Spatial transcriptomics at the brain-electrode interface in rat motor cortex and the relationship to recording quality.

Study of the foreign body reaction to implanted electrodes in the brain is an important area of research for the future development of neuroprostheses and experimental electrophysiology. After electrode implantation in the brain, microglial activation, reactive astrogliosis, and neuronal cell death create an environment immediately surrounding the electrode that is significantly altered from its homeostatic state. To uncover physiological changes potentially affecting device function and longevity, spatial transcriptomics was implemented to identify changes in gene expression driven by electrode implantation and compare this differential gene expression to traditional metrics of glial reactivity, neuronal loss, and electrophysiological recording quality. For these experiments, rats were chronically implanted with functional Michigan-style microelectrode arrays, from which electrophysiological recordings (multi-unit activity, local field potential) were taken over a six-week time course. Brain tissue cryosections surrounding each electrode were then mounted for spatial transcriptomics processing. The tissue was immunolabeled for neurons and astrocytes, which provided both a spatial reference for spatial transcriptomics and a quantitative measure of glial fibrillary acidic protein (GFAP) and neuronal nuclei (NeuN) immunolabeling surrounding each implant. Results from rat motor cortex within 300µm of the implanted electrodes at 24 hours, 1 week, and 6 weeks post-implantation showed up to 553 significantly differentially expressed (DE) genes between implanted and non-implanted tissue sections. Regression on the significant DE genes identified the 6-7 genes that had the strongest relationship to histological and electrophysiological metrics, revealing potential candidate biomarkers of recording quality and the tissue response to implanted electrodes .

Postoperative Adjacent Segment Disease in Minimally Invasive Transforaminal Lumbar Interbody Fusion with Adjacent Laminectomy for Grade I-II Spondylolisthesis and Adjacent Spinal Stenosis.

BACKGROUND AND OBJECTIVES: Studies have demonstrated increased risk of adjacent segment disease (ASD) after open fusion with adjacent-level laminectomy, with rates ranging from 16%-47%, potentially related to disruption of the posterior ligamentous complex. Minimally invasive surgical (MIS) approaches may offer a more durable result. We report institutional outcomes of simultaneous MIS transforaminal lumbar interbody fusion (MISTLIF) and adjacent-level laminectomy for patients with low grade spondylolisthesis and ASD. METHODS: Retrospective analysis was performed on patients who underwent MISTLIF with adjacent level laminectomy to treat grade I-II spondylolisthesis with adjacent stenosis at a single institution from 2007-2022. RESULTS: A total of 34 patients met criteria, with mean follow-up of 23.1 months. In total, 37 levels were fused and 45 laminectomies performed. In this group, 21 patients received a single level laminectomy and single-level MISTLIF, 10 patients received a 2-level laminectomy and single-level MISTLIF, 2 patients received a single-level laminectomy and 2-level MISTLIF, and 1 patient received a 2-level laminectomy and 2-level MISTLIF. Three (8.8%) patients experienced clinically significant postoperative ASD requiring reoperation. Three other patients required reoperation for other reasons. Multiple logistic regression did not reveal any association between development of ASD and surgical covariates. CONCLUSION: MISTLIF with adjacent-level laminectomy demonstrated a favorable safety profile with rates of postoperative ASD lower than published rates after open fusion and on par with the published rates of ASD from MISTLIF alone. Future prospective studies may better elucidate the durability of adjacent-level laminectomies when performed alongside MISTLIF, but retrospective data suggests it is safe and durable.

Growing Medical Educators from Medical Students by Supporting Self-directing Learning Opportunities Born Out of Cadaveric Dissection.

This study focuses on a subset of medical students who participated in an anatomy dissection program and undertook an additional self-directed learning (SDL) project investigating incidental findings of cadaveric pathology. The value of SDL activity is explored as a means of enhancing medical student education, particularly its student perceived value in preparing and developing them as future medical educators. It was assessed whether the project advanced student interest in medical education by analyzing their motivations for participation. The results of the study highlight the potential of SDL as an experiential learning opportunity for medical students and the role of anatomic pathology in connecting multiple domains of medical education.

Gene Expression Changes in Cultured Reactive Rat Astrocyte Models and Comparison to Device-Associated Effects in the Brain.

Implanted microelectrode arrays hold immense therapeutic potential for many neurodegenerative diseases. However, a foreign body response limits long-term device performance. Recent literature supports the role of astrocytes in the response to damage to the central nervous system (CNS) and suggests that reactive astrocytes exist on a spectrum of phenotypes, from beneficial to neurotoxic. The goal of our study was to gain insight into the subtypes of reactive astrocytes responding to electrodes implanted in the brain. In this study, we tested the transcriptomic profile of two reactive astrocyte culture models (cytokine cocktail or lipopolysaccharide, LPS) utilizing RNA sequencing, which we then compared to differential gene expression surrounding devices inserted into rat motor cortex via spatial transcriptomics. We interpreted changes in the genetic expression of the culture models to that of 24 hour, 1 week and 6 week rat tissue samples at multiple distances radiating from the injury site. We found overlapping expression of up to ∼250 genes between in vitro models and in vivo effects, depending on duration of implantation. Cytokine-induced cells shared more genes in common with chronically implanted tissue (≥1 week) in comparison to LPS-exposed cells. We revealed localized expression of a subset of these intersecting genes (e.g., Serping1, Chi3l1, and Cyp7b1) in regions of device-encapsulating, glial fibrillary acidic protein (GFAP)-expressing astrocytes identified with immunohistochemistry. We applied a factorization approach to assess the strength of the relationship between reactivity markers and the spatial distribution of GFAP-expressing astrocytes in vivo . We also provide lists of hundreds of differentially expressed genes between reactive culture models and untreated controls, and we observed 311 shared genes between the cytokine induced model and the LPS-reaction induced control model. Our results show that comparisons of reactive astrocyte culture models with spatial transcriptomics data can reveal new biomarkers of the foreign body response to implantable neurotechnology. These comparisons also provide a strategy to assess the development of in vitro models of the tissue response to implanted electrodes.

SPARED Collaboration: Patient Selection for Partial Gland Ablation in Men with Localized Prostate Cancer.

PURPOSE: The SPARED CRN (Study of Prostate Ablation Related Energy Devices Coordinated Registry Network) is a private-public partnership between academic and community urologists, the FDA (U.S. Food and Drug Administration), the Medical Device Epidemiology Network and device manufacturers to examine the safety and effectiveness of technologies for partial gland ablation in men with localized prostate cancer. MATERIALS AND METHODS: We report on a recent workshop at the FDA with thought leaders to discuss a critical framework for partial gland ablation, focusing on patient selection, surgical planning, followup, study design and appropriate comparators in terms of adverse events and cancer control outcomes. We summarize salient points from experts in urology, oncology and epidemiology that were presented and discussed in an open forum. RESULTS: Given the challenges in achieving patient and physician equipoise to perform a randomized trial, as well as an inherent paradigm shift when comparing partial gland ablation (inability to assess prostate specific antigen recurrence) to whole gland treatments, the group focused on objective performance criteria and goals as a platform to guide the creation of single arm studies in the SPARED CRN. CONCLUSIONS: This summit lays the foundation for prospective, multi-center data collection and evaluation of novel medical devices and drug/device combinations for partial gland ablation.

Development of a Nationally Representative Coordinated Registry Network for Prostate Ablation Technologies.

PURPOSE: The accumulation of data through a prospective, multicenter coordinated registry network is a practical way to gather real world evidence on the performance of novel prostate ablation technologies. Urological oncologists, targeted biopsy experts, industry representatives and representatives of the FDA (Food and Drug Administration) convened to discuss the role, feasibility and important data elements of a coordinated registry network to assess new and existing prostate ablation technologies. MATERIALS AND METHODS: A multiround Delphi consensus approach was performed which included the opinion of 15 expert urologists, representatives of the FDA and leadership from high intensity focused ultrasound device manufacturers. Stakeholders provided input in 3 consecutive rounds with conference calls following each round to obtain consensus on remaining items. Participants agreed that these elements initially developed for high intensity focused ultrasound are compatible with other prostate ablation technologies. Coordinated registry network elements were reviewed and supplemented with data elements from the FDA common study metrics. RESULTS: The working group reached consensus on capturing specific patient demographics, treatment details, oncologic outcomes, functional outcomes and complications. Validated health related quality of life questionnaires were selected to capture patient reported outcomes, including the IIEF-5 (International Index of Erectile Function-5), the I-PSS (International Prostate Symptom Score), the EPIC-26 (Expanded Prostate Cancer Index Composite-26) and the MSHQ-EjD (Male Sexual Health Questionnaire for Ejaculatory Dysfunction). Group consensus was to obtain followup multiparametric magnetic resonance imaging and prostate biopsy approximately 12 months after ablation with additional imaging or biopsy performed as clinically indicated. CONCLUSIONS: A national prostate ablation coordinated registry network brings forth vital practice pattern and outcomes data for this emerging treatment paradigm in the United States. Our multiple stakeholder consensus identifies critical elements to evaluate new and existing energy modalities and devices.