Informed Consent for Spine Procedures: Best Practice Guideline from the American Society of Pain and Neuroscience (ASPN).

Introduction: The evolution of treatment options for painful spinal disorders in diverse settings has produced a variety of approaches to patient care among clinicians from multiple professional backgrounds. The American Society of Pain and Neuroscience (ASPN) Best Practice group identified a need for a multidisciplinary guideline regarding appropriate and effective informed consent processes for spine procedures. Objective: The ASPN Informed Consent Guideline was developed to provide clinicians with a comprehensive evaluation of patient consent practices during the treatment of spine pathology. Methods: After a needs assessment, ASPN determined that best practice regarding proper informed consent for spinal procedures was needed and a process of selecting faculty was developed based on expertise, diversity, and knowledge of the subject matter. A comprehensive literature search was conducted and when appropriate, evidence grading was performed. Recommendations were based on evidence when available, and when limited, based on consensus opinion. Results: Following a comprehensive review and analysis of the available evidence, the ASPN Informed Consent Guideline group rated the literature to assist with specification of best practice regarding patient consent during the management of spine disorders. Conclusion: Careful attention to informed consent is critical in achieving an optimal outcome and properly educating patients. This process involves a discussion of risks, advantages, and alternatives to treatment. As the field of interventional pain and spine continues to grow, it is imperative that clinicians effectively educate patients and obtain comprehensive informed consent for invasive procedures. This consent should be tailored to the patient's specific needs to ensure an essential recognition of patient autonomy and reasonable expectations of treatment.

Plaque attack by microglial PLCγ2.

PLCγ2 is genetically linked to Alzheimer's disease (AD), but it is unclear how PLCγ2 contributes to pathology. Tsai et al. demonstrate that AD-associated PLCG2 variants bidirectionally orchestrate microglial responses to plaques and impact neural function in an AD mouse model. This positions PLCγ2 as a key microglial signaling node and shows that targeting PLCγ2 could have therapeutic benefits in AD.

Microglia ferroptosis is regulated by SEC24B and contributes to neurodegeneration.

Iron dysregulation has been implicated in multiple neurodegenerative diseases, including Parkinson's disease (PD). Iron-loaded microglia are frequently found in affected brain regions, but how iron accumulation influences microglia physiology and contributes to neurodegeneration is poorly understood. Here we show that human induced pluripotent stem cell-derived microglia grown in a tri-culture system are highly responsive to iron and susceptible to ferroptosis, an iron-dependent form of cell death. Furthermore, iron overload causes a marked shift in the microglial transcriptional state that overlaps with a transcriptomic signature found in PD postmortem brain microglia. Our data also show that this microglial response contributes to neurodegeneration, as removal of microglia from the tri-culture system substantially delayed iron-induced neurotoxicity. To elucidate the mechanisms regulating iron response in microglia, we performed a genome-wide CRISPR screen and identified novel regulators of ferroptosis, including the vesicle trafficking gene SEC24B. These data suggest a critical role for microglia iron overload and ferroptosis in neurodegeneration.

Best Practices for Postoperative Management of Posterior Sacroiliac Joint Fusion.

Sacroiliac joint (SIJ) pain is a common cause of low back pain. Traditionally, treatment for SIJ joint pain and dysfunction has consisted of physical therapy, medication management, SIJ injections, and SIJ ablations. Improved recognition of the SIJ as an etiology for back pain has led to advances in treatment options. Radiofrequency of the lateral sacral branches has been shown to be effective, though evidence is fraught with inconsistent patient selection, study design and procedural technique. It also does not directly address the mechanical dysfunction of the SIJ. In order to create a more enduring approach SIJ fusion has become an attractive option to reduce pain and to improve function. This method of SI joint treatment requires guidance in the perioperative phase of care from both the physicians and advanced practice providers (APP). In order to improve care and outcomes of those undergoing posterior SI joint fusion the American Society of Pain and Neuroscience appointed an expert panel of physicians and advanced practice providers to create a best practice for the post operative care of this approach. As with any best practice, the panel considered current peer reviewed literature and clinical expertise to create guidance today. This is intended to be a living document with modifications as additional evidence comes to light in data publication. The goals of this paper are to focus on (1) wound care, (2) medication use, (3) physical activity and (4) therapeutic exercises.

An Observational Study of Intraoperative Neuromonitoring as a Safety Mechanism in Placement of Percutaneous Dorsal Root Ganglion Stimulation and Spinal Cord Stimulation Systems.

INTRODUCTION: Percutaneous neurostimulator device placement, specifically dorsal root ganglion (DRG) stimulation and spinal cord stimulation (SCS), involves the placement of thin wires within the spinal canal at specific locations, the DRG or dorsal column of the spinal cord, respectively, to provide an electrical current that modifies the pain signal as it enters the central nervous system from the periphery. Placement of neurostimulator devices is generally safe overall, but not without risk of major and minor complications. In this study, we assess the use of intraoperative neuromonitoring (IONM) as a tool to improve the safety of placing neurostimulator devices and subsequently minimizing postoperative complications. METHODS: After IRB approval, an observational study was performed in 115 procedures to evaluate safety during placement of both temporary and permanent DRG and SCS systems and to document retrospectively any long-standing adverse events. RESULTS: The rate of intraoperative neuromonitoring abnormal activity was 1.7% (n = 2), which allowed prompt recognition of nerve irritation and lead repositioning. Of the 115 consecutive implant cases performed with IONM, the postoperative minor adverse event rate was 1.7% (n = 2), which were transient and corrected with reprogramming. There were no long-standing neurological complications. CONCLUSION: In the largest observational study to date, we show that IONM creates a safe environment for patients undergoing SCS and DRG neurostimulator placement with the potential to decrease neurological complication rates. The use of IONM may be an alternative method to improve patient safety and outcomes as compared to monitor anesthesia care.

The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation.

Schizophrenia is a disorder with a heterogeneous etiology involving complex interplay between genetic and environmental risk factors. The immune system is now known to play vital roles in nervous system function and pathology through regulating neuronal and glial development, synaptic plasticity, and behavior. In this regard, the immune system is positioned as a common link between the seemingly diverse genetic and environmental risk factors for schizophrenia. Synthesizing information about how the immune-brain axis is affected by multiple factors and how these factors might interact in schizophrenia is necessary to better understand the pathogenesis of this disease. Such knowledge will aid in the development of more translatable animal models that may lead to effective therapeutic interventions. Here, we provide an overview of the genetic risk factors for schizophrenia that modulate immune function. We also explore environmental factors for schizophrenia including exposure to pollution, gut dysbiosis, maternal immune activation and early-life stress, and how the consequences of these risk factors are linked to microglial function and dysfunction. We also propose that morphological and signaling deficits of the blood-brain barrier, as observed in some individuals with schizophrenia, can act as a gateway between peripheral and central nervous system inflammation, thus affecting microglia in their essential functions. Finally, we describe the diverse roles that microglia play in response to neuroinflammation and their impact on brain development and homeostasis, as well as schizophrenia pathophysiology.

A Pipeline using Bilateral In Utero Electroporation to Interrogate Genetic Influences on Rodent Behavior.

As genome-wide association studies shed light on the heterogeneous genetic underpinnings of many neurological diseases, the need to study the contribution of specific genes to brain development and function increases. Relying on mouse models to study the role of specific genetic manipulations is not always feasible since transgenic mouse lines are quite costly and many novel disease-associated genes do not yet have commercially available genetic lines. Additionally, it can take years of development and validation to create a mouse line. In utero electroporation offers a relatively quick and easy method to manipulate gene expression in a cell-type specific manner in vivo that only requires developing a DNA plasmid to achieve a particular genetic manipulation. Bilateral in utero electroporation can be used to target large populations of frontal cortex pyramidal neurons. Combining this gene transfer method with behavioral approaches allows one to study the effects of genetic manipulations on the function of prefrontal cortex networks and the social behavior of juvenile and adult mice.

Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction.

Schizophrenia is a severe mental disorder with an unclear pathophysiology. Increased expression of the immune gene C4 has been linked to a greater risk of developing schizophrenia; however, it is not known whether C4 plays a causative role in this brain disorder. Using confocal imaging and whole-cell electrophysiology, we demonstrate that overexpression of C4 in mouse prefrontal cortex neurons leads to perturbations in dendritic spine development and hypoconnectivity, which mirror neuropathologies found in schizophrenia patients. We find evidence that microglia-mediated synaptic engulfment is enhanced with increased expression of C4. We also show that C4-dependent circuit dysfunction in the frontal cortex leads to decreased social interactions in juvenile and adult mice. These results demonstrate that increased expression of the schizophrenia-associated gene C4 causes aberrant circuit wiring in the developing prefrontal cortex and leads to deficits in juvenile and adult social behavior, suggesting that altered C4 expression contributes directly to schizophrenia pathogenesis.

ErbB2 and p38γ MAPK mediate alcohol-induced increase in breast cancer stem cells and metastasis.

BACKGROUND: Both epidemiological and experimental studies suggest that excessive alcohol exposure increases the risk for breast cancer and enhances metastasis/recurrence. We have previously demonstrated that alcohol enhanced the migration/invasion of breast cancer cells and cancer cells overexpressing ErbB2/HER2 were more sensitive to alcohol exposure. However, the underlying mechanisms remain unclear. This study was designed to investigate the mechanisms underlying alcohol-enhanced aggressiveness of breast cancer. Cancer stem cells (CSCs) play a critical role in cancer metastasis and recurrence. METHODS: We evaluated the effect of chronic alcohol exposure on mammary tumor development/metastasis in MMTV-neu transgenic mice and investigated the cell signaling in response to alcohol exposure in breast cancer cells overexpressing ErbB2/HER2. RESULTS AND DISCUSSION: Chronic alcohol exposure increased breast cancer stem cell-like CSC population and enhanced the lung and colon metastasis in MMTV-neu transgenic mice. Alcohol exposure caused a drastic increase in CSC population and mammosphere formation in breast cancer cells overexpressing ErbB2/HER2. Alcohol exposure stimulated the phosphorylation of p38γ MAPK (p-p38γ) which was co-localized with phosphorylated ErbB2 and CSCs in the mammary tumor tissues. In vitro results confirmed that alcohol activated ErbB2/HER2 and selectively increased p-p38γ MAPK as well as the interaction between p38γ MAPK and its substrate, SAP97. However, alcohol did not affect the expression/phosphorylation of p38α/ß MAPKs. In breast cancer cell lines, high expression of ErbB2 and p-p38γ MAPK was generally correlated with more CSC population. Blocking ErbB2 signaling abolished heregulin ß1- and alcohol-stimulated p-p38γ MAPK and its association with SAP97. More importantly, p38γ MAPK siRNA significantly inhibited an alcohol-induced increase in CSC population, mammosphere formation and migration/invasion of breast cancer cells overexpressing ErbB2. CONCLUSIONS: p38γ MAPK is downstream of ErbB2 and plays an important role in alcohol-enhanced aggressiveness of breast cancer. Therefore, in addition to ErbB2/HER2, p38γ MAPK may be a potential target for the treatment of alcohol-enhanced cancer aggressiveness.

Ambient temperature influences the neural benefits of exercise.

Many of the neural benefits of exercise require weeks to manifest. It would be useful to accelerate onset of exercise-driven plastic changes, such as increased hippocampal neurogenesis. Exercise represents a significant challenge to the brain because it produces heat, but brain temperature does not rise during exercise in the cold. This study tested the hypothesis that exercise in cold ambient temperature would stimulate hippocampal neurogenesis more than exercise in room or hot conditions. Adult female rats had exercise access 2h per day for 5 days at either room (20 °C), cold (4.5 °C) or hot (37.5 °C) temperature. To label dividing hippocampal precursor cells, animals received daily injections of BrdU. Brains were immunohistochemically processed for dividing cells (Ki67+), surviving cells (BrdU+) and new neurons (doublecortin, DCX) in the hippocampal dentate gyrus. Animals exercising at room temperature ran significantly farther than animals exercising in cold or hot conditions (room 1490 ± 400 m; cold 440 ± 102 m; hot 291 ± 56 m). We therefore analyzed the number of Ki67+, BrdU+ and DCX+ cells normalized for shortest distance run. Contrary to our hypothesis, exercise in either cold or hot conditions generated significantly more Ki67+, BrdU+ and DCX+ cells compared to exercise at room temperature. Thus, a limited amount of running in either cold or hot ambient conditions generates more new cells than a much greater distance run at room temperature. Taken together, our results suggest a simple means by which to augment exercise effects, yet minimize exercise time.

Tunicamycin-induced unfolded protein response in the developing mouse brain.

Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) causes ER stress, resulting in the activation of the unfolded protein response (UPR). ER stress and UPR are associated with many neurodevelopmental and neurodegenerative disorders. The developing brain is particularly susceptible to environmental insults which may cause ER stress. We evaluated the UPR in the brain of postnatal mice. Tunicamycin, a commonly used ER stress inducer, was administered subcutaneously to mice of postnatal days (PDs) 4, 12 and 25. Tunicamycin caused UPR in the cerebral cortex, hippocampus and cerebellum of mice of PD4 and PD12, which was evident by the upregulation of ATF6, XBP1s, p-eIF2α, GRP78, GRP94 and MANF, but failed to induce UPR in the brain of PD25 mice. Tunicamycin-induced UPR in the liver was observed at all stages. In PD4 mice, tunicamycin-induced caspase-3 activation was observed in layer II of the parietal and optical cortex, CA1-CA3 and the subiculum of the hippocampus, the cerebellar external germinal layer and the superior/inferior colliculus. Tunicamycin-induced caspase-3 activation was also shown on PD12 but to a much lesser degree and mainly located in the dentate gyrus of the hippocampus, deep cerebellar nuclei and pons. Tunicamycin did not activate caspase-3 in the brain of PD25 mice and the liver of all stages. Similarly, immature cerebellar neurons were sensitive to tunicamycin-induced cell death in culture, but became resistant as they matured in vitro. These results suggest that the UPR is developmentally regulated and the immature brain is more susceptible to ER stress.