Structural connectivity changes in unilateral hearing loss.

Network connectivity, as mapped by the whole brain connectome, plays a crucial role in regulating auditory function. Auditory deprivation such as unilateral hearing loss might alter structural network connectivity; however, these potential alterations are poorly understood. Thirty-seven acoustic neuroma patients with unilateral hearing loss (19 left-sided and 18 right-sided) and 19 healthy controls underwent diffusion-weighted and T1-weighted imaging to assess edge strength, node strength, and global efficiency of the structural connectome. Edge strength was estimated by pair-wise normalized streamline density from tractography and connectomics. Node strength and global efficiency were calculated through graph theory analysis of the connectome. Pure-tone audiometry and word recognition scores were used to correlate the degree and duration of unilateral hearing loss with node strength and global efficiency. We demonstrate significantly stronger edge strength and node strength through the visual network, weaker edge strength and node strength in the somatomotor network, and stronger global efficiency in the unilateral hearing loss patients. No discernible correlations were observed between the degree and duration of unilateral hearing loss and the measures of node strength or global efficiency. These findings contribute to our understanding of the role of structural connectivity in hearing by facilitating visual network upregulation and somatomotor network downregulation after unilateral hearing loss.

Hippocampus diffusivity abnormalities in classical trigeminal neuralgia.

Introduction: Patients with chronic pain frequently report cognitive symptoms that affect memory and attention, which are functions attributed to the hippocampus. Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder characterized by paroxysmal attacks of unilateral orofacial pain. Given the stereotypical nature of TN pain and lack of negative symptoms including sensory loss, TN provides a unique model to investigate the hippocampal implications of chronic pain. Recent evidence demonstrated that TN is associated with macrostructural hippocampal abnormalities indicated by reduced subfield volumes; however, there is a paucity in our understanding of hippocampal microstructural abnormalities associated with TN. Objectives: To explore diffusivity metrics within the hippocampus, along with its functional and structural subfields, in patients with TN. Methods: To examine hippocampal microstructure, we utilized diffusion tensor imaging in 31 patients with TN and 21 controls. T1-weighted magnetic resonance images were segmented into hippocampal subfields and registered into diffusion-weighted imaging space. Fractional anisotropy (FA) and mean diffusivity were extracted for hippocampal subfields and longitudinal axis segmentations. Results: Patients with TN demonstrated reduced FA in bilateral whole hippocampi and hippocampal body and contralateral subregions CA2/3 and CA4, indicating microstructural hippocampal abnormalities. Notably, patients with TN showed significant correlation between age and hippocampal FA, while controls did not exhibit this correlation. These effects were driven chiefly by female patients with TN. Conclusion: This study demonstrates that TN is associated with microstructural hippocampal abnormalities, which may precede and potentially be temporally linked to volumetric hippocampal alterations demonstrated previously. These findings provide further evidence for the role of the hippocampus in chronic pain and suggest the potential for targeted interventions to mitigate cognitive symptoms in patients with chronic pain.

A Case Series of DuraMatrix-Onlay® Plus in Cranial Surgery Is Associated With a Low Complication Profile.

BACKGROUND: DuraMatrix-Onlay® Plus is a collagen dura membrane derived from purified bovine Achilles tendon. The matrix provides a scaffold for collagen synthesis and is intended to be used as an onlay without the need for dural sutures. The study aims to describe our experience with 33 consecutive patients who underwent a duraplasty procedure using the novel DuraMatrix-Onlay® Plus collagen dura membrane. METHODS: This is a retrospective case series of 33 patients who underwent a duraplasty procedure at a single academic hospital in Los Angeles, CA, USA between May 2016 and March 2017. The primary outcome was the incidence rate of cerebrospinal fluid (CSF) leak. Secondary outcomes included rates of patient infection, dural substitute complication, and removal. RESULTS: Thirty-three patients underwent a duraplasty procedure using the DuraMatrix-Onlay® Plus material. The average age of the patients was 41.12±7.34 years (range 2-75 years). There were 18 (54.5%) females and 15 (45.5%) males. The majority of procedures were elective operations for the resection of a lesion (n=19, 58%), and the average graft size was 17.69±4.73 cm². At an average follow-up of 3 months, there were no postoperative CSF leaks. The rates of patient infection, dural substitute complication, and removal were 6%, 6%, and 3%, respectively. CONCLUSION: DuraMatrix-Onlay® Plus is associated with a low rate of postoperative CSF leakage and an acceptable complication profile. This result supports the use of collagen matrices for dural closure in general neurosurgical procedures.

Effect of Enlarged Perivascular Spaces in Reliable Distinction of Prospective Targeting During Deep Brain Stimulation in Patients With Advanced Parkinson's Disease: A Study of Deterministic and Probabilistic Tractography.

BACKGROUND: Precise electrode position is vital for effective deep brain stimulation in treating motor symptoms in Parkinson's disease (PD). Enlarged perivascular spaces (PVSs) are associated with pathophysiology of neurodegenerative diseases including PD and may affect the microstructure of surrounding brain tissue. OBJECTIVE: To quantify the clinical implications of enlarged PVS on tractography-based stereotactic targeting in patients with advanced PD selected to undergo deep brain stimulation. METHODS: Twenty patients with PD underwent MRI scanning. The PVS areas were visualized and segmented. Based on the size of the PVS areas, the patient group was split into 2 categories of large vs small PVSs. Probabilistic and deterministic tractography methods were applied to a diffusion-weighted data set. Fiber assignment was performed using motor cortex as an initiation seed and the globus pallidus interna and subthalamic nucleus, separately, as inclusion masks. Two exclusion masks used consisted of cerebral peduncles and the PVS mask. The center of gravity of the tract density map was measured and compared between the tracts generated with and without consideration of the PVS mask. RESULTS: The average differences between the center of gravity of the tracts made by excluding PVS and without excluding PVS using deterministic and probabilistic tractography methods were less than 1 mm. Statistical analysis showed nonsignificant differences between deterministic and probabilistic methods and differences between patients with large and small PVSs ( P > .05). CONCLUSION: This study demonstrated that the presence of enlarged PVS is unlikely to affect targeting of basal ganglia nuclei based on tractography.

Exploring the Past, Present, and Future of Anti-Angiogenic Therapy in Glioblastoma.

Glioblastoma, a WHO grade IV astrocytoma, constitutes approximately half of malignant tumors of the central nervous system. Despite technological advancements and aggressive multimodal treatment, prognosis remains dismal. The highly vascularized nature of glioblastoma enables the tumor cells to grow and invade the surrounding tissue, and vascular endothelial growth factor-A (VEGF-A) is a critical mediator of this process. Therefore, over the past decade, angiogenesis, and more specifically, the VEGF signaling pathway, has emerged as a therapeutic target for glioblastoma therapy. This led to the FDA approval of bevacizumab, a monoclonal antibody designed against VEGF-A, for treatment of recurrent glioblastoma. Despite the promising preclinical data and its theoretical effectiveness, bevacizumab has failed to improve patients' overall survival. Furthermore, several other anti-angiogenic agents that target the VEGF signaling pathway have also not demonstrated survival improvement. This suggests the presence of other compensatory angiogenic signaling pathways that surpass the anti-angiogenic effects of these agents and facilitate vascularization despite ongoing VEGF signaling inhibition. Herein, we review the current state of anti-angiogenic agents, discuss potential mechanisms of anti-angiogenic resistance, and suggest potential avenues to increase the efficacy of this therapeutic approach.

Preoperative meningioma vascularity index is associated with significantly increased intraoperative blood loss and greater risk of subtotal resection.

OBJECTIVE: Surgical recovery of meningiomas relies on a variety of factors, including tumor volume, vascularity, embolization status, and blood loss during excision. Although hypervascular meningiomas can potentially be amendable to embolization, methods for determining optimal vascularity for this procedure are currently lacking. Our group previously established the meningioma vascularity index (MVI) as a marker of tumor vascularity. In this study, we aim to build on our previous work and further examine the relationship between MVI and intraoperative estimated blood loss (EBL). METHODS: A retrospective data extraction was conducted between August 2010 and October 2019 from patients undergoing craniotomy for meningioma. Of the 85 intracranial meningiomas included, 39 were embolized. Demographic data, extent of resection, embolization status, and EBL were among the extracted variables. Flow void volumes were measured on T2-weighted MRI images using a segmentation software with a voxel-based segmentation method. RESULTS: MVI was a predictor of EBL within the entire cohort, when controlling for tumor volume (R2 adjusted = 0.26; P = 0.027). A high MVI (> 2.01 cm3) was associated with higher likelihood of receiving subtotal resection (STR) (OR 4.07, 95% CI 1.17-14.15; P = 0.035). Although the mean MVI and tumor volume were higher in the embolized cohort (P = 0.009 and P = 0.005), there were no significant differences in EBL, or blood transfusion rates regardless of embolization status. CONCLUSIONS: MVI may be used as a non-invasive radiological marker to gauge meningioma vascularity, predict EBL, and guide the decision-making process when it comes to embolization and surgical planning.

Endoscopic endonasal approach for resection of a recurrent spheno-orbital meningioma resulting in complete resolution of visual symptoms: A case report and review of literature.

PURPOSE: Spheno-orbital meningiomas are rare tumors, accounting for up to 9% of all intracranial meningiomas. Patients commonly present with proptosis, and visual deficits. These slow growing tumors are hard to resect due to extension into several anatomical compartments, resulting in recurrence rates as high as 35-50%. Although open surgical approaches have been historically used for resection, a handful of endoscopic approaches have been reported in recent years. We aimed to review the literature and describe a case of spheno-orbital meningioma with severe vision loss which was resected with an endoscopic endonasal approach achieving complete resolution of visual symptoms. METHODS: A systematic review of literature was conducted in accordance with the PRISMA guidelines. PubMed, Cochrane, and Web of Science databases were queried for spheno-orbital meningiomas resected via an endoscopic endonasal approach. Furthermore, the presentation, surgical management, and post-operative outcomes of a 53-year-old female with a recurrent spheno-orbital meningioma are described. RESULTS: The search yielded 26 articles, of which 8 were included, yielding 19 cases. Average age at presentation was 60.5 years (range: 44-82), and 68.4% of patients were female. More than half of the cases achieved subtotal resection. Common complications associated with endoscopic endonasal surgery included CN V2 or CN V2/V3 hypoesthesia. Following surgical intervention, visual acuity and visual field remained stable or improved in the majority of the patients. CONCLUSION: Endoscopic approaches are slowly gaining momentum for treatment of spheno-orbital meningiomas. Further studies on the clinical benefits of this approach on patient outcomes and post-operative complications is warranted.

Evaluation of Superior Semicircular Canal Dehiscence Anatomical Location and Clinical Outcomes: A Single Institution's Experience.

BACKGROUND: Superior semicircular canal dehiscence (SSCD) is becoming increasingly recognized as a pathology underlying various auditory and vestibular complaints. To date, our understanding of the pathology has yet to attribute specific symptoms to the anatomic location of dehiscence in patients with SSCD. This study aims to address this issue by evaluating the relationship between symptomatology and anatomic location of dehiscence. METHODS: A single-institution retrospective review of SSCD patients was performed. Information was collected on patient demographics, symptomatology, and anatomic location of dehiscence. High-resolution computed tomography scans of the temporal bones were used to categorize the anatomic SSCD location into 1 of 3 groups: anterior limb, apex, and posterior limb. Lastly, we performed statistical analysis to determine the degree of association between each of the various perioperative factors and anatomic SSCD location. RESULTS: We studied 54 patients in total (32 women, 22 men). Mean age at diagnosis was 53 years (range: 20-82 years) and mean follow-up length was 5.5 months (range: 0.03-27.0 months). The most common anatomical location of superior semicircular canal dehiscence was the apex, which was seen in 68.5% of cases. While preoperative symptomatology was similar among the 3 cohorts, those with apical dehiscences had a significantly higher rate of postoperative improvement of autophony (P = 0.03), aural fullness (P = 0.03), and tinnitus (P = 0.05) as compared to their counterparts. CONCLUSIONS: Although our results do not support an association between preoperative characteristics-including symptomatology-and anatomic SSCD location, our findings do suggest that apical dehiscences are associated with greater postoperative symptomatic resolution.

The 100 Most Highly Cited Publications on Hearing Preservation for Vestibular Schwannomas.

OBJECTIVE: Vestibular schwannomas are benign, slow-growing tumors that often reduce patient quality of life by compressing nearby nerves. Neurological function preservation is one of the indicators of treatment success, with hearing preservation being the most difficult to obtain. This paper provides a bibliometric analysis of hearing preservation in treating acoustic neuromas and a greater understanding of the most highly cited articles, which have enhanced our understanding of this topic. METHODS: Key terms of "acoustic neuroma," "vestibular schwannoma," and "hearing preservation" were queried through Web of Science. Articles were sorted by citation frequency, and the top 100 articles were recorded for title, name of first author, journal title, year of publication, total number of citations (and associated rank), average number of citations per year, country of the first author's associated institution, and type of study. RESULTS: The top 100 cited articles were published from 1980 to 2014. The United States had the highest involvement as a country (55%), the University of Pittsburgh as an institution (13%), and The Journal of Neurosurgery as a publishing source (27%). Fourteen were reviews, and 86 were clinical papers. Of the 86, 73 were retrospective studies. CONCLUSION: Bibliometric analyses summarize and assess potential areas of strength and knowledge gaps within the literature. Studies on hearing preservation in vestibular schwannomas mostly consist of retrospective reviews that assess postoperative outcomes of microsurgery and radiosurgery. Prospective studies and novel treatment options for hearing preservation in vestibular schwannomas are needed to increase current literature diversity.

Assessment of Metabolic Markers and Osteoporosis in 250 Patients with Superior Semicircular Canal Dehiscence Treated With Middle Fossa Craniotomy.

BACKGROUND: Superior semicircular canal dehiscence (SSCD) is caused by bony defects in the osseous shell of the arcuate eminence separating the labyrinth and the intracranial space. This pathologic third window causes hydroacoustic transmission resulting in debilitating symptoms. We examine the pathophysiologic association between metabolic markers, previous medical history, and SSCD symptoms before and after middle fossa craniotomy (MFC) treatment. METHODS: This study was conducted between March 2011 and September 2020 with patients with SSCD who underwent MFC. We used a Fisher test to compare variables, including bilateral SSCD, second surgery, ear anomaly, osteoporosis, arthritis, vitamin D, and preoperative/postoperative symptoms, and others. Point-biserial correlation analysis was performed to test correlations between continuous variables and categorical variables. RESULTS: A total of 250 patients with SSCD underwent MFC repair. There was significant postoperative resolution in all symptoms (P < 0.0001). Laboratory 25-hydroxyvitamin D values correlated with preoperative aural fullness (rpb= 0.29; P = 0.03), and preoperative disequilibrium (rpb= -0.32; P = 0.02). Serum calcium values correlated with preoperative hearing loss (rpb= 0.16; P = 0.02). Osteoporosis history (n = 16; 6%) was more prevalent in female patients (P = 0.0001), associated with higher levels of preoperative hearing loss (odds ratio, 4.56; P = 0.02) and higher postoperative hearing loss resolution (odds ratio, 2.89; P = 0.0509). CONCLUSIONS: Certain metabolic markers may predict SSCD presentation before and after surgery. Previous history of osteoporosis, autoimmune conditions, or arthritis may play a role in SSCD pathophysiology and can help predict clinical outcomes. Future evaluation should take metabolic laboratory values and acquire an exact medical history.

Use of Functional MRI in Deep Brain Stimulation in Parkinson's Diseases: A Systematic Review.

Deep brain stimulation (DBS) has been used to modulate aberrant circuits associated with Parkinson's disease (PD) for decades and has shown robust therapeutic benefits. However, the mechanism of action of DBS remains incompletely understood. With technological advances, there is an emerging use of functional magnetic resonance imaging (fMRI) after DBS implantation to explore the effects of stimulation on brain networks in PD. This systematic review was designed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to summarize peer-reviewed articles published within the past 10 years in which fMRI was employed on patients with PD-DBS. Search in PubMed database provided 353 references, and screenings resulted in a total of 19 studies for qualitative synthesis regarding study designs (fMRI scan timepoints and paradigm), methodology, and PD subtypes. This review concluded that fMRI may be used in patients with PD-DBS after proper safety test; resting-state and block-based fMRI designs have been employed to explore the effects of DBS on brain networks and the mechanism of action of the DBS, respectively. With further validation of safety use of fMRI and advances in imaging techniques, fMRI may play an increasingly important role in better understanding of the mechanism of stimulation as well as in improving clinical care to provide subject-specific neuromodulation treatments.

The mitochondrial Nod-like receptor NLRX1 modifies apoptosis through SARM1.

NLRX1, the mitochondrial NOD-like receptor (NLR), modulates apoptosis in response to both intrinsic and extrinsic cues. Insights into the mechanism of how NLRX1 influences apoptosis remain to be determined. Here, we demonstrate that NLRX1 associates with SARM1, a protein with a toll/interleukin-1 receptor (TIR)-containing domain also found in adaptor proteins downstream of toll-like receptors, such as MyD88. While a direct role of SARM1 in innate immunity is unclear, the protein plays essential roles in Wallerian degeneration (WD), a type of neuronal catabolism occurring following axonal severing or damage. In non-neuronal cells, we found that endogenous SARM1 was equally distributed in the cytosol and the mitochondrial matrix, where association with NLRX1 occurred. In these cells, the apoptotic role of NLRX1 was fully dependent on SARM1, indicating that SARM1 was downstream of NLRX1 in apoptosis regulation. In primary murine neurons, however, Wallerian degeneration induced by vinblastine or NGF deprivation occurred in SARM1- yet NLRX1-independent manner, suggesting that WD requires the cytosolic pool of SARM1 or that NLRX1 levels in neurons are too low to contribute to WD regulation. Together, these results shed new light into the mechanisms through which NLRX1 controls apoptosis and provides evidence of a new link between NLR and TIR-containing proteins.

Mechanisms Associated with TDP-43 Neurotoxicity in ALS/FTLD.

The discovery of TDP-43 as a major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) was first made in 2006. Prior to 2006 there were only 11 publications related to TDP-43, now there are over 2000, indicating the importance of TDP-43 to unraveling the complex molecular mechanisms that underpin the pathogenesis of ALS/FTLD. Subsequent to this discovery, TDP-43 pathology was also found in other neurodegenerative diseases, including Alzheimer's disease, the significance of which is still in the early stages of exploration. TDP-43 is a predominantly nuclear DNA/RNA-binding protein, one of a number of RNA-binding proteins that are now known to be linked with ALS/FTLD, including Fused in Sarcoma (FUS), heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1). However, what sets TDP-43 apart is the vast number of cases in which TDP-43 pathology is present, providing a point of convergence, the understanding of which could lead to broadly applicable therapeutics. Here we will focus on TDP-43 in ALS/FTLD, its nuclear and cytoplasmic functions, and consequences should these functions go awry.

Unaffected mosaic C9orf72 case: RNA foci, dipeptide proteins, but upregulated C9orf72 expression.

OBJECTIVE: Suggested C9orf72 disease mechanisms for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration include C9orf72 haploinsufficiency, G4C2/C4G2 RNA foci, and dipeptide repeat (DPR) proteins translated from the G4C2 expansion; however, the role of small expansions (e.g., 30-90 repeats) is unknown and was investigated here. METHODS: We conducted a molecular and pathology study of a family in which the father (unaffected at age 90) carried a 70-repeat allele in blood DNA that expanded to ≈1,750 repeats in his children, causing ALS. RESULTS: Southern blotting revealed different degrees of mosaicism of small and large expansions in the father's tissues from the CNS. Surprisingly, in each mosaic tissue, C9orf72 mRNA levels were significantly increased compared to an ALS-affected daughter with a large expansion. Increased expression correlated with higher levels of the 70-repeat allele (the upregulation was also evident at the protein level). Remarkably, RNA foci and DPR burdens were similar or even significantly increased (in cerebellum) in the unaffected father compared to the daughter with ALS. However, the father did not display TDP-43 pathology and signs of neurodegeneration. CONCLUSION: The presence of RNA foci and DPR pathology was insufficient for disease manifestation and TDP-43 pathology in the mosaic C9orf72 carrier with upregulated C9orf72 expression. It is important to conduct an investigation of similar cases, which could be found among unaffected parents of sporadic C9orf72 patients (e.g., 21% among Finnish patients with ALS). Caution should be taken when consulting carriers of small expansions because disease manifestation could be dependent on the extent of the somatic instability in disease-relevant tissues.

Strains of Pathological Protein Aggregates in Neurodegenerative Diseases.

The presence of protein aggregates in the brain is a hallmark of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Considerable evidence has revealed that the pathological protein aggregates in many neurodegenerative diseases are able to self-propagate, which may enable pathology to spread from cell-to-cell within the brain. This property is reminiscent of what occurs in prion diseases such as Creutzfeldt-Jakob disease. A widely recognized feature of prion disorders is the existence of distinct strains of prions, which are thought to represent unique protein aggregate structures. A number of recent studies have pointed to the existence of strains of protein aggregates in other, more common neurodegenerative illnesses such as AD, PD, and related disorders. In this review, we outline the pathobiology of prion strains and discuss how the concept of protein aggregate strains may help to explain the heterogeneity inherent to many human neurodegenerative disorders.