Emerging Roles of Exosomes in Stroke Therapy.

Stroke is the number one cause of morbidity in the United States and number two cause of death worldwide. There is a critical unmet medical need for more effective treatments of ischemic stroke, and this need is increasing with the shift in demographics to an older population. Recently, several studies have reported the therapeutic potential of stem cell-derived exosomes as new candidates for cell-free treatment in stoke. This review focuses on the use of stem cell-derived exosomes as a potential treatment tool for stroke patients. Therapy using exosomes can have a clear clinical advantage over stem cell transplantation in terms of safety, cost, and convenience, as well as reducing bench-to-bed latency due to fewer regulatory milestones. In this review article, we focus on (1) the therapeutic potential of exosomes in stroke treatment, (2) the optimization process of upstream and downstream production, and (3) preclinical application in a stroke animal model. Finally, we discuss the limitations and challenges faced by exosome therapy in future clinical applications.

Ex vivo method for rapid quantification of post traumatic brain injury lesion volumes using ultrasound.

BACKGROUND: Studies of traumatic brain injury often involve the quantification of the lesion volume as a major outcome measure. The determination of lesion volume typically employs the cutting and mounting of brain tissue, and the calculation of the cross-sectional area of the lesion within each section of brain after histological staining. This is a time consuming and laborious task often requiring many weeks to determine the lesion volume for an individual brain. METHODS: In this report we present a method for determining the lesion volume within the brain following traumatic brain injury that involves the use of ultrasound imaging. With this process the lesion volume can be determined within a time period of 90 min per brain rather than weeks and months. Moreover, we have developed a pipeline that will combine the cross-sectional ultrasound images of the brain with the Allen Mouse Brain Atlas to provide the precise anatomical structures that are affected by traumatic injury to the brain. The anatomical detail was lastly paired with behavioral data showing neurological deficits correlated with specific areas of brain injury. RESULTS: The accuracy and precision of this method was shown to be highly consistent with the traditional histological approach. Additionally, the mapping process and behavioral data show that neurological recovery from 1 to 3 weeks post injury is not correlated with gross anatomical recovery of the TBI lesion in our TBI model. CONCLUSION: Together these approaches will enhance the pipeline for processing brain tissue in experimental conditions where the lesion volume is an important outcome parameter and provide more high resolution information about the identity of the damaged regions of the brain.

Probabilistic tractography of the extracranial branches of the trigeminal nerve using diffusion tensor imaging.

PURPOSE: The peripheral course of the trigeminal nerves is complex and spans multiple bony foramen and tissue compartments throughout the face. Diffusion tensor imaging of these nerves is difficult due to the complex tissue interfaces and relatively low MR signal. The purpose of this work is to develop a method for reliable diffusion tensor imaging-based fiber tracking of the peripheral branches of the trigeminal nerve. METHODS: We prospectively acquired imaging data from six healthy adult participants with a 3.0-Tesla system, including T2-weighted short tau inversion recovery with variable flip angle (T2-STIR-SPACE) and readout segmented echo planar diffusion weighted imaging sequences. Probabilistic tractography of the ophthalmic, infraorbital, lingual, and inferior alveolar nerves was performed manually and assessed by two observers who determined whether the fiber tracts reached defined anatomical landmarks using the T2-STIR-SPACE volume. RESULTS: All nerves in all subjects were tracked beyond the trigeminal ganglion. Tracts in the inferior alveolar and ophthalmic nerve exhibited the strongest signal and most consistently reached the most distal landmark (58% and 67%, respectively). All tracts of the inferior alveolar and ophthalmic nerve extended beyond their respective third benchmarks. Tracts of the infraorbital nerve and lingual nerve were comparably lower-signal and did not consistently reach the furthest benchmarks (9% and 17%, respectively). CONCLUSION: This work demonstrates a method for consistently identifying and tracking the major nerve branches of the trigeminal nerve with diffusion tensor imaging.

Effect of lesion temperature on the durability of percutaneous radiofrequency rhizotomies to treat trigeminal neuralgia.

OBJECTIVE: Percutaneous radiofrequency rhizotomy is a common procedure for trigeminal neuralgia (TN) that creates thermocoagulative lesions in the trigeminal ganglion. Lesioning parameters for the procedure are left to the individual surgeon's discretion, and published guidance is primarily anecdotal. The purpose of this work was to assess the role of lesioning temperature on long-term surgical outcomes. METHODS: This was a retrospective analysis of patients who underwent percutaneous radiofrequency rhizotomy from 2009 to 2020. Patient data, including demographics, disease presentation, surgical treatment, and outcomes, were collected from medical records. The primary endpoint was the recurrence of TN pain. Univariate and multivariate Cox proportional hazards regressions were used to assess the impact of chosen covariates on pain-free survival. RESULTS: A total of 280 patients who had undergone 464 procedures were included in the analysis. Overall, roughly 80% of patients who underwent rhizotomy would have a recurrence within 10 years. Lower lesion temperature was predictive of longer periods without pain recurrence (HR 1.05, p < 0.001). The inclusion of lesion time, postoperative numbness, prior history of radiofrequency rhizotomy, surgeon, and multiple sclerosis as confounding variables did not affect the hazard ratio or the statistical significance of this finding. Postoperative numbness and the absence of multiple sclerosis were significant protective factors in the model. CONCLUSIONS: The study findings suggest that lower lesion temperatures and, separately, postoperative numbness result in improved long-term outcomes for patients with TN who undergo percutaneous radiofrequency rhizotomies. Given the limitations of retrospective analysis, the authors suggest that a prospective multisite clinical trial testing lesion temperatures would provide definitive guidance on this issue with specific recommendations about the number needed to treat and trial design.

Biology and Hemodynamics of Aneurysm Rupture.

Predicting rupture risk in intracranial aneurysms is among one of the most critical questions in vascular surgery. The processes that govern an aneurysm growth are multifaceted and complex, but may be summarized into three components: hemodynamics, biology, and mechanics. We review and connect the literature in the three disciplines, identifying considerable strides in recent history and current gaps in research. Taken together, the findings from each field elucidate how and why certain aneurysms rupture, whereas others remain stable. These parameters could eventually inform a translatable predictive model that optimizes risk evaluation and physician's decision-making in treatment options for aneurysms.

Cell Reprogramming for Regeneration and Repair of the Nervous System.

A persistent barrier to the cure and treatment of neurological diseases is the limited ability of the central and peripheral nervous systems to undergo neuroregeneration and repair. Recent efforts have turned to regeneration of various cell types through cellular reprogramming of native cells as a promising therapy to replenish lost or diminished cell populations in various neurological diseases. This review provides an in-depth analysis of the current viral vectors, genes of interest, and target cellular populations that have been studied, as well as the challenges and future directions of these novel therapies. Furthermore, the mechanisms by which cellular reprogramming could be optimized as treatment in neurological diseases and a review of the most recent cellular reprogramming in vitro and in vivo studies will also be discussed.

Identifying symptomatic trigeminal nerves from MRI in a cohort of trigeminal neuralgia patients using radiomics.

INTRODUCTION: Trigeminal neuralgia (TN) is a devastating neuropathic condition. This work tests whether radiomics features derived from MRI of the trigeminal nerve can distinguish between TN-afflicted and pain-free nerves. METHODS: 3D T1- and T2-weighted 1.5-Tesla MRI volumes were retrospectively acquired for patients undergoing stereotactic radiosurgery to treat TN. A convolutional U-net deep learning network was used to segment the trigeminal nerves from the pons to the ganglion. A total of 216 radiomics features consisting of image texture, shape, and intensity were extracted from each nerve. Within a cross-validation scheme, a random forest feature selection method was used, and a shallow neural network was trained using the selected variables to differentiate between TN-affected and non-affected nerves. Average performance over the validation sets was measured to estimate generalizability. RESULTS: A total of 134 patients (i.e., 268 nerves) were included. The top 16 performing features extracted from the masks were selected for the predictive model. The average validation accuracy was 78%. The validation AUC of the model was 0.83, and sensitivity and specificity were 0.82 and 0.76, respectively. CONCLUSION: Overall, this work suggests that radiomics features from MR imaging of the trigeminal nerves correlate with the presence of pain from TN.

Characterizing Tissue Remodeling and Mechanical Heterogeneity in Cerebral Aneurysms.

Accurately assessing the complex tissue mechanics of cerebral aneurysms (CAs) is critical for elucidating how CAs grow and whether that growth will lead to rupture. The factors that have been implicated in CA progression - blood flow dynamics, immune infiltration, and extracellular matrix remodeling - all occur heterogeneously throughout the CA. Thus, it stands to reason that the mechanical properties of CAs are also spatially heterogeneous. Here, we present a new method for characterizing the mechanical heterogeneity of human CAs using generalized anisotropic inverse mechanics, which uses biaxial stretching experiments and inverse analyses to determine the local Kelvin moduli and principal alignments within the tissue. Using this approach, we find that there is significant mechanical heterogeneity within a single acquired human CA. These results were confirmed using second harmonic generation imaging of the CA's fiber architecture and a correlation was observed. This approach provides a single-step method for determining the complex heterogeneous mechanics of CAs, which has important implications for future identification of metrics that can improve accuracy in prediction risk of rupture.

Microglia and Macrophages in Neuroprotection, Neurogenesis, and Emerging Therapies for Stroke.

Stroke remains the number one cause of morbidity in the United States. Within weeks to months after an ischemic event, there is a resolution of inflammation and evidence of neurogenesis; however, years following a stroke, there is evidence of chronic inflammation in the central nervous system, possibly by the persistence of an autoimmune response to brain antigens as a result of ischemia. The mechanisms underlying the involvement of macrophage and microglial activation after stroke are widely acknowledged as having a role in ischemic stroke pathology; thus, modulating inflammation and neurological recovery is a hopeful strategy for treating the long-term outcomes after ischemic injury. Current treatments fail to provide neuroprotective or neurorestorative benefits after stroke; therefore, to ameliorate brain injury-induced deficits, therapies must alter both the initial response to injury and the subsequent inflammatory process. This review will address differences in macrophage and microglia nomenclature and summarize recent work in elucidating the mechanisms of macrophage and microglial participation in antigen presentation, neuroprotection, angiogenesis, neurogenesis, synaptic remodeling, and immune modulating strategies for treating the long-term outcomes after ischemic injury.

The foramen ovale "mirage" and how this impacts percutaneous cannulation for treatment of trigeminal neuralgia: a report of two cases.

Percutaneous stereotactic radiofrequency rhizotomy (PSR) for trigeminal neuralgia most commonly utilizes 2D fluoroscopy for intraoperative needle guidance into the foramen ovale (FO). We describe two cases in which needle advancement into FO was unachievable despite appropriate needle placement on biplane fluoroscopy. Intraoperative multiplanar reconstruction was helpful in more accurately depicting foraminal anatomy which allowed the manipulation of the tip of the needle, which was followed by successful FO cannulation. We propose that this "mirage" is likely created by the inherent nature of X-ray-based fluoroscopy in which the FO appears to be readily penetrable, when in fact the 3D anatomy actually prevents cannulation.

Minimally-invasive tubular retraction ports for intracranial neurosurgery: History and future perspectives.

Brain retraction is a necessary yet potentially damaging requirement of accessing lesions located in deep structures. The development of minimally-invasive tubular retractors (MITRs) provides the theoretical advantage of maximizing visualization of and access to deep-seated lesions, all while minimizing collateral tissue damage. These advantages make MITRs preferable to traditional bladed retractors in the majority of deep-seated lesions. Several commercially-available MITR systems currently exist and have been shown to aid in achieving excellent outcomes with acceptable safety profiles. Nevertheless, important drawbacks to currently-available MITR systems exist. Continued pursuit of an ideal MITR system that provides maximal visualization and access to deep-seated lesions while minimizing retraction-related tissue damage is therefore important. In this review, we discuss the historical development of MITRs, the advantages of MITRs compared to traditional bladed retractors, and opportunities to improve the development of prospective MITRs.

Microsurgical Management of the Middle Cerebral Artery Bifurcation Aneurysms: An Anatomic Feasibility Study.

BACKGROUND: The proper head positioning decreases the surgical complications by enabling a better surgical maneuverability. Middle cerebral artery (MCA) bifurcation aneurysms have been classified by Dashti et al. [Surg Neurol. 2007 May;67(5):441-56] as the intertruncal, inferior, lateral, insular, and complex types based on dome projection. Our aim was to identify the optimum head positions and to explain the anatomic variables, which may affect the surgical strategy of MCA bifurcation aneurysms. METHODS: The lateral supraorbital approach bilaterally was performed in the 4 cadaveric heads. All steps of the dissection were recorded using digital camera. RESULTS: The distal Sylvian fissure (SF) dissection may be preferred for insular type and the proximal SF dissection may be preferred for all other types. Fifteen degrees head rotation was found as the most suitable position for the intertruncal, lateral type and subtype of complex aneurysms related with superior trunk. Thirty degrees head rotation was found the most suitable position for the inferior type, insular type, and subtype of complex aneurysms related with inferior trunk. CONCLUSIONS: The head positioning in middle cerebral bifurcation aneurysms surgery is a critical step. It should be tailored according to the projection and its relationship with the parent vessels of the middle cerebral bifurcation.

Neurosurgical management of aneurysms of the vertebrobasilar system: increasing indications for endovascular therapy with a continued role for open microneurosurgery.

Aneurysms of the vertebrobasilar system remain among the most challenging subsets of aneurysms to treat with an open surgical approach. Since Charles Drake's pioneering work in the 1960s, several advances in microsurgical techniques have improved outcomes and feasibility in the open surgical management of these aneurysms. In parallel, the field of endovascular neurosurgery has provided several safe and effective treatment options. Multiple trials have suggested that endovascular therapy for aneurysms of the vertebrobasilar system is superior to open surgical management in most cases. In some instances, however, open surgical management likely represents a more effective and durable option relative to endovascular therapy. Therefore, continued training of future cerebrovascular specialists in open surgery of vertebrobasilar aneurysms remains crucial. With widespread utilization of endovascular techniques, however, proper exposure of trainees to such aneurysms is growing increasingly difficult. In this review, we discuss the recent advances in the endovascular management of vertebrobasilar aneurysms while also emphasizing the continued importance of open microneurosurgery in such cases.

The Rate of Symptomatic Ischemic Events after Passing Balloon Test Occlusion of the Major Intracranial Arteries: Meta-Analysis.

BACKGROUND: Balloon test occlusion is a widely used method for predicting tolerance of vessel occlusion in the treatment of aneurysms, fistulae, and head and neck neoplasms. However, the false-negative rate is variably reported due in part to the diversity of perfusion monitoring methods. OBJECTIVE: To evaluate the rate of symptomatic ischemic events after a negative balloon test occlusion and determine whether perfusion monitoring methods contribute to differences in these rates. METHODS: PubMed was systematically searched for studies between 1990 and 2020 that reported rates of ischemic outcomes of parental vessel occlusion in patients who passed balloon test occlusion. A generalized linear mixed model meta-analysis was performed. Results were expressed as the rate of symptomatic ischemic events after parental vessel occlusion without vessel bypass in patients who passed balloon test occlusion. RESULTS: Thirty-two studies met the inclusion criteria. The overall pooled rate of ischemic events after passing balloon test occlusion was 3.7% (95% confidence interval [CI]: 1.7-7.8). This rate was 3.8% (95% CI: 1.1-12.8) when monitored with angiography, 2.2% (95% CI: 0.4-10.2) when monitored by a form of computed tomography, and 5.3% (95% CI: 1.2-20.4) when monitored by 2 or more methods of perfusion assessment. The complication rate of balloon test occlusion was 0.8% (95% CI: 0.2-2.7). CONCLUSIONS: Balloon test occlusion results in a low rate of subsequent ischemic events, without conclusive evidence of variation between methods of perfusion assessment. The choice of method should focus on reduction of complication risk, experience of the interventional team, and avoidance of prolonged test occlusion times.

Zika virus-based immunotherapy enhances long-term survival of rodents with brain tumors through upregulation of memory T-cells.

Zika virus (ZIKV) exhibits a tropism for brain tumor cells and has been used as an oncolytic virus to target brain tumors in mice with modest effects on extending median survival. Recent studies have highlighted the potential for combining virotherapy and immunotherapy to target cancer. We postulated that ZIKV could be used as an adjuvant to enhance the long-term survival of mice with malignant glioblastoma and generate memory T-cells capable of providing long-term immunity against cancer remission. To test this hypothesis mice bearing malignant intracranial GL261 tumors were subcutaneously vaccinated with irradiated GL261 cells previously infected with the ZIKV. Mice also received intracranial injections of live ZIKV, irradiation attenuated ZIKV, or irradiated GL261 cells previously infected with ZIKV. Long-term survivors were rechallenged with a second intracranial tumor to examine their immune response and look for the establishment of protective memory T-cells. Mice with subcutaneous vaccination plus intracranial irradiation attenuated ZIKV or intracranial irradiated GL261 cells previously infected with ZIKV exhibited the greatest extensions to overall survival. Flow cytometry analysis of immune cells within the brains of long-term surviving mice after tumor rechallenge revealed an increase in the number of T-cells, including CD4+ and tissue-resident effector/ effector memory CD4+ T-cells, in comparison to long-term survivors that were mock-rechallenged, and in comparison to naïve untreated mice challenged with intracranial gliomas. These results suggest that ZIKV can serve as an adjuvant to subcutaneous tumor vaccines that enhance long-term survival and generate protective tissue-resident memory CD4+ T-cells.

From the Historical Examples of Drs. Osler, Cushing, and Van Wagenen: Lessons on the Importance of Mentorship in Contemporary Neurosurgery.

Although the historical relationships between William Osler, Harvey Williams Cushing, and William Perine Van Wagenen are well known in the neurosurgical world, the nature of the mentor-mentee relationships that existed between these historical giants is not widely appreciated. In this historical vignette, we describe and exemplify such relationships, while at the same time extract important and applicable principles from them. We reviewed relevant primary and secondary sources that documented the interactions between Cushing, Osler, and Van Wagenen. In founding the field of neurological surgery, the brilliant yet volatile Dr. Harvey Cushing received guidance from his mentor, Dr. William Osler. Through our review, it is undeniable that Dr. Osler's personal and professional guidance was vital to young Dr. Cushing's success as the founder of modern neurosurgery. Likewise, Cushing's tutelage of Van Wagenen enabled Van Wagenen to become a leader of a second generation of neurosurgeons, thereby perpetuating the existence of Cushing's high neurosurgical standards. These historical mentor-mentee relationships were built on 4 primary components: accurate recognition of talent, guidance, arrangement of opportunity, and sustenance of mentorship-actions that are commonly implicated in effective mentorship in contemporary studies. Proper mentorship remains indispensable for the success of neurosurgical trainees.