Single-cell atlas of the human brain vasculature across development, adulthood and disease.

A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood1. Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell-cell interaction analyses predict substantial endothelial-to-perivascular cell ligand-receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks. Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.

Cross-sectional analysis of women in neurosurgery: a Canadian perspective.

OBJECTIVE: Although the past decades have seen a steady increase of women in medicine in general, women continue to represent a minority of the physician-training staff and workforce in neurosurgery in Canada and worldwide. As such, the aim of this study was to analyze the experiences of women faculty practicing neurosurgery across Canada to better understand and address the factors contributing to this disparity. METHODS: A historical, cross-sectional, and mixed-method analysis of survey responses was performed using survey results obtained from women attending neurosurgeons across Canada. A web-based survey platform was utilized to collect responses. Quantitative analyses were performed on the responses from the study questionnaire, including summary and comparative statistics. Qualitative analyses of free-text responses were performed using axial and open coding. RESULTS: A total of 19 of 31 respondents (61.3%) completed the survey. Positive enabling factors for career success included supportive colleagues and work environment (52.6%); academic accomplishments, including publications and advanced degrees (36.8%); and advanced fellowship training (47.4%). Perceived barriers reported included inequalities with regard to career advancement opportunities (57.8%), conflicting professional and personal interests (57.8%), and lack of mentorship (36.8%). Quantitative analyses demonstrated emerging themes of an increased need for women mentors as well as support and recognition of the contributions to career advancement of personal and family-related factors. CONCLUSIONS: This study represents, to the authors' knowledge, the first analysis of factors influencing career success and satisfaction in women neurosurgeons across Canada. This study highlights several key factors contributing to the low representation of women in neurosurgery and identifies specific actionable items that can be addressed by training programs and institutions. In particular, female mentorship, opportunities for career advancement, and increased recognition and integration of personal and professional roles were highlighted as areas for future intervention. These findings will provide a framework for addressing these factors and improving the recruitment and retention of females in this specialty.

To drive or not to drive, that is still the question: current challenges in driving recommendations for patients with brain tumours.

Driving is a complex task that requires integration of various skills that may be impaired in patients with brain tumours. Determining fitness to drive is a responsibility of all physicians in Canada; however, it is an inconsistent practice based on few objective guidelines. The primary purpose of the study is to determine the consistency of driving recommendations amongst health care professionals in Ontario. Secondary aims include evaluation of physician awareness of driving regulations and determination of whether physicians would benefit from more specific driving guidelines. An 18-item questionnaire was sent to 126 health care professionals who take care of patients with brain tumours in Ontario. Seventy-five health care professionals responded to the survey. Less than 10% said they could reliably determine fitness to drive and almost an equal percentage of respondents indicated that determining fitness to drive should be a shared responsibility. The factors deemed important in determining driving safety were highly variable; 70% indicated that cognitive and emotional deficits were important. Over a third of respondents never heard of the CMA guidelines and of those who were familiar with it, 12.5% felt they were sufficient to inform clinical decisions. 90% of respondents wanted more specific and detailed driving guidelines for patients with brain tumours. The current guidelines for physicians are not specific enough for physicians to confidently determine fitness to drive in this population. These findings suggest the need for more detailed guidelines for driving safety that are based on empirical studies on driving habits and performance in patients with a variety of brain tumours.

Functional Outcome After Poor-Grade Subarachnoid Hemorrhage: A Single-Center Study and Systematic Literature Review.

BACKGROUND AND PURPOSE: Poor-grade subarachnoid hemorrhage (SAH) (World Federation of Neurosurgical Societies grade 4 and 5) is associated with high mortality rates and unfavorable functional outcomes. We report a single-center cohort of poor-grade SAH patients, combined with a systematic review of studies reporting functional outcome in the poor-grade SAH population. METHODS: Data on a cohort of poor-grade SAH patients treated between 2009 and 2013 were retrospectively collected and combined with a systematic review (from inception to November 2015; PubMed, Embase). Two reviewers assessed the studies independently based on predefined inclusion criteria: consecutive poor-grade SAH, functional outcome measured at least 3 months after hemorrhage, and the report of patients who died before aneurysm treatment. RESULTS: The search yielded 329 publications, and 23 met our inclusion criteria with 2713 subjects enrolled from 1977 to 2014 in 10 countries (including 179 poor-grade patients from our cohort). Mortality rate was 60 % (1683 patients), of which 806 (29 %) died before and 877 (31 %) died after aneurysm treatment, respectively. Treatment was undertaken in 1775 patients (1775/2826-63 %): 1347 by surgical clipping (1347/1775-76 %) and 428 (428/1775-24 %) by endovascular methods. Outcome was favorable in 794 patients (28 %) and unfavorable in 1867 (66 %). When the studies were grouped into decades, favorable outcome increased from 13 % in the late 1970s to early 1980s to 35 % in the late 1980s to early 1990s, and remained unchanged thereafter. CONCLUSION: Although mortality remains high in poor-grade SAH patients, a favorable functional outcome can be achieved in approximately one-third of patients. The development of new diagnostic methods and implementation of therapeutic approaches were probably responsible for the decrease in mortality and improvement in the functional outcome from 1970 to the 1990s. The plateau in functional outcome seen thereafter might be explained by the treatment of sicker and older patients and by the lack of new therapeutic interventions specific for SAH.

Aneurysmal subarachnoid haemorrhage from a neuroimaging perspective.

Neuroimaging is a key element in the management of patients suffering from subarachnoid haemorrhage (SAH). In this article, we review the current literature to provide a summary of the existing neuroimaging methods available in clinical practice. Noncontrast computed tomography is highly sensitive in detecting subarachnoid blood, especially within 6 hours of haemorrhage. However, lumbar puncture should follow a negative noncontrast computed tomography scan in patients with symptoms suspicious of SAH. Computed tomography angiography is slowly replacing digital subtraction angiography as the first-line technique for the diagnosis and treatment planning of cerebral aneurysms, but digital subtraction angiography is still required in patients with diffuse SAH and negative initial computed tomography angiography. Delayed cerebral ischaemia is a common and serious complication after SAH. The modern concept of delayed cerebral ischaemia monitoring is shifting from modalities that measure vessel diameter to techniques focusing on brain perfusion. Lastly, evolving modalities applied to assess cerebral physiological, functional and cognitive sequelae after SAH, such as functional magnetic resonance imaging or positron emission tomography, are discussed. These new techniques may have the advantage over structural modalities due to their ability to assess brain physiology and function in real time. However, their use remains mainly experimental and the literature supporting their practice is still scarce.

Neuroanatomical correlates of laparoscopic surgery training.

BACKGROUND: Better understanding of the brain regions involved in performing laparoscopic surgery is likely to provide important insights for improving laparoscopic training and assessment in the future. To our knowledge, this is the first study using real Fundamentals of Laparoscopy Training (FLS)-based laparoscopic surgery training tasks in the functional magnetic resonance imaging (fMRI) environment to provide extensive characterization of the brain regions involved in this specific task execution. METHODS: Nine right-handed subjects practiced five FLS-modified laparoscopic surgery-training tasks with a training box for ten sessions in a simulated fMRI environment. Following the last practice session, they underwent 3 T fMRI while performing each task. RESULTS: An increase in the extent of brain activation was observed as the complexity of the tasks increased. Activation in the precentral gyrus, postcentral gyrus, and premotor regions was observed in the performance of all tasks, whereas the superior parietal lobe (SPL) was activated in the more complex tasks. The mean score and brain activation for performance with the dominant hand were larger than those observed during performance with the non-dominant hand. CONCLUSIONS: Performing more complex tasks requires higher visual spatial ability and motor planning. Given the need for ambidextrous skills during laparoscopic tasks, the finding that lower scores and smaller brain recruitment occurred in executing tasks with the non-dominant hand than with the dominant hand suggests designing future training tasks to train the non-dominant hand more effectively. This may serve to improve overall performance in bi-manual tasks. Studies of this kind may facilitate the evidence-based development of strategies to improve the quality of laparoscopy training and assessment.

The expansion of liquid biopsies to vascular care: an overview of existing principles, techniques and potential applications to vascular malformation diagnostics.

Vascular malformations are congenital lesions that occur due to mutations in major cellular signalling pathways which govern angiogenesis, cell proliferation, motility, and cell death. These pathways have been widely studied in oncology and are substrates for various small molecule inhibitors. Given their common molecular biology, there is now a potential to repurpose these cancer drugs for vascular malformation care; however, a molecular diagnosis is required in order to tailour specific drugs to the individual patient's mutational profile. Liquid biopsies (LBs), emerging as a transformative tool in the field of oncology, hold significant promise in this feat. This paper explores the principles and technologies underlying LBs and evaluates their potential to revolutionize the management of vascular malformations. The review begins by delineating the fundamental principles of LBs, focusing on the detection and analysis of circulating biomarkers such as cell-free DNA, circulating tumor cells, and extracellular vesicles. Subsequently, an in-depth analysis of the technological advancements driving LB platforms is presented. Lastly, the paper highlights the current state of research in applying LBs to various vascular malformations, and uses the aforementioned principles and techniques to conceptualize a liquid biopsy framework that is unique to vascular malformation research and clinical care.

Defining the Role of Oral Pathway Inhibitors as Targeted Therapeutics in Arteriovenous Malformation Care.

Arteriovenous malformations (AVMs) are vascular malformations that are prone to rupturing and can cause significant morbidity and mortality in relatively young patients. Conventional treatment options such as surgery and endovascular therapy often are insufficient for cure. There is a growing body of knowledge on the genetic and molecular underpinnings of AVM development and maintenance, making the future of precision medicine a real possibility for AVM management. Here, we review the pathophysiology of AVM development across various cell types, with a focus on current and potential druggable targets and their therapeutic potentials in both sporadic and familial AVM populations.

Vascular malformations: An overview of their molecular pathways, detection of mutational profiles and subsequent targets for drug therapy.

Vascular malformations are anomalies in vascular development that portend a significant risk of hemorrhage, morbidity and mortality. Conventional treatments with surgery, radiosurgery and/or endovascular approaches are often insufficient for cure, thereby presenting an ongoing challenge for physicians and their patients. In the last two decades, we have learned that each type of vascular malformation harbors inherited germline and somatic mutations in two well-known cellular pathways that are also implicated in cancer biology: the PI3K/AKT/mTOR and RAS/RAF/MEK pathways. This knowledge has led to recent efforts in: (1) identifying reliable mechanisms to detect a patient's mutational burden in a minimally-invasive manner, and then (2) understand how cancer drugs that target these mutations can be repurposed for vascular malformation care. The idea of precision medicine for vascular pathologies is growing in potential and will be critical in expanding the clinician's therapeutic armamentarium.

Comparison of intrathecal baclofen pump insertion and selective dorsal rhizotomy for nonambulatory children with predominantly spastic cerebral palsy.

OBJECTIVE: In nonambulatory children with predominantly spastic cerebral palsy (CP), the authors compared care needs, symptom burden, and complications after surgical treatment with either intrathecal baclofen (ITB) pump insertion or selective dorsal rhizotomy (SDR). The patients were treated at two Canadian centers with variability in practice pertaining to these surgical options. METHODS: The authors performed a retrospective analysis of nonambulatory children with predominantly spastic quadriplegic or diplegic CP who underwent treatment with ITB or SDR. These two strategies were retrospectively assessed by comparing patient data from the two treatment groups for demographic characteristics, outcomes, and complications. A partial least-squares analysis was performed to identify patient phenotypes associated with outcomes. RESULTS: Thirty patients who underwent ITB and 30 patients who underwent SDR were included for analysis. Patients in the ITB group were older and had lower baseline functional status, with greater burdens of spasticity, dystonia, pain, deformity, bladder dysfunction, and epilepsy than patients in the SDR group. In addition, children who underwent SDR had lower Gross Motor Function Classification System (GMFCS) levels and were less likely to experience complications than those who underwent ITB. However, children treated with SDR had fewer improvements in pain than children treated with ITB. A single significant latent variable explaining 88% of the variance in the data was identified. CONCLUSIONS: Considerable baseline differences exist within this pediatric CP patient population. Factors specific to individual children must be taken into account when determining whether ITB or SDR is the appropriate treatment.

The safety profile and angioarchitectural changes after acute targeted embolization of ruptured arteriovenous malformations.

OBJECTIVE: The aim of this study was to 1) compare the safety and efficacy of acute targeted embolization of angiographic weak points in ruptured brain arteriovenous malformations (bAVMs) versus delayed treatment, and 2) explore the angioarchitectural changes that follow this intervention. METHODS: The authors conducted a retrospective analysis of a prospectively acquired database of ruptured bAVMs. Three hundred sixteen patients with ruptured bAVMs who presented to the hospital within 48 hours of ictus were included in the analysis. The first analysis compared clinical and functional outcomes of acutely embolized patients to those with delayed management paradigms. The second analysis compared these outcomes of patients with acute embolization to those with angiographic targets who did not undergo acute embolization. Finally, a subset of 20 patients with immediate postembolization angiograms and follow-up angiograms within 6 weeks of treatment were studied to determine the angioarchitectural changes after acute targeted embolization. Kaplan-Meier curves for survival between the groups were devised. Multivariate logistical regression analysis was conducted. RESULTS: There were three deaths (0.9%) and an overall rerupture rate of 4.8% per year. There was no statistical difference in demographic variables, mortality, and rerupture rate between patients with acute embolization and those with delayed management. Patients with acute embolization were more likely to present functionally worse (46.9% vs 69.8%, modified Rankin Scale score 0-2, p = 0.018) and to require an adjuvant therapy (71.9% vs 26.4%, p < 0.001). When comparing acutely embolized patients to those nonacutely embolized angiographic targets, there was a significant protective effect of acute targeted therapy on rerupture rate (annual risk 1.2% vs 4.3%, p = 0.025) and no difference in treatment complications. Differences in the survival curves for rerupture were statistically significant. Multivariate analyses significantly predicted lower rerupture in acute targeted treatment and higher rerupture in those with associated aneurysms, deep venous anatomy, and higher Spetzler-Martin grade. All patients with acute embolization experienced complete obliteration of the angiographic weak point with various degrees of resolution of the nidus; however, some had spontaneous recurrence of their bAVM, while others had spontaneous resolution over time. No patients developed new angiographic weak points. CONCLUSIONS: This study demonstrates that acute targeted embolization of angiographic weak points, particularly aneurysms, is technically safe and protective in the early phase of recovery from ruptured bAVMs. Serial follow-up imaging is necessary to monitor the evolution of the nidus after targeted and definitive treatments. Larger prospective studies are needed to validate these findings.

Awake Craniotomy in a Low- to Middle-Income Country: A Sustainability Analysis.

OBJECTIVE: This study evaluated the sustainability of teaching awake craniotomy in Indonesia. We explored the factors affecting how awake craniotomy can be taught in a low- to middle-income (LMIC) country and the factors affecting the utilization of awake craniotomy in Indonesia. METHODS: This is a prospective mixed-methods study in Indonesia. A questionnaire was administered to 100 neurosurgeons at a conference on their experience with neuro-oncology, awake craniotomy, and teaching missions. Thirty-three physicians participated in semi-structured interviews elaborating on these topics. Data on tumor caseload and resources were collected. RESULTS: Thirty-three of 88 respondents (41.3%) indicated that they still perform awake craniotomy. Although 87.3% felt that it was beneficial for patients and resource sparing, less than a quarter of them felt they had sufficient exposure/training in awake craniotomy. Almost all of them wanted further training and to maintain a relationship with international mentors. Four themes emerged about the factors that affect how we teach awake craniotomy in an LMIC: 1) the sustainability of a teaching mission is dependent on a culture of information sharing and 2) the support of multiple health care providers; 3) hospital structure affects how changes are implemented; and 4) health care professionals in Indonesia value opportunities for international training. Regarding the uptake of awake craniotomy in Indonesia, there are sociocultural factors that affect patients' receptiveness to surgery and the national insurance plan restricts the provision of neurosurgical care. CONCLUSIONS: Many factors need to be explored when planning a neurosurgical mission in LMICs to ensure its sustainability.

Driving habits and behaviors of patients with brain tumors: a self-report, cognitive and driving simulation study.

The purpose of the study is to determine driving habits and behaviors of patients with brain tumors in order to better inform discussions around driving safety in this population. Eight-four patients with brain tumors participated in a survey on their driving behaviors since their diagnosis. Thirteen of these patients and thirteen sex- and age-matched healthy controls participated in cognitive testing and several driving simulation scenarios in order to objectively assess driving performance. Survey responses demonstrated that patients with brain tumors engage in a variety of driving scenarios with little subjectve difficulty. On the driving simulation tasks, patients and healthy controls performed similarly except that patients had more speed exceedances (U = 41, p < 0.05) and a greater variability in speed (U = 57, p < 0.05). Performance on the selective attention component of the UFOV was significantly associated with greater total errors in the Bus Following task for patients with brain tumors compared to healthy controls (rs = 0.722, p < 0.05, CI [0.080, 0.957]). Better comprehensive driving assessments are needed to identify patients with driving behaviors that put themselves and others at risk on the road.

A Nonliquid Crystal Display Screen Computer for Treatment of Photosensitivity and Computer Screen Intolerance in Post-Concussion Syndrome.

Liquid crystal display (LCD) screens refresh at a rate of 60 times per second, which can be perceived by concussed individuals who have photosensitivity, leading to computer intolerance. A non-LCD computer screen that refreshes at a much lower rate could relieve this photosensitivity and computer screen intolerance in patients with post-concussion syndrome (PCS). Twenty-nine patients with PCS, computer intolerance, and photosensitivity performed a reading task for a maximum of 30 min, with an LCD computer or a non-LCD device, and were given a comprehension test after completion of the reading task. The Sport Concussion Assessment Tool 3 was administered before and after each reading task. Symptom scores, amount of time spent reading, and performance on the comprehension tests were compared between the two devices. Patients also completed a self-report questionnaire of their subjective experience. The LCD screen computer produced significantly greater symptom exacerbation (median difference = 5, W = 315, p < 0.01) and a greater number of symptoms (median difference = 1, W = 148, p < 0.01) than the non-LCD screens. The non-LCD screen resulted in a longer symptom-free reading time (median = 48 sec, W = 147, p < 0.01), but not a greater number of words read (median = 281, W = 148, p = 0.098). Females were more likely to have greater symptom exacerbation with the LCD screen (U = 14.0, p < 0.01). No significant difference was found in performance on the comprehension test. Subjective reports showed that the non-LCD experience was more favorable, and most patients stated they would recommend this device for other patients with PCS. This study is the first to show the clinical utility of non-LCD screen computers in the management of photosensitivity and computer screen intolerance in patients with PCS. The non-LCD screen computer has the potential to facilitate return-to-work or return-to-school in concussed individuals.