improve functional outcomes and depression scores.

STUDY DESIGN: Retrospective review. INTRODUCTION: Lumbar radiculopathy and claudicant leg pain are common degenerative spinal conditions often treated by elective microdiscectomy or decompression. Published outcome data for these procedures have focused on improvement in pain scores, and not on grounded functional outcome or depression scores.1,2,3 Moreover, depression is considered by many surgeons to be a red flag for poor outcome for surgical treatment. We asked what effect lumbar microdiscectomy and laminectomy procedures had on functional outcome and depression scores in our clinical population. METHODS: Beginning in January 2010, the following outcome data were prospectively gathered before and after surgery from all patients at the Cleveland Clinic undergoing either lumbar microdiscectomy or lumbar decompression: EQ-5D (EuroQOL, quality-of-life measure), PHQ-9 (measure of depressive symptoms), PDQ (pain disability questionnaire), and Rankin scores (disability or dependence in daily activities). RESULTS: The mean EuroQOL scores improved by 35% (from 0.4-0.75 of a maximum of 1.0) for both microdiscectomy and lumbar laminectomies. The mean PHQ-9 scores (measure of depressive symptoms) significantly improved for most patients undergoing either procedure. In line with previously published reports, we also found improvement in Rankin scores and Pain Disability Questionnaire scores. CONCLUSIONS: Our outcome data indicate that microdiscectomy and lumbar decompression not only reduce disability and pain but also improve depressive symptoms and overall quality of life for patients. These findings support operative treatment of lumbar radiculopathy and neurogenic claudication including treatment performed in the depressed population.

A microfluidic device to investigate axon targeting by limited numbers of purified cortical projection neuron subtypes.

While much is known about general controls over axon guidance of broad classes of projection neurons (those with long-distance axonal connections), molecular controls over specific axon targeting by distinct neuron subtypes are poorly understood. Corticospinal motor neurons (CSMN) are prototypical and clinically important cerebral cortex projection neurons; they are the brain neurons that degenerate in amyotrophic lateral sclerosis (ALS) and related motor neuron diseases, and their injury is central to the loss of motor function in spinal cord injury. Primary culture of purified immature murine CSMN has been recently established, using either fluorescence-activated cell sorting (FACS) or immunopanning, enabling a previously unattainable level of subtype-specific investigation, but the resulting number of CSMN is quite limiting for standard approaches to study axon guidance. We developed a microfluidic system specifically designed to investigate axon targeting of limited numbers of purified CSMN and other projection neurons in culture. The system contains two chambers for culturing target tissue explants, allowing for biologically revealing axonal growth "choice" experiments. This device will be uniquely enabling for investigation of controls over axon growth and neuronal survival of many types of neurons, particularly those available only in limited numbers.

Functional brain mapping and its applications to neurosurgery.

Functional brain mapping may be useful for both preoperative planning and intraoperative neurosurgical decision making. "Gold standard" functional studies such as direct electrical stimulation and recording are complemented by newer, less invasive techniques such as functional magnetic resonance imaging. Less invasive techniques allow more areas of the brain to be mapped in more subjects (including healthy subjects) more often (including pre- and postoperatively). Expansion of the armamentarium of tools allows convergent evidence from multiple brain mapping techniques to bear on pre- and intraoperative decision making. Functional imaging techniques are used to map motor, sensory, language, and memory areas in neurosurgical patients with conditions as diverse as brain tumors, vascular lesions, and epilepsy. In the future, coregistration of high resolution anatomic and physiological data from multiple complementary sources will be used to plan more neurosurgical procedures, including minimally invasive procedures. Along the way, new insights on fundamental processes such as the biology of tumors and brain plasticity are likely to be revealed.

Cellular magnetic resonance imaging: nanometer and micrometer size particles for noninvasive cell localization.

The use of nanometer and micrometer-sized superparamagnetic iron oxide particles as cellular contrast agents allows for the noninvasive detection of labeled cells on high-resolution magnetic resonance images. The development and application of these techniques to neurologic disorders is likely to accelerate the development of cell transplantation therapies and allow for the detailed study of in vivo cellular biology. This review summarizes the early development of iron oxide-based cellular contrast agents and the more recent application of this technology to noninvasive imaging of cellular transplants. The ability of this technique to allow for the noninvasive detection of in vivo transplants on the single-cell level is highlighted.