Mobile Stroke Unit Operational Metrics: Institutional Experience, Systematic Review and Meta-Analysis.

Background: The available literature on mobile stroke units (MSU) has focused on clinical outcomes, rather than operational performance. Our objective was to establish normalized metrics and to conduct a meta-analysis of the current literature on MSU performance. Methods: Our MSU in upstate New York serves 741,000 people. We present prospectively collected, retrospectively analyzed data from the inception of our MSU in October of 2018, through March of 2021. Rates of transportation/dispatch and MSU utilization were reported. We also performed a meta-analysis using MEDLINE, SCOPUS, and Cochrane Library databases, calculating rates of tPA/dispatch, tPA-per-24-operational-hours ("per day"), mechanical thrombectomy (MT)/dispatch and MT/day. Results: Our MSU was dispatched 1,719 times in 606 days (8.5 dispatches/24-operational-hours) and transported 324 patients (18.8%) to the hospital. Intravenous tPA was administered in 64 patients (3.7% of dispatches) and the rate of tPA/day was 0.317 (95% CI 0.150-0.567). MT was performed in 24 patients (1.4% of dispatches) for a MT/day rate of 0.119 (95% CI 0.074-0.163). The MSU was in use for 38,742 minutes out of 290,760 total available minutes (13.3% utilization rate). Our meta-analysis included 14 articles. Eight studies were included in the analysis of tPA/dispatch (342/5,862) for a rate of 7.2% (95% CI 4.8-9.5%, I2 = 92%) and 11 were included in the analysis of tPA/day (1,858/4,961) for a rate of 0.358 (95% CI 0.215-0.502, I2 = 99%). Seven studies were included for MT/dispatch (102/5,335) for a rate of 2.0% (95% CI 1.2-2.8%, I2 = 67%) and MT/day (103/1,249) for a rate of 0.092 (95% CI 0.046-0.138, I2 = 91%). Conclusions: In this single institution retrospective study and meta-analysis, we outline the following operational metrics: tPA/dispatch, tPA/day, MT/dispatch, MT/day, and utilization rate. These metrics are useful for internal and external comparison for institutions with or considering developing mobile stroke programs.

Mobile stroke care expedites intravenous thrombolysis and endovascular thrombectomy.

BACKGROUND: The number of mobile stroke programmes has increased with evidence, showing they expedite intravenous thrombolysis. Outstanding questions include whether time savings extend to patients eligible for endovascular therapy and impact clinical outcomes. OBJECTIVE: Our mobile stroke unit (MSU), based at an academic medical centre in upstate New York, launched in October 2018. We reviewed prospective observational data sets over 26 months to identify MSU and non-MSU emergency medical service (EMS) patients who underwent intravenous thrombolysis or endovascular thrombectomy for comparison of angiographic and clinical outcomes. RESULTS: Over 568 days in service, the MSU was dispatched 1489 times (2.6/day) and transported 300 patients (20% of dispatches). Intravenous tissue plasminogen activator (tPA) was administered to 57 MSU patients and the average time from 911 call-to-tPA was 42.5 min (±9.2), while EMS transported 73 patients who received tPA at 99.4 min (±35.7) (p<0.001). Seven MSU patients (12%) received tPA from 3.5 hours to 4.5 hours since last known well and would likely have been outside the window with EMS care. Endovascular thrombectomy was performed on 21 MSU patients with an average 911 call-to-groin puncture time of 99.9 min (±18.1), while EMS transported 54 patients who underwent endovascular thrombectomy (ET) at 133.0 min (±37.0) (p=0.0002). There was no difference between MSU and traditional EMS in modified Rankin score at 90-day clinic follow-up for patients undergoing intravenous thrombolysis or endovascular thrombectomy, whether assessed as a dichotomous or ordinal variable. CONCLUSIONS: Mobile stroke care expedited both intravenous thrombolysis and endovascular thrombectomy. There is an ongoing need to show improved functional outcomes with MSU care.

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.

Reorganized language network connectivity after left arcuate fasciculus resection: A case study.

Understanding the neural mechanisms that support spontaneous recovery of cognitive abilities can place important constraints on mechanistic theories of brain organization and function, and holds potential to inform clinical interventions. Connectivity-based MRI measures have emerged as a way to study how recovery from brain injury is modulated by changes in intra- and inter-hemispheric connectivity. Here we report a detailed and multi-modal case study of a 26 year-old male who presented with a left inferior parietal glioma infiltrating the left arcuate fasciculus. The patient underwent pre- and post-operative functional MRI and Diffusion Tensor Imaging, as well as behavioral assessments of language, motor, vision and praxis. The surgery for removal of the tumor was carried out with the patient awake, and direct electrical stimulation mapping was used to evaluate cortical language centers. The patient developed a specific difficulty with repeating sentences toward the end of the surgery, after resection of the tumor and partial transection of the arcuate fasciculus. The patient recovered from the sentence repetition impairments over several months after the operation. Coincident with the patient's cognitive recovery, we document a pattern whereby intra-hemispheric functional connectivity was reduced in the left hemisphere, while inter-hemispheric connectivity increased between classic left hemisphere language regions and their right hemisphere homologues. These findings suggest that increased synchrony between the two hemispheres, in the setting of focal transection of the left arcuate fasciculus, can facilitate functional recovery.

Direct electrical stimulation mapping of cognitive functions in the human brain.

Direct electrical stimulation (DES) is a well-established clinical tool for mapping cognitive functions while patients are undergoing awake neurosurgery or invasive long-term monitoring to identify epileptogenic tissue. Despite the proliferation of a range of invasive and noninvasive methods for mapping sensory, motor and cognitive processes in the human brain, DES remains the clinical gold standard for establishing the margins of brain tissue that can be safely removed while avoiding long-term neurological deficits. In parallel, and principally over the last two decades, DES has emerged as a powerful scientific tool for testing hypotheses of brain organization and mechanistic hypotheses of cognitive function. DES can cause transient "lesions" and thus can support causal inferences about the necessity of stimulated brain regions for specific functions, as well as the separability of sensory, motor and cognitive processes. This Special Issue of Cognitive Neuropsychology emphasizes the use of DES as a research tool to advance understanding of normal brain organization and function.

Translational Brain Mapping at the University of Rochester Medical Center: Preserving the Mind Through Personalized Brain Mapping.

The Translational Brain Mapping Program at the University of Rochester is an interdisciplinary effort that integrates cognitive science, neurophysiology, neuroanesthesia, and neurosurgery. Patients who have tumors or epileptogenic tissue in eloquent brain areas are studied preoperatively with functional and structural MRI, and intraoperatively with direct electrical stimulation mapping. Post-operative neural and cognitive outcome measures fuel basic science studies about the factors that mediate good versus poor outcome after surgery, and how brain mapping can be further optimized to ensure the best outcome for future patients. In this article, we describe the interdisciplinary workflow that allows our team to meet the synergistic goals of optimizing patient outcome and advancing scientific understanding of the human brain.

Direct electrical stimulation of the left frontal aslant tract disrupts sentence planning without affecting articulation.

Sentence production involves mapping from deep structures that specify meaning and thematic roles to surface structures that specify the order and sequencing of production ready elements. We propose that the frontal aslant tract is a key pathway for sequencing complex actions with deep hierarchical structure. In the domain of language, and primarily with respect to the left FAT, we refer to this as the 'Syntagmatic Constraints On Positional Elements' (SCOPE) hypothesis. One prediction made by the SCOPE hypothesis is that disruption of the frontal aslant tract should disrupt sentence production at grammatical phrase boundaries, with no disruption of articulatory processes.  We test this prediction in a patient undergoing direct electrical stimulation mapping of the frontal aslant tract during an awake craniotomy to remove a left frontal brain tumor. We found that stimulation of the left FAT prolonged inter-word durations at the start of grammatical phrases, while inter-word durations internal to noun phrases were unaffected, and there was no effect on intra-word articulatory duration. These results provide initial support for the SCOPE hypothesis, and motivate novel directions for future research to explore the functions of this recently discovered component of the language system.

Domain-Specific Diaschisis: Lesions to Parietal Action Areas Modulate Neural Responses to Tools in the Ventral Stream.

Neural responses to small manipulable objects ("tools") in high-level visual areas in ventral temporal cortex (VTC) provide an opportunity to test how anatomically remote regions modulate ventral stream processing in a domain-specific manner. Prior patient studies indicate that grasp-relevant information can be computed about objects by dorsal stream structures independently of processing in VTC. Prior functional neuroimaging studies indicate privileged functional connectivity between regions of VTC exhibiting tool preferences and regions of parietal cortex supporting object-directed action. Here we test whether lesions to parietal cortex modulate tool preferences within ventral and lateral temporal cortex. We found that lesions to the left anterior intraparietal sulcus, a region that supports hand-shaping during object grasping and manipulation, modulate tool preferences in left VTC and in the left posterior middle temporal gyrus. Control analyses demonstrated that neural responses to "place" stimuli in left VTC were unaffected by lesions to parietal cortex, indicating domain-specific consequences for ventral stream neural responses in the setting of parietal lesions. These findings provide causal evidence that neural specificity for "tools" in ventral and lateral temporal lobe areas may arise, in part, from online inputs to VTC from parietal areas that receive inputs via the dorsal visual pathway.

For the further training of individuals in neurosurgery: a history of the William P. Van Wagenen Fellowship.

The William P. Van Wagenen Fellowship, celebrating its 50th anniversary, is an annual award given by the AANS and administered by the Neurosurgery Research and Education Foundation (NREF). Named after its benefactor, Dr. William Van Wagenen, the fellowship continues his legacy of mentorship and innovation. As the premier research award for young neurosurgeons, it has provided a foundation for career development for many thought leaders in the field. The award was created in the spirit of Van Wagenen's belief in collaboration with other institutions as a means of refining neurosurgical technique, creating new research initiatives, and improving patient outcomes. Van Wagenen's commitment was informed by his early experiences in neurosurgery with his mentor Dr. Harvey Cushing, who helped to fund Van Wagenen's scientific endeavors in Europe. This journey catalyzed Van Wagenen's lifelong commitment to mentorship, which is exemplified by his instrumental role in the creation of the Harvey Cushing Society, now the AANS. Over the last 50 years, the recipients of this award have used the endowment to lay the groundwork for many scientific and technical innovations in neurosurgery. The fellowship remains an unmatched opportunity to explore new lines of investigation, foster academic and research goals, incorporate new technology and skills into American neurosurgical practice, and motivate young neurosurgeons to transform the field. The legacy of mentorship, scientific inquiry, and clinical excellence personified by Cushing and Van Wagenen is memorialized in the William P. Van Wagenen Fellowship.

A Role for the Frontal Aslant Tract in Speech Planning: A Neurosurgical Case Study.

Frontal and temporal white matter pathways play key roles in language processing, but the specific computations supported by different tracts remain a matter of study. A role in speech planning has been proposed for a recently described pathway, the frontal aslant tract (FAT), which connects the posterior inferior frontal gyrus to the pre-SMA. Here, we use longitudinal functional and structural MRI and behavioral testing to evaluate the behavioral consequences of a lesion to the left FAT that was incurred during surgical resection of a frontal glioma in a 60-year-old woman, Patient AF. The pattern of performance in AF is compared, using the same measures, with that in a 37-year-old individual who underwent a left anterior temporal resection and hippocampectomy (Patient AG). AF and AG were both cognitively intact preoperatively but exhibited specific and doubly dissociable behavioral deficits postoperatively: AF had dysfluent speech but no word finding difficulty, whereas AG had word finding difficulty but otherwise fluent speech. Probabilistic tractography showed that the left FAT was lesioned postoperatively in AF (but not AG) whereas the inferior longitudinal fasciculus was lesioned in AG (but not AF). Those structural changes were supported by corresponding changes in functional connectivity to the posterior inferior frontal gyrus: decreased functional connectivity postoperatively between the posterior inferior frontal gyrus and pre-SMA in AF (but not AG) and decreased functional connectivity between the posterior inferior frontal gyrus and the middle temporal gyrus in AG (but not AF). We suggest from these findings that the left FAT serves as a key communicative link between sentence planning and lexical access processes.

Direct Electrical Stimulation in the Human Brain Disrupts Melody Processing.

Prior research using functional magnetic resonance imaging (fMRI) [1-4] and behavioral studies of patients with acquired or congenital amusia [5-8] suggest that the right posterior superior temporal gyrus (STG) in the human brain is specialized for aspects of music processing (for review, see [9-12]). Intracranial electrical brain stimulation in awake neurosurgery patients is a powerful means to determine the computations supported by specific brain regions and networks [13-21] because it provides reversible causal evidence with high spatial resolution (for review, see [22, 23]). Prior intracranial stimulation or cortical cooling studies have investigated musical abilities related to reading music scores [13, 14] and singing familiar songs [24, 25]. However, individuals with amusia (congenitally, or from a brain injury) have difficulty humming melodies but can be spared for singing familiar songs with familiar lyrics [26]. Here we report a detailed study of a musician with a low-grade tumor in the right temporal lobe. Functional MRI was used pre-operatively to localize music processing to the right STG, and the patient subsequently underwent awake intraoperative mapping using direct electrical stimulation during a melody repetition task. Stimulation of the right STG induced "music arrest" and errors in pitch but did not affect language processing. These findings provide causal evidence for the functional segregation of music and language processing in the human brain and confirm a specific role of the right STG in melody processing. VIDEO ABSTRACT.

A Randomized, Double-blind, Placebo-Controlled Crossover Trial of Oxymorphone Hydrochloride and Propoxyphene/Acetaminophen Combination for the Treatment of Neurogenic Claudication Associated With Lumbar Spinal Stenosis.

STUDY DESIGN: Randomized, double-blind, placebo-controlled, single-dose crossover study. OBJECTIVE: To test the analgesic efficacy of oxymorphone hydrochloride (OH) and propoxyphene/acetaminophen (PA) for patients with neurogenic claudication associated with lumbar spinal stenosis. SUMMARY OF BACKGROUND DATA: Although opioids are often prescribed for neurogenic claudication, no randomized controlled studies support their efficacy for this condition. Patients with neurogenic claudication are generally excluded from clinical trials or included with patients who have nonspecific chronic low back pain, yielding a heterogeneous study population with very different pathophysiologies and clinical presentations. METHODS: Participants received a single dose of each of the 3 treatments in random order. Treatments were separated by at least 3-day washout periods. The primary outcome variable was the time to first treadmill walking-induced moderate pain (≥4 out of 10 on a Numeric Rating Scale) (Tfirst) assessed 90 minutes after treatment administration. Secondary outcome measures included patient global assessment of low back pain, Roland-Morris Disability Questionnaire, Modified Brief Pain Inventory-Short Form, Oswestry Disability Index, and Swiss Spinal Stenosis Questionnaire. RESULTS: The study was prematurely terminated because of the removal of PA from the US market. Twenty-four patients were randomized; 21 completed all 3 treatment periods. There were no significant differences among the treatment groups with respect to the median Tfirst (OH-placebo: median [98.3% confidence limits]=-0.25 min [-6.54, 5.00]; PA-placebo: 0.02 min [-7.65, 4.90]; OH-PA: -0.27 min [-5.56, 6.66]). CONCLUSION: This trial failed to demonstrate a benefit of OH or PA in patients experiencing neurogenic claudication. Considering the potential negative side effects of chronic opioid use, additional research is necessary to evaluate the efficacy of sustained opioid treatment specifically for neurogenic claudication. LEVEL OF EVIDENCE: 2.

Double-blind, randomized, controlled, crossover trial of pregabalin for neurogenic claudication.

OBJECTIVES: To test the effects of pregabalin on the induction of neurogenic claudication. METHODS: This study was a randomized, double-blind, active placebo-controlled, 2-period, crossover trial. Twenty-nine subjects were randomized to receive pregabalin followed by active placebo (i.e., diphenhydramine) or active placebo followed by pregabalin. Each treatment period lasted 10 days, including a 2-step titration. Periods were separated by a 10-day washout period, including a 3-day taper phase after the first period. The primary outcome variable was the time to first moderate pain symptom (Numeric Rating Scale score ≥4) during a 15-minute treadmill test (Tfirst). Secondary outcome measures included pain intensity at rest, pain intensity at the end of the treadmill test, distance walked, and validated self-report measures of pain and functional limitation including the Roland-Morris Disability Questionnaire, modified Brief Pain Inventory-Short Form, Oswestry Disability Index, and Swiss Spinal Stenosis Questionnaire. RESULTS: No significant difference was found between pregabalin and active placebo for the time to first moderate pain symptom (difference in median Tfirst = -1.08 [95% confidence interval -2.25 to 0.08], p = 0.61). In addition, none of the secondary outcome measures of pain or functional limitation were significantly improved by pregabalin compared with active placebo. CONCLUSIONS: Pregabalin was not more effective than active placebo in reducing painful symptoms or functional limitations in patients with neurogenic claudication associated with lumbar spinal stenosis. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with neurogenic claudication, compared with diphenhydramine, pregabalin does not increase the time to moderate pain during a treadmill test.

The history of neurosurgery at the University of Rochester.

The Department of Neurosurgery at the University of Rochester has a long legacy of excellent patient care and innovation in the neurosciences. The department's founder, Dr. William Van Wagenen, was a direct pupil of Harvey Cushing and the first president of the Harvey Cushing Society. His successor, Dr. Frank P. Smith, was also a leader in organized neurosurgery and helped to permanently memorialize his mentor with an endowed fellowship that today is one of the most prestigious training awards in neurosurgery. The first 2 chiefs are honored every year by the department with memorial invited lectureships in their names. The department is home to a thriving multidisciplinary research program that fulfills the lifelong vision of its founder, Dr. Van Wagenen.

William P. Van Wagenen (1897-1961): pupil, mentor, and neurosurgical pioneer.

William Perrine ("Van") Van Wagenen (1897-1961) was the first Chief of Neurosurgery at the University of Rochester Medical Center (URMC), serving from 1928 to 1954, and was a leading figure in 20th-century neurosurgery. He was a devoted pupil of Dr. Harvey Cushing and helped to found the Harvey Cushing Society (now the AANS) in honor of his mentor and was elected as its first President in 1932. He served as the 27th President of the Society of Neurological Surgeons in 1952. Upon his death in 1961 he bequeathed an endowment for the Van Wagenen Fellowship, which has advanced the education of many leaders in American neurosurgery. His legacy of operative skill, his commitment to resident education and research in neurological disease, his inspiration for the foundation of the Cushing Brain Tumor registry, and his contributions to organized neurosurgery form the foundation of the legacy of neurosurgery at URMC.

Stereotactic radiosurgery for glioblastoma: retrospective analysis.

PURPOSE: This retrospective study was done to better understand the conditions for which stereotactic radiosurgery (SRS) for glioblastoma may be efficacious. METHODS: Between 2000 and 2007, 33 patients with a pathological diagnosis of glioblastoma received SRS with the Novalis Shaped Beam Radiosurgery system. Eighteen patients (54%) underwent salvage SRS for recurrence while 15 (45%) patients received upfront SRS following standard fractionated RT for newly diagnosed glioblastoma. RESULTS: There were no RTOG grade >2 acute side effects. The median survival after SRS was 6.7 months (range 1.4 - 74.7). There was no significant difference in overall survival (from the time of initial diagnosis) with respect to the timing of SRS (p = 0.2). There was significantly better progression free survival in patients treated with SRS as consolidation versus at the time of recurrence (p = 0.04). The majority of patients failed within or at the margin of the SRS treatment volume (21/26 evaluable for recurrence). CONCLUSION: SRS is well tolerated in the treatment of glioblastoma. As there was no difference in survival whether SRS is delivered upfront or at recurrence, the treatment for each patient should be individualized. Future studies are needed to identify patients most likely to respond to SRS.

Statin treatment of adult human glial progenitors induces PPAR gamma-mediated oligodendrocytic differentiation.

The statins have been proposed as possible therapeutic agents for a variety of autoimmune disorders, including multiple sclerosis. In a genomic screen, we found that glial progenitor cells (GPCs) of the adult human white matter expressed significant levels of the principal statin target, HMG-CoA reductase, as well as additional downstream members of the sterol synthesis pathway. We therefore asked if statin treatment might influence the differentiated fate of adult glial progenitor cells. To assess the functional importance of the sterol synthesis pathway to adult human glial progenitors, we used simvastatin or pravastatin to inhibit HMG-CoA reductase, and then assessed the phenotypic differentiation of the progenitors, as well as the molecular concomitants thereof. We found that both statins induced a dose-dependent induction of oligodendrocyte phenotype, and concomitant reduction in progenitor number. Oligodendrocyte commitment was associated with induction of the sterol-regulated nuclear co-receptor PPARgamma, and could be blocked by the specific PPARgamma antagonist GW9662. Thus, statins may promote oligodendrocyte lineage commitment by parenchymal glial progenitor cells; this might reduce the available progenitor pool, and hence degrade the long-term regenerative competence of the adult white matter.

Special cases: mechanical ventilation of neurosurgical patients.

Mechanical ventilation has evolved greatly over the last half century, guided primarily by improved comprehension of the relevant pathology/physiology. Neurosurgical patients are a unique subgroup of patients who heavily use this technology for both support, and less commonly, as a therapy. Such patients demand special consideration with regard to mode of ventilation, use of positive end-expiratory pressure, and monitoring. In addition, meeting the ventilatory needs of neurosurgical patients while minimizing ventilatory-induced lung damage can be a challenging aspect of care.

Complementary patterns of gene expression by human oligodendrocyte progenitors and their environment predict determinants of progenitor maintenance and differentiation.

OBJECTIVE: Glial progenitor cells are abundant in adult human white matter. This study was designed to identify signaling pathways regulating their self-renewal and fate. METHODS: We compared the transcriptional profiles of freshly sorted adult human white matter progenitor cells (WMPCs), purified by A2B5-based immunomagnetic sorting, with those of the white matter from which they derived. RESULTS: We identified 132 genes differentially expressed by WMPCs; these included principal components of five receptor-defined signaling pathways, represented by platelet derived growth factor receptor alpha (PDGFRA) and type 3 fibroblast growth factor receptor (FGFR3), receptor tyrosine phosphatase-beta/zeta (RTPZ), notch, and syndecan3. WMPCs also differentially expressed the bone morphogenetic protein 4 (BMP4) inhibitors neuralin and BAMBI (BMP and activin membrane-bound inhibitor), suggesting tonic defense against BMP signaling. Differential overexpression of RTPZ was accompanied by that of its modulators pleiotrophin, NrCAM, tenascin, and the chondroitin sulfate proteoglycans, suggesting the importance of RTPZ signaling to WMPCs. When exposed to the RTPZ inhibitor bpV(phen), or lentiviral-shRNAi against RTPZ, WMPCs differentiated as oligodendrocytes. Conversely, when neuralin and BAMBI were antagonized by BMP4, astrocytic differentiation was induced, which was reversible by noggin. INTERPRETATION: The RTPZ and BMP pathways regulate the self-maintenance of adult human WMPCs, and can be modulated to induce their oligodendrocytic or astrocytic differentiation. As such, they provide targets by which to productively mobilize resident progenitor cells of the adult human brain.