Blood supply to the corticospinal tract: A pictorial review with application to cranial surgery and stroke.

The corticospinal tract (CST) is the main neural pathway responsible for conducting voluntary motor function in the central nervous system. The CST condenses into fiber bundles as it descends from the frontoparietal cortex, traveling down to terminate at the anterior horn of the spinal cord. The CST is at risk of injury from vascular insult from strokes and during neurosurgical procedures. The aim of this article is to identify and describe the vasculature associated with the CST from the cortex to the medulla. Dissection of cadaveric specimens was carried out in a manner, which exposed and preserved the fiber tracts of the CST, as well as the arterial systems that supply them. At the level of the motor cortex, the CST is supplied by terminal branches of the anterior cerebral artery and middle cerebral artery. The white matter tracts of the corona radiata and internal capsule are supplied by small perforators including the lenticulostriate arteries and branches of the anterior choroidal artery. In the brainstem, the CST is supplied by anterior perforating branches from the basilar and vertebral arteries. The caudal portions of the CST in the medulla are supplied by the anterior spinal artery, which branches from the vertebral arteries. The non-anastomotic nature of the vessel systems of the CST highlights the importance of their preservation during neurosurgical procedures. Anatomical knowledge of the CST is paramount to clinical diagnosis and treatment of heterogeneity of neurodegenerative, neuroinflammatory, cerebrovascular, and skull base tumors.

Mortality in Patients with Brainstem Cavernous Malformations.

OBJECTIVE: Brainstem cavernous malformations (BSCM)-associated mortality has been reported up to 20% in patients managed conservatively, whereas postoperative mortality rates range from 0 to 1.9%. Our aim was to analyze the actual risk and causes of BSCM-associated mortality in patients managed conservatively and surgically based on our own patient cohort and a systematic literature review. METHODS: Observational, retrospective single-center study encompassing all patients with BSCM that presented to our institution between 2006 and 2018. In addition, a systematic review was performed on all studies encompassing patients with BSCM managed conservatively and surgically. RESULTS: Of 118 patients, 54 were treated conservatively (961.0 person years follow-up in total). No BSCM-associated mortality was observed in our conservatively as well as surgically managed patient cohort. Our systematic literature review and analysis revealed an overall BSCM-associated mortality rate of 2.3% (95% CI: 1.6-3.3) in 22 studies comprising 1,251 patients managed conservatively and of 1.3% (95% CI: 0.9-1.7) in 99 studies comprising 3,275 patients with BSCM treated surgically. CONCLUSION: The BSCM-associated mortality rate in patients managed conservatively is almost as low as in patients treated surgically and much lower than in frequently cited reports, most probably due to the good selection nowadays in regard to surgery.

Outcome after acute ischemic stroke is linked to sex-specific lesion patterns.

Acute ischemic stroke affects men and women differently. In particular, women are often reported to experience higher acute stroke severity than men. We derived a low-dimensional representation of anatomical stroke lesions and designed a Bayesian hierarchical modeling framework tailored to estimate possible sex differences in lesion patterns linked to acute stroke severity (National Institute of Health Stroke Scale). This framework was developed in 555 patients (38% female). Findings were validated in an independent cohort (n = 503, 41% female). Here, we show brain lesions in regions subserving motor and language functions help explain stroke severity in both men and women, however more widespread lesion patterns are relevant in female patients. Higher stroke severity in women, but not men, is associated with left hemisphere lesions in the vicinity of the posterior circulation. Our results suggest there are sex-specific functional cerebral asymmetries that may be important for future investigations of sex-stratified approaches to management of acute ischemic stroke.

The predictors of clinical outcomes in brainstem arteriovenous malformations after stereotactic radiosurgery.

ABSTRACT: The brainstem arteriovenous malformations (BS-AVMs) have a high morbidity and mortality and stereotactic radiosurgery (SRS) has been widely used to treat BS-AVMs. However, no consensus is reached in the explicit predictors of obliteration for BS-AVMs after SRS.To identify the predictors of clinical outcomes for BS-AVMs treated by SRS, we performed a retrospective observational study of BS-AVMs patients treated by SRS at our institution from 2006 to 2016. The primary outcomes were obliteration of nidus and favorable outcomes (AVM nidus obliteration with mRS score ≤2). For getting the outcomes more accurate, we also pooled the results of previous studies as well as our study by meta-analysis.A total of 26 patients diagnosed with BS-AVMs, with mean volume of 2.6 ml, were treated with SRS. Hemorrhage presentation accounted for 69% of these patients. Overall obliteration rate was 42% with mean follow-up of more than five years and two patients (8%) had a post-SRS hemorrhage. Favorable outcomes were observed in 8 patients (31%). Higher margin dose (>15Gy) was associated with higher obliteration (P = .042) and small volume of nidus was associated with favorable outcomes (P = .036). After pooling the results of 7 studies and present study, non-prior embolization (P = .049) and higher margin dose (P = .04) were associated with higher obliteration rate, in addition, the lower Virginia Radiosurgery AVM Scale (VRAS) was associated with favorable outcomes (P = .02) of BS-AVMs after SRS.In the BS-AVMs patients treated by SRS, higher margin dose (19-24Gy) and non-prior embolization were the independent predictors of higher obliteration rate. In addition, smaller volume of nidus and lower VRAS were the potential predictors of long-term favorable outcomes for these patients.

Perfusion and permeability as diagnostic biomarkers of cavernous angioma with symptomatic hemorrhage.

Cavernous angiomas with symptomatic hemorrhage (CASH) have a high risk of rebleeding, and hence an accurate diagnosis is needed. With blood flow and vascular leak as established mechanisms, we analyzed perfusion and permeability derivations of dynamic contrast-enhanced quantitative perfusion (DCEQP) MRI in 745 lesions of 205 consecutive patients. Thirteen respective derivations of lesional perfusion and permeability were compared between lesions that bled within a year prior to imaging (N = 86), versus non-CASH (N = 659) using machine learning and univariate analyses. Based on logistic regression and minimizing the Bayesian information criterion (BIC), the best diagnostic biomarker of CASH within the prior year included brainstem lesion location, sporadic genotype, perfusion skewness, and high-perfusion cluster area (BIC = 414.9, sensitivity = 74%, specificity = 87%). Adding a diagnostic plasma protein biomarker enhanced sensitivity to 100% and specificity to 85%. A slightly modified derivation achieved similar accuracy (BIC = 321.6, sensitivity = 80%, specificity = 82%) in the cohort where CASH occurred 3-12 months prior to imaging after signs of hemorrhage would have disappeared on conventional MRI sequences. Adding the same plasma biomarker enhanced sensitivity to 100% and specificity to 87%. Lesional blood flow on DCEQP may distinguish CASH after hemorrhagic signs on conventional MRI have disappeared and are enhanced in combination with a plasma biomarker.

Parasympathetic brainstem origin sites of triggered external and internal carotid vasodilation are not distributed topographically in the rat.

Cranial parasympathetic activation produces vasodilation in the head and neck region, but little is known about its central and peripheral mechanisms. This study was conducted to examine whether external and internal carotid-vasodilation origin sites triggered by chemical stimulation are distributed topographically in the parasympathetic brainstems of anesthetized rats, and to examine the effects of peripheral receptors on vasodilation. Microinjection of the neuromodulator candidate l-cysteine revealed that external and internal carotid vasodilation-triggering sites were distributed non-topographically along the full extent of the parasympathetic parvocellular reticular formation (PcRt). Intravenous injection of a muscarinic blocker and a nitric oxide synthase inhibitor abolished external carotid vasodilation, suggesting the peripheral involvement of muscarinic and nitric oxide receptors. Further work is needed to fully understand the PcRt mechanisms underlying timely and appropriate vasodilation to support various cranial functions.

The Longitudinal Distribution and Stability of Curved Basilar Artery Plaque: A Study Based on HR-MRI.

AIMS: This study aims to evaluate the differences in the characteristics of atherosclerotic plaques in the proximal, curved, and distal segments of the curved basilar artery (BA) through high-resolution magnetic resonance imaging(HR-MRI). METHODS: The imaging and clinical data of 146 patients were retrospectively analyzed. On the basis of three-dimensional (3D) time -of -flight magnetic resonance angiography (3D-TOF-MRA), 51 patients with BA curvature were selected for the study. The BA plaque is divided into three groups: proximal, curved, and distal. Plaques were identified and analyzed according to spin echo acquisition imaging via T1-weighted 3D volumetric isotropic Tse acquisition (T1W-3D -VISTA), and compare the differences in clinical related factors and plaque characteristics between groups. Diffusion-weighted imaging (DWI) and/or T2WI identified brainstem infarction. The patients were divided into symptomatic and asymptomatic groups. The correlation between plaque location and symptoms was identified and analyzed. RESULTS: Among 51 patients, a total of 376 plaques were detected. Plaques in the proximal and curved segments are more common than those in the distal segments. Proximal plaques are more likely to have intraplaque hemorrhage ( P=0.002 ＜0.05). There was no significant difference in the distribution of criminal plaques and non-criminal plaques between each group (P=0.36 ＞0.05). CONCLUSION: Plaques in the proximal and curved segments of the BA are more common than those in the distal segments. The proximal plaque is more prone to intraplaque hemorrhage.

Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis.

Long-COVID is a postviral illness that can affect survivors of COVID-19, regardless of initial disease severity or age. Symptoms of long-COVID include fatigue, dyspnea, gastrointestinal and cardiac problems, cognitive impairments, myalgia, and others. While the possible causes of long-COVID include long-term tissue damage, viral persistence, and chronic inflammation, the review proposes, perhaps for the first time, that persistent brainstem dysfunction may also be involved. This hypothesis can be split into two parts. The first is the brainstem tropism and damage in COVID-19. As the brainstem has a relatively high expression of ACE2 receptor compared with other brain regions, SARS-CoV-2 may exhibit tropism therein. Evidence also exists that neuropilin-1, a co-receptor of SARS-CoV-2, may be expressed in the brainstem. Indeed, autopsy studies have found SARS-CoV-2 RNA and proteins in the brainstem. The brainstem is also highly prone to damage from pathological immune or vascular activation, which has also been observed in autopsy of COVID-19 cases. The second part concerns functions of the brainstem that overlap with symptoms of long-COVID. The brainstem contains numerous distinct nuclei and subparts that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be linked to long-COVID. As neurons do not readily regenerate, brainstem dysfunction may be long-lasting and, thus, is long-COVID. Indeed, brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome.

Methyl palmitate modulates the nicotine-induced increase in basilar arterial blood flow.

Methyl palmitate (MP) is a fatty acid methyl ester. Our recent study indicated that adrenergic nerve-dependent functional sympathetic-sensory nerve interactions were abolished by MP in mesenteric arteries. However, the effect of MP on perivascular nerves and cerebral blood flow remains unclear. In this study, the increase in basilar arterial blood flow (BABF) after the topical application of nicotinic acetylcholine receptor agonists was measured using laser Doppler flowmetry in anesthetized rats. The choline (a selective α7-nicotinic acetylcholine receptor agonist)-induced increase in BABF was abolished by tetrodotoxin (a neurotoxin), NG -nitro-L-arginine (a nonselective NO synthase inhibitor), α-bungarotoxin (a selective α7-nicotinic acetylcholine receptor inhibitor), and chronic sympathetic denervation. In addition, the nicotine (a nicotinic acetylcholine receptor agonist)-induced increase in BABF was inhibited by MP in a concentration-dependent manner. The acetylcholine-induced increase in BABF was not affected by MP. The myography results revealed that nicotine-induced vasorelaxation was significantly inhibited by MP, but was reversed by chelerythrine (a protein kinase C inhibitor). MP-induced vasodilation was significantly greater in BA rings without endothelium compared to those with endothelium. Meanwhile, MP did not affect baseline BABF. Our results indicate that MP acts as a neuromodulator in the cerebral circulation where it activates the PKC pathway and causes a diminished nicotine-induced increase in blood flow in the brainstem, and that the vasorelaxation effect of MP may play a minor role.

Early tracheostomy is associated with better prognosis in patients with brainstem hemorrhage.

Brainstem hemorrhage is presumed to be invariably associated with a poor prognosis in people with spontaneous hypertensive cerebral hemorrhage. The optimal timing of tracheostomy placement in brainstem hemorrhage patients, who generally require endotracheal intubation for airway protection, remains uncertain. Our research aim was to analyze the impact of early tracheostomy versus late tracheostomy on brainstem hemorrhage patients related outcomes and prognostic factors at 30 days. We identified early tracheostomy and how it could benefit the patients with brainstem hemorrhage and ameliorate the predictors of functional recovery at 30 days. Data on 136 patients with brainstem hemorrhage and Glasgow Coma Scale score ≤ 8, were retrospectively collected from 2012 to 2019. Patients were divided into the early tracheostomy group and the late tracheostomy group. Patients in the early tracheostomy group had a significantly lower neurosurgical intensive care unit stay (both overall and survival) compared with the late tracheostomy group (15.6 days vs. 19.0 days, P = 0.041, overall and 14.5 vs. 19.5 days, P = 0.023, survival). Also, the good outcomes (modified Rankin Score ≤ 3) were higher in the early tracheostomy group (P = 0.036). Multivariate analysis demonstrated that less hemorrhagic volume, high Glasgow Coma Scale score on admission, young age, and early tracheostomy were significantly associated with a better 30-day functional outcome. In conclusion, an early tracheostomy in patients with brainstem hemorrhage can reduce neurosurgical intensive care unit stay, and in addition to improvements in prognosis at 30 days.

Mild hypoxia triggers transient blood-brain barrier disruption: a fundamental protective role for microglia.

We recently demonstrated that when mice are exposed to chronic mild hypoxia (CMH, 8% O2), blood vessels in the spinal cord show transient vascular leak that is associated with clustering and activation of microglia around disrupted vessels. Importantly, microglial depletion profoundly increased hypoxia-induced vascular leak, implying that microglia play a critical role maintaining vascular integrity in the hypoxic spinal cord. The goal of the current study was to examine if microglia play a similar vasculo-protective function in the brain. Employing extravascular fibrinogen leak as an index of blood-brain barrier (BBB) disruption, we found that CMH provoked transient vascular leak in cerebral blood vessels that was associated with activation and aggregation of Mac-1-positive microglia around leaky vessels. Interestingly, CMH-induced vascular leak showed regional selectivity, being much more prevalent in the brainstem and olfactory bulb than the cerebral cortex and cerebellum. Pharmacological depletion of microglia with the colony stimulating factor-1 receptor inhibitor PLX5622, had no effect under normoxic conditions, but markedly increased hypoxia-induced cerebrovascular leak in all regions examined. As in the spinal cord, this was associated with endothelial induction of MECA-32, a marker of leaky CNS endothelium, and greater loss of endothelial tight junction proteins. Brain regions displaying the highest levels of hypoxic-induced vascular leak also showed the greatest levels of angiogenic remodeling, suggesting that transient BBB disruption may be an unwanted side-effect of hypoxic-induced angiogenic remodeling. As hypoxia is common to a multitude of human diseases including obstructive sleep apnea, lung disease, and age-related pulmonary, cardiac and cerebrovascular dysfunction, our findings have important translational implications. First, they point to a potential pathogenic role of chronic hypoxia in triggering BBB disruption and subsequent neurological dysfunction, and second, they demonstrate an important protective role for microglia in maintaining vascular integrity in the hypoxic brain.

Possible affective cognitive cerebellar syndrome in a young patient with COVID-19 CNS vasculopathy and stroke.

Early case series suggest that about one-third of patients with COVID-19 present with neurological manifestations, including cerebrovascular disease, reported in 2%-6% of hospitalised patients. These are generally older patients with severe infection and comorbidities. Here we discuss the case of a previously fit and well 39-year-old man who presented with fever and respiratory symptoms, evolving in pneumonia with hypoxia but only requiring continuous positive airway pressure. After resolution of the respiratory disease, the patient developed focal neurology and was found to have bilateral occipital, thalamic and cerebellar infarcts. A diagnosis of COVID-19 central nervous system vasculopathy was made. He developed a florid neuropsychiatric syndrome, including paranoia, irritability, aggression and disinhibition, requiring treatment with antipsychotics and transfer to neurorehabilitation. Neuropsychometry revealed a wide range of cognitive deficits. The rapid evolution of the illness was matched by fast resolution of the neuropsychiatric picture with mild residual cognitive impairment.

Postictal brainstem hypoperfusion and risk factors for sudden unexpected death in epilepsy.

OBJECTIVE: Since the strongest risk factor for sudden unexpected death in epilepsy (SUDEP) is frequent bilateral tonic-clonic seizures (BTCS), our aim was to determine whether postictal hypoperfusion in brainstem respiratory centers (BRCs) is more common following tonic-clonic seizures. METHODS: We studied 21 patients with focal epilepsies who underwent perfusion imaging with arterial spin labeling MRI. Subtraction maps of cerebral blood flow were obtained from the postictal and baseline scans. We identified 6 regions of interest in the brainstem that contain key BRCs. Patients were considered to have postictal BRC hypoperfusion if any of the 6 regions of interest were significantly hypoperfused. RESULTS: All 6 patients who experienced BTCS during the study had significant clusters of postictal hypoperfusion in BRCs compared to 7 who had focal impaired awareness seizures (7/15). The association between seizure type studied and the presence of BRC hypoperfusion was significant. Duration of epilepsy and frequency of BTCS were not associated with postictal brainstem hypoperfusion despite also being associated with risk for SUDEP. CONCLUSION: Postictal hypoperfusion in brainstem respiratory centers occurs more often following BTCS than other seizure types, providing a possible explanation for the increased risk of SUDEP in patients who regularly experience BTCS.

Brainstem iron overload and injury in a rat model of brainstem hemorrhage.

BACKGROUND AND PURPOSE: Brainstem hemorrhage (BSH) is the most devastating subtype of intracerebral hemorrhage (ICH) with the highest mortality ranging from 56 % to 61.2 %. However, there is no effective medical or surgical therapy to improve its outcomes in clinic to date due to lack of understanding of its injury mechanisms. Herein, we explored the brainstem iron overload and injury in a rat model of BSH. METHODS: Neurological scores were examined on day 1, 3, and 7 after modeling, and mortality of the rats was recorded to draft a survival curve. Rats were monitored by MRI using T2 and susceptibility weighted imaging (SWI) before sacrifice for examination of histology and immunofluorescence on day 1, 3, and 7. RESULTS: BSH rats had a high mortality of 56 % and demonstrated the severe neurological deficits mimicking the clinical conditions. SWI showed that the same increasing tendency in change of hypointense area with that in iron deposition by Perls staining from day 1 to 7. Expression of heme oxygenase 1 (HO-1) and generation of reactive oxygen species (ROS) had similar tendency and both peaked on day 3. Neuronal degeneration occurred and stayed elevated from day 1 to 7, while myelin sheath injury was initially observed on day 1 but without significant difference within 7 days. CONCLUSIONS: The time courses of erythrocyte lysis, HO-1 expression, iron deposition and ROS generation are related to each other after BSH. Besides, brainstem injury including neuronal degeneration and myelin damage were observed and discussed.

Natural History of Infratentorial Intracerebral Hemorrhages: Two Subgroups with Distinct Presentations and Outcomes.

BACKGROUND/OBJECTIVE: Infratentorial intracerebral hemorrhage (ICH) is associated with worse prognosis than supratentorial ICH; however, infratentorial ICH is often excluded or underrepresented in clinical trials of ICH. We sought to evaluate the natural history of infratentorial ICH stratified by brainstem or cerebellar location using a prospective observational study inclusive of all spontaneous ICH. METHODS: Using a prospective, single center cohort of patients with spontaneous ICH between 2008-2019, we conducted a descriptive analysis of baseline demographics, severity of injury scores, and long-term functional outcomes of infratentorial ICH stratified by cerebellar or brainstem location. RESULTS: Infratentorial ICH occurred in 82 (13%) of 632 patients in our ICH cohort. Among infratentorial ICH, cerebellar ICH occurred in 45 (55%) and brainstem ICH occurred in 37 (45%). Compared to cerebellar ICH, patients with brainstem ICH had significantly worse severity of injury scores, including lower admission Glasgow Coma Scale (median 14 [7.0 - 15.0] versus 4 [3.0 - 8.0], respectively; P < 0.001) and higher ICH Score (median 2 [1.0 - 3.0] versus 3 [2.75 - 4.0], respectively; P =  0.02). Patients with cerebellar ICH were more likely to be discharged home or to acute rehabilitation (OR 4.8, 95% CI 1.8 - 12.8) but there was no difference in in-hospital mortality (OR 0.4, 95% CI 0.1 - 1.1, P =  0.08) or cause of death (P =  0.5). Modified Rankin Scale scores at 3 months were significantly better in patients with cerebellar ICH compared to brainstem ICH (median 3.5 [1.8 - 6.0] versus median 6 [5.0 - 6.0], P =  0.03). CONCLUSIONS: Location of infratentorial ICH is an important determinant of admission severity and clinical outcome in unselected patients with ICH. Patients with cerebellar ICH have less severe symptoms at presentation and more favorable functional outcomes compared to patients with brainstem ICH.

A review on four different paths to respiratory arrest from brain injury in children; implications for child abuse.

Child abuse was suspected in a case of out-of-hospital arrest with minor brain injuries. Confronted with continued disputes on pathophysiologic correlates even after autopsy, to assist the differentiation of potential causes of sudden cardiopulmonary arrest in children, we tried to identify the mechanism of cardiopulmonary arrest in brain injuries from different causes. Systematic review was carried out in two stages. First, major external causes of cardiopulmonary arrest among children and infants were identified from Pubmed and Google Scholar search, and then the exact sequence of cardiopulmonary arrest, and their pathophysiologic features were identified based on articles of animal models of brain injury. From the review, we have identified four major groups of external circumstances for rather sudden cardiopulmonary arrest from brain damage in children, after excluding congenital and other unrelated diseases; 1) impact brain apnea, 2) anoxic insults, 3) drug or other substance induced central nervous system depression, and 4) traumatic brain damage. Each group has different features in the course of cardiac and respiratory arrests. Based on this review of pathophysiologic features of cardio-respiratory responses from external causes, we have presented a suspected, but unlikely, child abuse case of respiratory arrest from brain injury. The social consequences of both unknowingly missing, and falsely incriminating the abuse can be grave, and the identification of the mechanisms of cardiopulmonary arrest from brain injury can be important for the differentiation of various potential causes.

miR-22 and cerebral microbleeds in brainstem and deep area are associated with depression one month after ischemic stroke.

In this study, we aimed to explore the relationship among miR-22, deep cerebral microbleeds (CMBs), and post-stroke depression (PSD) 1 month after ischemic stroke. We consecutively recruited 257 patients with first-ever and recurrent acute cerebral infarction and performed PSD diagnosis in accordance with the Diagnostic and Statistical Manual IV criteria for depression. Clinical information, assessments of stroke severity, and imaging data were recorded on admission. We further detected plasma miR-22 using quantitative PCR and analyzed the relationship among miR-22, clinical data, and PSD using SPSS 23.0 software. Logistic regression showed that deep (OR=1.845, 95%CI: 1.006-3.386, P=0.047) and brain stem CMBs (OR=2.652, 95%CI: 1.110-6.921, P=0.040), as well as plasma miR-22 levels (OR=2.094, 95%CI: 1.066-4.115, P=0.032) were independent risk factors for PSD. In addition, there were significant differences in baseline National Institutes of Health Stroke Scale scores (OR=1.881, 95%CI: 1.180-3.011, P=0.007) and Widowhood scores (OR=1.903, 95%CI: 1.182-3.063, P=0.012). Analysis of the receiver operating curve (AUC=0.723, 95%CI: 0.562-0.883, P=0.016) revealed that miR-22 could predict PSD one month after ischemic stroke. Furthermore, plasma miR-22 levels in brainstem and deep CMBs patients showed an upward trend (P=0.028) relative to the others. Patients with acute ischemic stroke, having brainstem and deep cerebral microbleeds, or a higher plasma miR-22 were more likely to develop PSD. These findings indicate that miR-22 might be involved in cerebral microvascular impairment and post-stroke depression.

Microsurgical Resection of Brainstem Arteriovenous Malformation: 2-Dimensional Operative Video.

Brainstem arteriovenous malformations (AVMs) are rare lesions (2%-6% of all intracranial AVMs) that are surgically challenging because of the high eloquence of the brainstem, including dense fiber tracts, cranial nerves, and multiple vital cerebrovascular structures. All these lesions possess eloquence and deep venous drainage, making them innately Spetlzer-Martin grade III or above. This patient had a large midbrain AVM with a complex clinical course beginning with ventriculoperitoneal shunting due to mass effect; the patient experienced 4 hemorrhages, underwent radiation treatment, and finally underwent surgical resection. The surgical approach involved a large torcular craniotomy exposing all posterior sinuses at the confluence. The vein of Galen was exposed and carried deeply to permit ambient cistern opening and relaxation of the cerebellum. Because of earlier radiation therapy, the vessels had undergone hyalinosis, which resulted in difficult manipulation of the nidus but did permit excellent coagulation of the vessels. The complete nidus was removed, as confirmed on postoperative angiography. The patient gave informed consent for surgery and video recording. Institutional review board approval was deemed unnecessary. Used with permission from Barrow Neurological Institute, Phoenix, Arizona.

Differential blockade by huperzine A and donepezil of sympathetic nicotinic acetylcholine receptor-mediated nitrergic neurogenic dilations in porcine basilar arteries.

Nicotinic acetylcholine receptor activation on the perivascular sympathetic nerves via axo-axonal interaction mechanism causes norepinephrine release, which triggers the neurogenic nitrergic relaxation in basilar arteries to meet the need of a brain. Donepezil and huperzine A, which are the cholinesterase inhibitors used for Alzheimer's disease therapy, exert controversial effects on nicotinic acetylcholine receptors. Therefore, we investigated how donepezil and huperzine A via the axo-axonal interaction regulate the neurogenic vasodilation of isolated porcine basilar arteries and define their action on different subtypes of the nicotinic acetylcholine receptor by using blood vessel myography, calcium imaging, and electrophysiological techniques. Both nicotine (100 µM) and transmural nerve stimulation (TNS, 8 Hz) induce NO-mediated dilation in the arteries. Nicotine-induced vasodilations were concentration-dependently inhibited by huperzine A and donepezil, with the former being 30 fold less potent than the latter. Both cholinesterase inhibitors weakly and equally decreased TNS-elicited nitrergic vasodilations. Neither huperzine A nor donepezil affected isoproterenol (a ß adrenoceptor-agonist)- or sodium nitroprusside (a NO donor)-induced vasodilation. Further, huperzine A was less potent than donepezil in inhibiting nicotine-elicited calcium influxes in rodent superior cervical ganglionic neurons and inward currents in α7- and α3ß2-nicotinic acetylcholine receptor-expressing Xenopus oocytes. In conclusion, huperzine A may exert less harmful effect over donepezil on maintaining brainstem circulation and on the nicotinic acetylcholine receptor-associated cognition deficits during treatment for Alzheimer's disease.