High-Gamma Activity Is Coupled to Low-Gamma Oscillations in Precentral Cortices and Modulates with Movement and Speech.

Planning and executing motor behaviors requires coordinated neural activity among multiple cortical and subcortical regions of the brain. Phase-amplitude coupling between the high-gamma band amplitude and the phase of low frequency oscillations (theta, alpha, beta) has been proposed to reflect neural communication, as has synchronization of low-gamma oscillations. However, coupling between low-gamma and high-gamma bands has not been investigated. Here, we measured phase-amplitude coupling between low- and high-gamma in monkeys performing a reaching task and in humans either performing finger-flexion or word-reading tasks. We found significant coupling between low-gamma phase and high-gamma amplitude in multiple sensorimotor and premotor cortices of both species during all tasks. This coupling modulated with the onset of movement. These findings suggest that interactions between the low and high gamma bands are markers of network dynamics related to movement and speech generation.

The impact of opioid administration for post gamma knife radiosurgery frame removal: a prospective quality-improvement study.

PURPOSE: In our center, five Gamma Knife proceduralists differed in opioid administration practices prior to Leksell frame removal, providing the opportunity to improve the care of patients with brain metastases by studying whether opioid medications improve pain scores and patient satisfaction during Gamma Knife treatment in a prospective, pseudorandomized fashion. METHODS: We prospectively administered a questionnaire to patients undergoing Gamma Knife Radiosurgery for metastases between November, 2017 and July, 2018. Using multivariable methods, we assessed whether opioid pain medication administration influenced the change in pain scores after frame removal, and whether they influenced patient satisfaction on how often their pain was controlled, and their overall satisfaction. RESULTS: We included 142 patients. Mean age was 65.2 ± 10.8 years and 52.7% were female. Morphine was the most commonly administered medication. Pain increases were greater around frame removal than placement. Opioids were not associated with any difference in the change in pain scores before and after frame removal, or patient satisfaction. Patients with higher pre-removal pain scores had smaller increases in pain scores after removal; they also had worse pain control and overall satisfaction with their treatment. CONCLUSION: Morphine administration prior to frame removal did not improve pain scores or pain control satisfaction. Absence of efficacy may be related to delayed onset of action, and stronger and faster-acting agents should be explored. Pre-removal pain scores were associated with decreased pain control and overall satisfaction, further identifying earlier and stronger pain treatment as a potential area for improvement.

Regulations of Tumor Microenvironment by Prostaglandins.

Prostaglandins, the bioactive lipids generated from the metabolism of arachidonic acid through cyclooxygenases, have potent effects on many constituents of tumor microenvironments. In this review, we will describe the formation and activities of prostaglandins in the context of the tumor microenvironment. We will discuss the regulation of cancer-associated fibroblasts and immune constituents by prostaglandins and their roles in immune escapes during tumor progression. The review concludes with future perspectives on improving the efficacy of immunotherapy through repurposing non-steroid anti-inflammatory drugs and other prostaglandin modulators.

High-gamma activity is coupled to low-gamma oscillations in precentral cortices and modulates with movement and speech.

Planning and executing motor behaviors requires coordinated neural activity among multiple cortical and subcortical regions of the brain. Phase-amplitude coupling between the high-gamma band amplitude and the phase of low frequency oscillations (theta, alpha, beta) has been proposed to reflect neural communication, as has synchronization of low-gamma oscillations. However, coupling between low-gamma and high-gamma bands has not been investigated. Here, we measured phase-amplitude coupling between low- and high-gamma in monkeys performing a reaching task and in humans either performing finger movements or speaking words aloud. We found significant coupling between low-gamma phase and high-gamma amplitude in multiple sensorimotor and premotor cortices of both species during all tasks. This coupling modulated with the onset of movement. These findings suggest that interactions between the low and high gamma bands are markers of network dynamics related to movement and speech generation.

Outcomes following stereotactic radiosurgery for foramen magnum meningiomas: a single-center experience and systematic review of the literature.

OBJECTIVE: Foramen magnum meningiomas (FMMs) pose a unique challenge given their intimate anatomical relationship with the craniovertebral junction. While resection has been studied extensively, much less has been reported about the use of stereotactic radiosurgery (SRS) for FMMs. This study includes what is to the authors' knowledge the first systematic review in the literature that summarizes patient and treatment characteristics and synthesizes outcomes following SRS for FMMs. METHODS: A retrospective chart review was conducted at a single major academic institution, and a systematic review was performed according to PRISMA guidelines. The initial search on the PubMed and Scopus databases yielded 530 results. Key data extracted from both databases included Karnofsky Performance Status (KPS) score and neurological deficits at presentation, tumor location, treatment indication, target volume, single versus multiple fractions, marginal and maximum doses, isodose line, clinical and radiographic follow-up times, and primary (clinical stability and local control at last follow-up) and secondary (mortality, adverse radiation events, time to regression, progression-free survival) outcomes. RESULTS: The study patients included 9 patients from the authors' institution and 165 patients across 4 studies who received SRS for FMMs. The weighted median age at treatment was 60.2 years, and 73.9% of patients were female. Common presenting symptoms included headache (33.9%), dizziness/ataxia (29.7%), cranial nerve deficit(s) (27.9%), numbness (22.4%), weakness (15.2%), and hydrocephalus (4.2%). Lateral/ventrolateral (64.2%) was the most common tumor location. SRS was utilized as the primary therapy in 63.6% of patients and as salvage (21.8%) or adjuvant (14.5%) therapy for the rest of the patients. Most patients (91.5%) were treated with a single fraction. A tumor with a weighted median target volume of 2.9 cm3 was treated with a weighted median marginal dose, maximum dose, and isodose line of 12.9 Gy, 22.8 Gy, and 58%, respectively. Clinical stability and local control at last follow-up were achieved in 98.8% and 97.0% of patients, respectively. Only one possible adverse radiation event occurred, and no mortality directly related to the tumor or SRS was reported. CONCLUSIONS: In this retrospective analysis and systematic review, the authors demonstrate SRS to be an effective and safe treatment option for carefully selected patients with FMMs.

A Systematic Review of Outpatient Telemedicine Use in Neurosurgery Since the Start of Coronavirus Disease 2019.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has sparked interest in telemedicine, resulting in an increase in neurosurgical publications focused on it. We summarize this new literature to evaluate telemedicine applications to neurosurgery. METHODS: A systematic literature review was performed in accordance with the PRISMA guidelines by searching PubMed, Embase, and Scopus for journal articles published after January 1, 2020. All journal articles that included data after the start of COVID-19 and evaluated any aspect of telemedicine relevant to outpatient neurosurgical visits were included. The premise and key findings of each included study were extracted, as well as patient and provider satisfaction with and preference for telemedicine. RESULTS: Thirty-seven articles met the inclusion criteria. Four studies proposed and evaluated a remote neurologic examination. Two studies reported similar postvisit outcomes between remote and in-person visits. Twenty-four studies reported a combination of patient and provider opinions toward telemedicine. Of 9834 patients and 116 providers, 82.4% and 65.2% were satisfied overall with telemedicine, respectively. Of 3526 patients and 168 providers, 57.0% and 66.5% preferred telemedicine to in-person visits, respectively. CONCLUSIONS: Overall, most patients and providers have a high opinion of telemedicine for outpatient visits, and increasing evidence suggests that remote visits yield favorable clinical outcomes. The high rates of patient and provider satisfaction and preference may be considered for further adoption of remote neurosurgical visits beyond the COVID-19 era.

Outcomes Following Penetrating Brain Injuries in Military Settings: A Systematic Review and Meta-Analysis.

OBJECTIVE: While neurosurgeons are experienced in treating penetrating brain injuries (PBIs) in civilian settings, much less is known about management and outcomes of PBIs in military settings. METHODS: A systematic review was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Data extracted included surgical management, age, gender, location/type of injury, initial Glasgow Coma Scale (GCS) score, and outcomes. The primary outcomes were last reported Glasgow Outcome Score (GOS) and mortality. The secondary outcomes included central nervous system infections, seizures, and cerebrospinal fluid leak/fistula. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used for outcome analysis. RESULTS: Twelve studies with 1738 patients treated for PBIs in military settings were included. The weighted mean age was 27.8 years, 86.7% were male, and 64.3% underwent neurosurgical intervention. Most patients (64.3%) presented with a GCS score >8, while 31.0% presented in a coma (GCS score <8). Over a median last follow-up time of 9 months, 68.6% achieved a favorable (GOS = 4-5) outcome and 34.2% achieved a poor (GCS score = 1-3) outcome. The overall mortality was 18.0%. A meta-analysis was performed using 5 of 12 studies to evaluate the effect of the presenting GCS score on primary outcomes. Patients with an initial GCS score <8 had statistically significant lower odds of a favorable (GOS = 4-5) outcome (OR: 0.03; 95% CI: 0.00-0.19; P: 0.000) and higher odds of mortality (OR: 28.46; 95% CI: 8.62-94; P: 0.000) than patients with an initial GCS score >8. The pooled rates of central nervous system infection, seizures, and cerebrospinal fluid leak/fistula were 13.8%, 13.2%, and 5.4%, respectively. CONCLUSIONS: In this first systematic review and meta-analysis of outcomes following combat-related PBIs, a GCS score >8 at presentation was found to be an important predictor of a favorable GOS and decreased mortality.

Five-Year Outcomes After Decompression and Fusion Versus Decompression Alone in the Treatment of Lumbar Synovial Cysts.

BACKGROUND: Spinal synovial cysts are acquired, fluid-filled lesions of the facet joint that most commonly occur in the lumbar spine. They are thought to arise from degenerative changes and to result from segmental instability. Although the treatment of these lesions has been studied, the long-term implications and effects of the different strategies for surgical intervention (i.e., decompression and fusion vs. decompression alone) have not yet been elucidated or established. METHODS: Using an all-payer database with 53 million patient records (MARINER-53), patients with a diagnosis of lumbar synovial cysts were identified. Patients who had undergone lumbar fusion versus laminectomy were matched 1:1 using binomial and gaussian logistic regression models to evaluate the need for future lumbar surgery within 5 years after their index procedure. RESULTS: No statistically significant differences were noted between the 5-year rates of subsequent intervention, additional laminectomy, or fusion among patients who had undergone index decompression and fusion (n = 51; 10.5%) versus decompression alone (n = 43; 8.8%; P = 0.39). Furthermore, no significant differences were found in the odds of intervention type after index decompression and fusion versus decompression alone (subsequent laminectomy: odds ratio, 0.59; 95% confidence interval, 0.32-1.09; subsequent fusion: odds ratio, 1.14; 95% confidence interval, 0.64-2.02). CONCLUSIONS: Patient-specific factors and surgeon-patient-shared decision-making should be used when planning interventions for these lesions. However, synovial cysts might not require a fusion procedure for presumed instability. Further investigation is required, using randomized and prospective studies, to further evaluate the effective treatment of this entity.

The role of neurosurgery in the management of tuberous sclerosis complex-associated epilepsy: a systematic review.

OBJECTIVE: Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem neurocutaneous disorder associated with cortical tubers, brain lesions seen in nearly all patients with TSC, which are frequently epileptogenic. Seizures are often the earliest clinical manifestation of TSC, leading to epilepsy in over 70% of patients. Medical management with antiepileptic drugs constitutes early therapy, but over 50% develop medically refractory epilepsy, necessitating surgical evaluation and treatment. The objective of this study was to summarize the literature and report seizure outcomes following surgical treatment for TSC-associated epilepsy. METHODS: A systematic literature review was performed in accordance with the PRISMA guidelines. The PubMed and Embase databases were searched for journal articles reporting seizure outcomes following epilepsy surgery in TSC patients. Included studies were placed into one of two groups based on the surgical technique used. Excellent and worthwhile seizure reductions were defined for each group as outcomes and extracted from each study. RESULTS: A total of 46 studies were included. Forty of these studies reported seizure outcomes following any combination of resection, disconnection, and ablation on a collective 1157 patients. Excellent and worthwhile seizure reductions were achieved in 59% (683/1157) and 85% (450/528) of patients, respectively. Six of these studies reported seizure outcomes following treatment with neuromodulation. Excellent and worthwhile seizure reductions were achieved in 34% (24/70) and 76% (53/70) of patients, respectively. CONCLUSIONS: Surgery effectively controls seizures in select patients with TSC-associated epilepsy, but outcomes vary. Further understanding of TSC-associated epilepsy, improving localization strategies, and emerging surgical techniques represent promising avenues for improving surgical outcomes.

Comparison of Using Intraoperative Computed Tomography-Based 3-Dimensional Navigation and Fluoroscopy in Anterior Cervical Diskectomy and Fusion for Cervical Spondylosis.

OBJECTIVE: Anterior cervical diskectomy and fusion (ACDF) is a highly successful procedure to treat spinal cord or nerve root compression; however, complications can still occur. With advancements in imaging, 3-dimensional (3D) reconstruction allows real-time instrument tracking in a surgical field relative to the patient's anatomy. Here, we compare plate positioning and short-term outcomes when using 3D navigation to fluoroscopy in ACDF for degenerative spine disease. METHODS: All ACDFs for cervical spondylosis performed by 6 surgeons at a single center between 2010 and 2018 were included. ACDFs were divided into those performed using 3D navigation or fluoroscopy. Records were assessed for patient demographics, American Society of Anesthesiology score, number of operated interspaces, operative time, length of stay, perioperative complications, and 90-day readmissions. Postoperative images were reviewed for lateral and angular plate deviations. RESULTS: A total of 193 ACDFs performed with 3D navigation and 728 performed with fluoroscopy were included. After controlling for demographics and surgical characteristics, using 3D navigation was associated with less lateral plate deviation (P = 0.048) and longer operative times per interspace (P < 0.001) but was not associated with angular plate deviation (P = 0.724), length of stay (P = 0.393), perioperative complications (P = 0.844), and 90-day readmissions (P = 0.539). CONCLUSIONS: Using 3D navigation in ACDF for degenerative disease is associated with slightly more midline plate positioning and comparable short-term outcomes as using fluoroscopy and can be a suitable alternative. Advantages of using this technology, such as improved visualization of anatomy, should be weighed against disadvantages, such as increased operative time, on a per-patient basis.

Clinical Utility of the Transthoracic Echocardiogram for Isolated Lacunar Infarcts: A Single-Center Experience.

BACKGROUND: Stroke is a prominent and financially burdensome disease. Lacunar strokes are traditionally attributed to small vessel disease rather than cardioemboli, which typically occlude larger arteries. Thus, the benefit of screening for potential sources of cardioemboli in lacunar stroke patients is unclear. We evaluated the clinical utility of the transthoracic echocardiogram performed in patients with lacunar strokes. METHODS: A single-center retrospective analysis of ischemic stroke patients from January 2013 through December 2017 was performed. Brain magnetic resonance imaging was used to select patients with a single lacunar infarct. Patients presenting with acute symptoms of cardiac disease or an abnormal electrocardiogram were excluded. Transthoracic echocardiogram results were reviewed, and their utility in decision-making was evaluated. RESULTS: Of the 442 patients at our institution diagnosed with ischemic stroke during the inclusion period, 89 met inclusion criteria. Transthoracic echocardiogram detected a patent foramen ovale in 5.6% of patients, mitral annular calcification in 9.0% of patients, and abnormal wall motion in 4.5% of patients. For all patients, there were no findings that prompted anticoagulation, antibiotic, or surgical intervention. The cost of an inpatient transthoracic echocardiogram is $4100, resulting in $364,900 in unnecessary health care spending. CONCLUSIONS: Transthoracic echocardiogram appears to have minimal therapeutic value in most patients with lacunar strokes. In stroke patients with no acute symptoms of cardiac disease and a normal electrocardiogram, it may be reasonable to forgo the transthoracic echocardiogram if the brain magnetic resonance imaging shows an isolated lacunar infarct.

Portable, open-source solutions for estimating wrist position during reaching in people with stroke.

Arm movement kinematics may provide a more sensitive way to assess neurorehabilitation outcomes than existing metrics. However, measuring arm kinematics in people with stroke can be challenging for traditional optical tracking systems due to non-ideal environments, expense, and difficulty performing required calibration. Here, we present two open-source methods, one using inertial measurement units (IMUs) and another using virtual reality (Vive) sensors, for accurate measurements of wrist position with respect to the shoulder during reaching movements in people with stroke. We assessed the accuracy of each method during a 3D reaching task. We also demonstrated each method's ability to track two metrics derived from kinematics-sweep area and smoothness-in people with chronic stroke. We computed correlation coefficients between the kinematics estimated by each method when appropriate. Compared to a traditional optical tracking system, both methods accurately tracked the wrist during reaching, with mean signed errors of 0.09 ± 1.81 cm and 0.48 ± 1.58 cm for the IMUs and Vive, respectively. Furthermore, both methods' estimated kinematics were highly correlated with each other (p < 0.01). By using relatively inexpensive wearable sensors, these methods may be useful for developing kinematic metrics to evaluate stroke rehabilitation outcomes in both laboratory and clinical environments.

Megestrol acetate is a specific inducer of CYP3A4 mediated by human pregnane X receptor.

PURPOSE: Megestrol acetate is a synthetic progestogen used to treat some cancers and cancer-associated cachexia, but its potential interactions with other drugs are not well known. This study aims to determine the regulation of drug metabolizing enzymes by megestrol acetate. METHODS: Primary human hepatocytes were treated and analyzed by PCR array to identify genes involved in drug metabolism that are impacted by megestrol acetate. P450 3A4 (CYP3A4) reporter gene assay and HPLC analyses of nifedipine metabolites were used to determine CYP3A4 gene expression and activities. Competitive ligand binding assay was used to determine the affinity of megestrol acetate toward human pregnane x receptor (hPXR). Electrophoretic mobility shift assay and mammalian two hybrid assay were used to determine the mechanism of megestrol to activate hPXR. RESULTS: The levels and activities of CYP3A4 were significantly induced (> 4-folds) by megestrol acetate in human hepatocytes and HepG2 cells. Megestrol treatment induced CYP3A4 through the activation of hPXR, a ligand-activated transcription factor that plays a role in drug metabolism and transport. Other tested nuclear receptors showed no response. The mechanism studies showed that megestrol activated hPXR by binding to the ligand binding domain (LBD) of hPXR and increasing the recruitment of the cofactors such as steroid receptor cofactor (SRC-1). CONCLUSION: The results suggest that megestrol acetate is a specific inducer of CYP3A4 mediated by hPXR and therefore has the potential to cause drug interactions, especially in the co-administration with drugs that are substrates of CYP3A4.

Utility of Head Computed Tomography Scans Before Outpatient Follow-up for Low-Risk Mild Traumatic Brain Injury.

BACKGROUND: Neurosurgeons are frequently consulted for traumatic brain injuries (TBIs) resulting in intracranial hemorrhage (ICH). After inpatient confirmation of hemorrhage stability, outpatient head computed tomography (CT) is often performed to assess for hemorrhage resolution. Our objective was to assess the practice patterns and clinical utility of routine outpatient head CT scans for patients with mild TBI (mTBI). MATERIALS AND METHODS: A retrospective review was performed on all adult mTBI patients with ICH who presented to a level I trauma center over a 4-year period. A combination of the patient's initial clinical evaluation and CT findings was used to identify mTBI patients at low risk for neurologic deterioration and neurosurgical intervention. Findings from the outpatient follow-up clinical evaluation and head CT were assessed. Patients without outpatient follow-up within 3 months were excluded. RESULTS: Forty-nine patients met inclusion criteria for the study. Thirty-two had an outpatient head CT before their follow-up appointment. Twenty-one patients had at least 1 neurologic finding at the earliest follow-up appointment. All patients except those with a subdural hematoma (SDH) had smaller or resolving ICH on outpatient CT scans. Seven patients with an SDH had unchanged or expanded hemorrhage on outpatient imaging, 2 of whom had traumatic brain injury-related hospitalizations and 1 of whom underwent neurosurgical intervention due to an enlarging SDH. CONCLUSIONS: Routine outpatient head CT scans before follow-up for low-risk mTBI patients without an SDH appears to have limited clinical utility. In low-risk mTBI patients with an SDH, obtaining an outpatient head CT is reasonable to monitor for resolution.

Assessing the efficacy of mild traumatic brain injury management.

OBJECTIVE: Intracranial hemorrhage (ICH) is frequently found on computed tomography (CT) after mild traumatic brain injury (mTBI) prompting transfer to centers with neurosurgical coverage and repeat imaging to confirm hemorrhage stability. Studies suggest routine repeat imaging has little utility in patients with minimal ICH, no anticoagulant/antiplatelet use, and no neurological decline. Additionally, it is unclear which mTBI patients benefit from transfer for neurosurgery consultation. The authors sought to assess the clinical utility and cost effectiveness of routine repeat head CTs and transfer to tertiary centers in patients with low-risk, mTBI. METHODS: Retrospective evaluation of patients receiving a neurosurgical consultation for TBI during a 4-year period was performed at a level 1 trauma center. Patients were stratified according to risk for neurosurgical intervention based on their initial clinical evaluation and head CT. Only patients with low-risk, mTBI were included. RESULTS: Of 531 patients, 119 met inclusion criteria. Eighty-eight (74.0 %) received two or more CTs. Direct cost of repeat imaging was $273,374. Thirty-seven (31.1 %) were transferred to our facility from hospitals without neurosurgical coverage, costing $61,384. No patient had neurosurgical intervention or mTBI-related in-hospital mortality despite enlarging ICH on repeat CT in three patients. Two patients had mTBI related 30-day readmission for seizure without ICH expansion. CONCLUSION: Routine repeat head CT or transfer of low-risk, mTBI patients to a tertiary center did not result in neurosurgical intervention. Serial neurological examinations may be a safe, cost-effective alternative to repeat imaging for select mTBI patients. A large prospective analysis is warranted for further evaluation.