Neurovascular Research Research Articles

Advances and Challenges of Bioassembly Strategies in Neurovascular In Vitro Modeling: An Overview of Current Technologies with a Focus on Three-Dimensional Bioprinting.

Bioassembly encompasses various techniques such as bioprinting, microfluidics, organoids, and self-assembly, enabling advances in tissue engineering and regenerative medicine. Advancements in bioassembly technologies have enabled the precise arrangement and integration of various cell types to more closely mimic the complexity functionality of the neurovascular unit (NVU) and that of other biodiverse multicellular tissue structures. In this context, bioprinting offers the ability to deposit cells in a spatially controlled manner, facilitating the construction of interconnected networks. Scaffold-based assembly strategies provide structural support and guidance cues for cell growth, enabling the formation of complex bio-constructs. Self-assembly approaches utilize the inherent properties of cells to drive the spontaneous organization and interaction of neuronal and vascular components. However, recreating the intricate microarchitecture and functional characteristics of a tissue/organ poses additional challenges. Advancements in bioassembly techniques and materials hold great promise for addressing these challenges. The further refinement of bioprinting technologies, such as improved resolution and the incorporation of multiple cell types, can enhance the accuracy and complexity of the biological constructs; however, developing bioinks that support the growth of cells, viability, and functionality while maintaining compatibility with the bioassembly process remains an unmet need in the field, and further advancements in the design of bioactive and biodegradable scaffolds will aid in controlling cell adhesion, differentiation, and vascularization within the engineered tissue. Additionally, integrating advanced imaging and analytical techniques can provide real-time monitoring and characterization of bioassembly, aiding in quality control and optimization. While challenges remain, ongoing research and technological advancements propel the field forward, paving the way for transformative developments in neurovascular research and tissue engineering. This work provides an overview of the advancements, challenges, and future perspectives in bioassembly for fabricating neurovascular constructs with an add-on focus on bioprinting technologies.

Miniaturized photoacoustic microscope for multi-segmental spinal cord imaging in freely moving mice.

Long-term and non-narcotic hemodynamic imaging is indispensable for observing factual physiological information of the spinal cord. Unfortunately, achieving label-free, high-resolution, and widefield spinal cord imaging for mice under freely moving conditions is challenging. In this study, we developed a miniaturized photoacoustic microscope along with a corresponding photoacoustic spinal window to realize high-resolution, multi-segmental hemodynamic imaging of the spinal cord for freely moving mice. The microscope has an outer size of 32 mm × 23 mm × 10 mm, a weight of 5.8 g, and a 4.4 µm lateral resolution within an effective field of view (FOV) of 2.6 mm × 1.8 mm. To eliminate the off-focus phenomena during spinal imaging, the microscope is equipped with a miniature motor to adapt the focal plane. Besides, the microscope is slidable along a customized rail on the window to expand the FOV. We evaluated the stability of the microscope and analyzed vascular images of the spinal cord under various physiological states. The results suggest that the microscope is capable of performing stable, multi-segmental spinal cord imaging in freely moving mice, offering new insights into spinal cord hemodynamics and neurovascular coupling research.

Endothelial Piezo1 channel mediates mechano-feedback control of brain blood flow

Hyperemia in response to neural activity is essential for brain health. A hyperemic response delivers O2 and nutrients, clears metabolic waste, and concomitantly exposes cerebrovascular endothelial cells to hemodynamic forces. While neurovascular research has primarily centered on the front end of hyperemia—neuronal activity-to-vascular response—the mechanical consequences of hyperemia have gone largely unexplored. Piezo1 is an endothelial mechanosensor that senses hyperemia-associated forces. Using genetic mouse models and pharmacologic approaches to manipulate endothelial Piezo1 function, we evaluated its role in blood flow control and whether it impacts cognition. We provide evidence of a built-in brake system that sculpts hyperemia, and specifically show that Piezo1 activation triggers a mechano-feedback system that promotes blood flow recovery to baseline. Further, genetic Piezo1 modification led to deficits in complementary memory tasks. Collectively, our findings establish a role for endothelial Piezo1 in cerebral blood flow regulation and a role in its behavioral sequelae.

Fabrication, characterization and numerical validation of a novel thin-wall hydrogel vessel model for cardiovascular research based on a patient-specific stenotic carotid artery bifurcation

In vitro vascular models, primarily made of silicone, have been utilized for decades for studying hemodynamics and supporting the development of implants for catheter-based treatments of diseases such as stenoses and aneurysms. Hydrogels have emerged as prominent materials in tissue-engineering applications, offering distinct advantages over silicone models for fabricating vascular models owing to their viscoelasticity, low friction, and tunable mechanical properties. Our study evaluated the feasibility of fabricating thin-wall, anatomical vessel models made of polyvinyl alcohol hydrogel (PVA-H) based on a patient-specific carotid artery bifurcation using a combination of 3D printing and molding technologies. The model’s geometry, elastic modulus, volumetric compliance, and diameter distensibility were characterized experimentally and numerically simulated. Moreover, a comparison with silicone models with the same anatomy was performed. A PVA-H vessel model was integrated into a mock circulatory loop for a preliminary ultrasound-based assessment of fluid dynamics. The vascular model's geometry was successfully replicated, and the elastic moduli amounted to 0.31 ± 0.007 MPa and 0.29 ± 0.007 MPa for PVA-H and silicone, respectively. Both materials exhibited nearly identical volumetric compliance (0.346 and 0.342% mmHg−1), which was higher compared to numerical simulation (0.248 and 0.290% mmHg−1). The diameter distensibility ranged from 0.09 to 0.20% mmHg−1 in the experiments and between 0.10 and 0.18% mmHg−1 in the numerical model at different positions along the vessel model, highlighting the influence of vessel geometry on local deformation. In conclusion, our study presents a method and provides insights into the manufacturing and mechanical characterization of hydrogel-based thin-wall vessel models, potentially allowing for a combination of fluid dynamics and tissue engineering studies in future cardio- and neurovascular research.

Novel intravital approaches to quantify deep vascular structure and perfusion in the aging mouse brain using ultrasound localization microscopy (ULM)

Intra-vital visualization of deep cerebrovascular structures and blood flow in the aging brain has been a difficult challenge in the field of neurovascular research, especially when considering the key role played by the cerebrovasculature in the pathogenesis of both vascular cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD). Traditional imaging methods face difficulties with the thicker skull of older brains, making high-resolution imaging and cerebral blood flow (CBF) assessment challenging. However, functional ultrasound (fUS) imaging, an emerging non-invasive technique, provides real-time CBF insights with notable spatial-temporal resolution. This study introduces an enhanced longitudinal fUS method for aging brains. Using elderly (24-month C57BL/6) mice, we detail replacing the skull with a polymethylpentene window for consistent fUS imaging over extended periods. Ultrasound localization mapping (ULM), involving the injection of a microbubble (<<10 μm) suspension allows for recording of high-resolution microvascular vessels and flows. ULM relies on the localization and tracking of single circulating microbubbles in the blood flow. A FIJI-based analysis interprets these high-quality ULM visuals. Testing on older mouse brains, our method successfully unveils intricate vascular specifics even in-depth, showcasing its utility for longitudinal studies that require ongoing evaluations of CBF and vascular aspects in aging-focused research.

Transcranial volumetric imaging using a conformal ultrasound patch.

Accurate and continuous monitoring of cerebral blood flow is valuable for clinical neurocritical care and fundamental neurovascular research. Transcranial Doppler (TCD) ultrasonography is a widely used non-invasive method for evaluating cerebral blood flow1, but the conventional rigid design severely limits the measurement accuracy of the complex three-dimensional (3D) vascular networks and the practicality for prolonged recording2. Here we report a conformal ultrasound patch for hands-free volumetric imaging and continuous monitoring of cerebral blood flow. The 2 MHz ultrasound waves reduce the attenuation and phase aberration caused by the skull, and the copper mesh shielding layer provides conformal contact to the skin while improving the signal-to-noise ratio by 5 dB. Ultrafast ultrasound imaging based on diverging waves can accurately render the circle of Willis in 3D and minimize human errors during examinations. Focused ultrasound waves allow the recording of blood flow spectra at selected locations continuously. The high accuracy of the conformal ultrasound patch was confirmed in comparison with a conventional TCD probe on 36 participants, showing a mean difference and standard deviation of difference as -1.51 ± 4.34 cm s-1, -0.84 ± 3.06 cm s-1 and -0.50 ± 2.55 cm s-1 for peak systolic velocity, mean flow velocity, and end diastolic velocity, respectively. The measurement success rate was 70.6%, compared with 75.3% for a conventional TCD probe. Furthermore, we demonstrate continuous blood flow spectra during different interventions and identify cascades of intracranial B waves during drowsiness within 4 h of recording.

331 Trends in Public and Private Funding of Neurosurgical Subspecialties From 2015 to 2021

INTRODUCTION: The Centers for Medicare and Medicaid Services established the Open Payments Database (OPD), designed to track all general and research payments made by corporations to physicians, to promote greater financial transparency. While previous studies have analyzed general payments using the OPD database, there has been no investigation into public vs. private research payments related to neurosurgery from 2015 to 2021. METHODS: A cross-sectional analysis of the OPD and NIH RePORTER was conducted from 2015 to 2021 for research payments to neurosurgeons and payments tagged with the keyword “neurosurgery.” The data was cleaned; the primary investigators were subclassified according to the neurosurgical subspecialty of their research, and descriptive statistics were computed for payments at the provider and manufacturer levels. RESULTS: The total public and private funding for neurosurgery from 2015 to 2021 was $1,008,953,855.00 and $171,326,087.05, respectively. Public funding has a compound annual growth rate (CAGR) of 5.37%, and private funding has a CAGR of 7.46%. Neurovascular was the highest privately funded subspecialty at 26.2%, and neuro-oncology was the highest publicly funded subspecialty at 32.1%. CONCLUSIONS: We found significant growth in neurosurgery funding in the private and public sectors from 2015 to 2021. Private funding emphasizes neurovascular research the most and neurosurgical pediatric research the least, whereas public funding focuses on neuro-oncology research, with the least funding for neurosurgical spine research. These findings offer valuable insights into funding trends and characteristics in neurological research, highlighting the differences between funding sources and promoting equitable distribution to advance the field.

Generalized Venous Prominence on Susceptibility-Weighted Imaging Correlates With Global Cerebral Blood Flow Decline.

Objective This study investigated the global correlation between cerebral blood flow (CBF) decline and increased venous prominence, utilizing arterial spin labeling (ASL) and susceptibility-weighted imaging (SWI) MRI techniques. Methods The study was conducted at the Department of Diagnostic Imaging, St. Marina University Hospital, Varna, Bulgaria. Through a retrospective analysis, we examined data from 115 patients undergoing neurological assessment. CBF decline was assessed through ASL MRI, while global venous visibility was evaluated using SWI MRI. Results The analysis revealed a significant positive correlation between CBF decline and venous prominence (Spearman's rho = 0.261, p = 0.005), indicating a systemic interaction between cerebral perfusion and the venous system. Logistic regression further underscored CBF decline as a significant predictive factor for increased venous visibility (odds ratio (OR) = 1.690, p = 0.004). The assessments' high inter-rater reliability (Cohen's kappa = 0.82) supports the consistency and validity of our findings. Conclusion The integration of ASL and SWI MRI provides critical insights into cerebral hemodynamics, emphasizing the significance of these imaging modalities in both neurovascular research and clinical practice. Our findings suggest a systemic relationship between CBF decline and venous system alterations, underscoring the potential for these techniques to enhance our understanding of neurovascular disorders. Future studies should pursue longitudinal and quantitative analyses to deepen our comprehension of these relationships and their clinical implications.

Advances in neurovascular research: Scientific highlights from the 15th world stroke congress

Advances in neurovascular research: Scientific highlights from the 15th world stroke congress

Abstract 275: Hypothesizing After Results are Known (HARKing) in Neurovascular Research Induced by Meeting Abstract Preparation Guidelines

Introduction A “reproducibility crisis” has afflicted the recent medical literature, affecting 75‐89% of major reported findings. An important cause of the inability to replicate results is hypothesizing after the results are known (HARKing): presenting a post hoc hypothesis according with findings as if it were a confirmed a priori hypothesis. Meeting abstract instructions may affect the frequency of HARKing. Methods We tested the hypothesis that, compared with abstract instructions NOT indicating a "hypothesis" should be stated, instructions indicating THAT a "hypothesis" should be stated would increase the proportion of abstracts judged by field content experts to exhibit HARKing. [Hypothesis pre‐registered at AsPredicted.org (#5019)]. We analyzed randomly sampled abstracts from 4 International Stroke Conference (ISC) meeting years with highly forceful (2015), moderately forceful (2017), and non‐forceful (2013 and 2022) requirements for statement of a “hypothesis” in abstract preparation instructions, regardless of whether a hypothesis statement was appropriate (confirmatory science) or inappropriate (exploratory science). Results The 163 abstracts (39 to 43 in each meeting year) equally sampled the 14‐17 ISC topic categories. Explicit “hypothesis” statements were more common in the highly and moderately forceful instruction years (30% and 27%) than in the non‐forceful instruction years (9% and 13%) (p = 0.006). Among the total 32 hypothesis statements, 81% were deemed falsifiable, and 19% non‐falsifiable. None (0%) of hypotheses were stated as pre‐registered prior to study conduct. Overall, 59% (19/32) of the hypothesis statements were adjudicated by two independent content experts as likely to be hypothesizing after the results were known (HARKing). HARKing was more common in the highly and moderately forceful instruction years (20% and 15%) than the non‐forceful instruction years (9% and 3%) (p = 0.03). Conclusion Abstract preparation instructions requiring the use of a hypothesis statement promoted hypothesizing after the results are known, with HARKing present in 1 out of every 5 meeting abstracts. To improve reproducibility of neurovascular research studies, appropriate meeting abstract preparation instructions are desirable, recommending hypothesis statements only for the small proportion of stroke studies that are of confirmatory, rather than exploratory, design.

Two decades of astrocytes in neurovascular coupling.

The brain is a highly energy demanding organ, which accounts in humans for the 20% of total energy consumption at resting state although comprising only 2% of the body mass. The necessary delivery of nutrients to brain parenchyma is ensured by the cerebral circulatory system, through the exchange of glucose and oxygen (O2) at the capillary level. Notably, a tight spatial and temporal correlation exists between local increases in neuronal activity and the subsequent changes in regional cerebral blood flow. The recognized concept of neurovascular coupling (NVC), also named functional hyperemia, expresses this close relationship and stands at the basis of the modern functional brain imaging techniques. Different cellular and molecular mechanisms have been proposed to mediate this tight coupling. In this context, astrocytes are ideally positioned to act as relay elements that sense neuronal activity through their perisynaptic processes and release vasodilator agents at their endfeet in contact with brain parenchymal vessels. Two decades after the astrocyte involvement in neurovascular coupling has been proposed, we here review the experimental evidence that contributed to unraveling the molecular and cellular mechanisms underlying cerebral blood flow regulation. While traveling through the different controversies that moved the research in this field, we keep a peculiar focus on those exploring the role of astrocytes in neurovascular coupling and conclude with two sections related to methodological aspects in neurovascular research and to some pathological conditions resulting in altered neurovascular coupling.

Opening a window to the acutely injured brain: Simultaneous retinal and cerebral vascular monitoring in rats.

Many recent research projects have described typical chronic changes in the retinal vasculature for diverse neurovascular and neurodegenerative disorders such as stroke or Alzheimer's disease. Unlike cerebral vasculature, retinal blood vessels can be assessed non-invasively by retinal vessel analysis. To date, there is only a little information about potential simultaneous reactions of retinal and cerebral vessels in acute neurovascular diseases. The field of applications of retinal assessment could significantly be widened if more information about potential correlations between those two vascular beds and the feasibility of non-invasive retinal vessel analysis in acute neurovascular disease were available. Here, we present our protocol for the simultaneous assessment of retinal and cerebral vessels in an acute setting in anesthetized rats using a non-invasive retinal vessel analyzer and a superficial tissue imaging system for laser speckle contrast analysis via a closed bone window. We describe the experimental set-up in detail, outline the pitfalls of repeated retinal vessel analyses in an experimental set-up of several hours, and address issues that arise from the simultaneous use of two different assessment tools. Finally, we demonstrate the robustness and variability of the reactivity of retinal vessels to hypercapnia at baseline as well as their reproducibility over time using two anesthetic protocols common for neurovascular research. In summary, the procedures described in this protocol allow us to directly compare retinal and cerebral vascular beds and help to substantiate the role of the retina as a "window to the brain."

A Virtual Photovoice Study of Older African Americans Perceptions of Neurovascular Clinical Trials.

Alzheimer disease (AD) poses a major public health crisis, especially among African Americans (AAs) who are up to 3 times more likely to develop AD compared with non-Hispanic Whites. Moreover, cardiovascular risk factors represent a precursor to cognitive decline, which contributes to racial/ethnic disparities seen within AD. Despite these disparities, AAs are underrepresented in neurovascular research. The purpose of this qualitative virtual photovoice project is to explore how older Midwestern AAs perceive neurovascular clinical trials. Five photovoice sessions were held virtually over a 3-month period. Participants took photos each week that captured the salient features of their environment that described their perceptions and experiences related to neurovascular clinical trials. Structured discussion using the SHOWED method was used to generate new understandings about the perspectives and experiences in neurovascular clinical trials. Data was analyzed using strategies in participatory visual research. A total of 10 AAs aged 55 years and older participated and a total of 6 themes emerged from the photovoice group discussions. Findings from this study inform the development of culturally appropriate research protocols and effective recruitment strategies to enhance participation among older AAs in neurovascular clinical trials.

Abstract Number ‐ 180: A Novel Internet Platform for Neurovascular Research Collaboration and Funding

Introduction The current neurovascular research funding environment is highly competitive, stifling collaboration and hindering progress. Further, specific groups of researchers/research topics are disproportionately affected, resulting in inequity in the funding process. These include early‐career researchers, women, and researchers from low‐middle income countries. Certain conditions, e.g., rare, stroke‐related diseases are due to their low prevalence not suitable for clinical trials, and therefore even less likely to receive funding. Currently, there is no easy way for people working on such topics to come together and collaborate. To address this problem, a novel internet‐based platform, Collavidence (www.collavidence.com), was designed. The idea is to complement current systems of neurovascular research collaboration and funding for more inclusive, efficient, and impactful research results. The aim of this study is to present the initial performance of the platform in achieving this goal. Methods Analytics on pre‐defined user‐, project‐, and interaction‐based metrics will be performed to describe the level of platform engagement in the initial months following launch. These include the number of users and projects posted, the amount of funding accumulated, the proportion of successfully funded projects, and the iterative improvement of the proposals. Further, the relative engagement of early‐career, female researchers, and researchers from low‐middle‐income countries will be assessed. Results A qualitative assessment of the value of the overall platform, the process of iterative review, and possibilities for collaboration will be presented. Further, trends in platform engagement during the initial 3 months, including the relative distribution of specific user demographics to assess the platform’s success in encouraging equity, diversity, and inclusion, will be presented. Conclusions This study will assess the feasibility and initial success of Collavidence as a unique platform for neurovascular research collaboration and funding.

Imaging Advances in Stroke: Use of Advanced Neurovascular Imaging or Disruptive Innovation With Artificial Intelligence?

HomeStrokeVol. 54, No. 4Imaging Advances in Stroke: Use of Advanced Neurovascular Imaging or Disruptive Innovation With Artificial Intelligence? No AccessArticle CommentaryRequest AccessFull TextAboutView Full TextView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessArticle CommentaryRequest AccessFull TextImaging Advances in Stroke: Use of Advanced Neurovascular Imaging or Disruptive Innovation With Artificial Intelligence? David S. Liebeskind, MD and Joanna M. Wardlaw, MD David S. LiebeskindDavid S. Liebeskind Correspondence to: David S. Liebeskind, MD, 635 Charles E Young Dr South, Ste 225, Los Angeles, CA 90095. Email E-mail Address: [email protected] https://orcid.org/0000-0002-5109-8736 Neurovascular Imaging Research Core, UCLA, Los Angeles, CA (D.S.L., J.M.W.). Search for more papers by this author and Joanna M. WardlawJoanna M. Wardlaw https://orcid.org/0000-0002-9812-6642 Neurovascular Imaging Research Core, UCLA, Los Angeles, CA (D.S.L., J.M.W.). Centre for Clinical Brain Sciences, Edinburgh Imaging and UK Dementia Research Institute, University of Edinburgh (J.M.W.). Search for more papers by this author Originally published23 Feb 2023https://doi.org/10.1161/STROKEAHA.123.042308Stroke. 2023;54:1123–1126FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 1125–1126.Correspondence to: David S. Liebeskind, MD, 635 Charles E Young Dr South, Ste 225, Los Angeles, CA 90095. Email [email protected]com

Photoacoustic imaging for microcirculation.

Microcirculation facilitates the blood-tissue exchange of nutrients and regulates blood perfusion. It is, therefore, essential in maintaining tissue health. Aberrations in microcirculation are potentially indicative of underlying cardiovascular and metabolic pathologies. Thus, quantitative information about it is of great clinical relevance. Photoacoustic imaging (PAI) is a capable technique that relies on the generation of imaging contrast via the absorption of light and can image at micron-scale resolution. PAI is especially desirable to map microvasculature as hemoglobin strongly absorbs light and can generate a photoacoustic signal. This paper reviews the current state of the art for imaging microvascular networks using photoacoustic imaging. We further describe how quantitative information about blood dynamics such as the total hemoglobin concentration, oxygen saturation, and blood flow rate is obtained using PAI. We also discuss its importance in understanding key pathophysiological processes in neurovascular, cardiovascular, ophthalmic, and cancer research fields. We then discuss the current challenges and limitations of PAI and the approaches that can help overcome these limitations. Finally, we provide the reader with an overview of future trends in the field of PAI for imaging microcirculation.

Bibliometric Trends in Open Surgical and Endovascular Cerebrovascular Research.

The last decade has witnessed a major expansion in endovascular interventions concurrent with a contraction of open neurovascular surgeries. Whether research efforts have also shifted from open to endovascular neurosurgery is an effect that has not been explored extensively. Understanding the bibliometric trend is important for researchers, funding agencies, and publishing journals. The aim of this review is to explore this potential shift.We compared the bibliometrics of open cerebrovascular and endovascular research articles published in two neurosurgical journals (Journal of Neurosurgery, Neurosurgery) and two neuroradiological journals (Journal of Neurointerventional Surgery, American Journal of Neuroradiology). Data were collected between September 26, 2021, and October 18, 2021. Articles published in 2011, 2013, 2015, 2017, and 2019 from the journals were screened. Neurovascular articles were classified into open surgical, endovascular, or mixed. Bibliometric parameters were collected via SCOPUS and journals’ websites. A total of 8,018 articles were screened, of which 1,551 were included (16.2% open, 62.2% endovascular, 21.5% mixed). Most articles were related to aneurysms (76%). Open-access status correlated with increased citations (p<0.001) and Altmetric (p<0.001), which measures online activity. Comparing 2011 and 2019, the article distribution (open/endovascular/mixed) has changed significantly (χ2 test, p=0.002), with open articles dropping from 23.6% (68/288) to 12.9% (44/342) and endovascular articles rising from 56.6% (163/288) to 65.8% (225/342). Using the Kruskal-Wallis test, the citation distribution is different across the three groups in 2019 (p<0.001), favoring endovascular articles, but not in the other years. Our study suggests a trend of diminishing open neurovascular research output and increasing endovascular research output, in terms of both the number of articles and the citations. More time for citation accumulation may be required to verify this trend.

Real-time whole-brain imaging of hemodynamics and oxygenation at micro-vessel resolution with ultrafast wide-field photoacoustic microscopy

High-speed high-resolution imaging of the whole-brain hemodynamics is critically important to facilitating neurovascular research. High imaging speed and image quality are crucial to visualizing real-time hemodynamics in complex brain vascular networks, and tracking fast pathophysiological activities at the microvessel level, which will enable advances in current queries in neurovascular and brain metabolism research, including stroke, dementia, and acute brain injury. Further, real-time imaging of oxygen saturation of hemoglobin (sO2) can capture fast-paced oxygen delivery dynamics, which is needed to solve pertinent questions in these fields and beyond. Here, we present a novel ultrafast functional photoacoustic microscopy (UFF-PAM) to image the whole-brain hemodynamics and oxygenation. UFF-PAM takes advantage of several key engineering innovations, including stimulated Raman scattering (SRS) based dual-wavelength laser excitation, water-immersible 12-facet-polygon scanner, high-sensitivity ultrasound transducer, and deep-learning-based image upsampling. A volumetric imaging rate of 2 Hz has been achieved over a field of view (FOV) of 11 × 7.5 × 1.5 mm3 with a high spatial resolution of ~10 μm. Using the UFF-PAM system, we have demonstrated proof-of-concept studies on the mouse brains in response to systemic hypoxia, sodium nitroprusside, and stroke. We observed the mouse brain’s fast morphological and functional changes over the entire cortex, including vasoconstriction, vasodilation, and deoxygenation. More interestingly, for the first time, with the whole-brain FOV and micro-vessel resolution, we captured the vasoconstriction and hypoxia simultaneously in the spreading depolarization (SD) wave. We expect the new imaging technology will provide a great potential for fundamental brain research under various pathological and physiological conditions.

Challenges and opportunities in research funding for neurovascular diseases from a clinical researcher's perspective.

Neurovascular research is underfunded, imposing substantial challenges on clinical researchers in the field of neurovascular diseases. We explored what physicians perceive to be the greatest challenges with regard to neurovascular research funding, and how they think the funding crisis in neurovascular research could be overcome. We performed an international, multi-disciplinary survey among physicians involved in the medical care of patients with neurovascular diseases. After providing their demographic data, physicians were asked closed-ended questions on their personal opinion regarding challenges in neurovascular research funding, and how these challenges could be overcome. Physicians also described in their own words what they perceived to be the biggest challenges in obtaining funding. Data were analyzed using descriptive statistics and response clustering. Of 233 participating physicians (70.4% male,82.8% senior staff) from 48 countries, 217(97.4%) perceived the discrepancy between required and available funding to be a problem;172(73.8%) considered it a major problem. High competitiveness (61/118 available free text responses[51.7%]), time-consuming application processes (28/118[23.7%]) and administrative requirements (25/118[21.1%]) were identified as key obstacles. Traditional big funding agencies were perceived to be most capable of closing the neurovascular research funding gap, followed by specialty-specific organizations and industry, while philanthropy and crowdfunding were perceived to be less important. The gap between required and available funding was perceived to be a major problem in neurovascular research, with high competitiveness, time-consuming funding processes and excessive administrative requirements being the key obstacles to obtaining funding. Traditional funding agencies were perceived to be most capable of closing this funding gap.

Understanding the importance of the primary trial hypothesis: The randomized trial on the timing of ruptured aneurysm surgery

Background and purposeThe primary hypothesis of a trial must be explicitly formulated. The primary hypothesis is essential for the proper interpretation of trial results. MethodsWe review the seminal Finnish randomized trial on the timing of aneurysm surgery, and re-examine how trial results could have been interpreted at the time had a precise primary hypothesis been pre-specified. Finally, we compare the power of this single center randomized trial with the multicenter International Cooperative (observational) Study that examined the same clinical problem. ResultsHad the Finnish authors worked under a pragmatic hypothesis in favor of early surgery (within 3days) versus delayed surgery, the trial results could have been interpreted as conclusive. The randomized trial was more appropriate, more ethical, and more efficient than the inconclusive International Cooperative study. ConclusionThe randomized trial on the timing of aneurysm surgery was a landmark in neurovascular research. A precise pragmatic primary hypothesis is a crucial step in trial design and interpretation.