Macrophage imaging within human cerebral aneurysms wall using ferumoxytol-enhanced MRI: a pilot study.

OBJECTIVE: Macrophages play a critical role in cerebral aneurysm formation and rupture. The purpose of this study is to demonstrate the feasibility and optimal parameters of imaging macrophages within human cerebral aneurysm wall using ferumoxytol-enhanced MRI. METHODS AND RESULTS: Nineteen unruptured aneurysms in 11 patients were imaged using T2*-GE-MRI sequence. Two protocols were used. Protocol A was an infusion of 2.5 mg/kg of ferumoxytol and imaging at day 0 and 1. Protocol B was an infusion of 5 mg/kg of ferumoxytol and imaging at day 0 and 3. All images were reviewed independently by 2 neuroradiologists to assess for ferumoxytol-associated loss of MRI signal intensity within aneurysm wall. Aneurysm tissue was harvested for histological analysis. Fifty percent (5/10) of aneurysms in protocol A showed ferumoxytol-associated signal changes in aneurysm walls compared to 78% (7/9) of aneurysms in protocol B. Aneurysm tissue harvested from patients infused with ferumoxytol stained positive for both CD68+, demonstrating macrophage infiltration, and Prussian blue, demonstrating uptake of iron particles. Tissue harvested from controls stained positive for CD68 but not Prussian blue. CONCLUSIONS: Imaging with T2*-GE-MRI at 72 hours postinfusion of 5 mg/kg of ferumoxytol establishes a valid and useful approximation of optimal dose and timing parameters for macrophages imaging within aneurysm wall. Further studies are needed to correlate these imaging findings with risk of intracranial aneurysm rupture.

Upregulation of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase-1 (mPGES-1) in wall of ruptured human cerebral aneurysms: preliminary results.

BACKGROUND AND PURPOSE: Cyclooxygenase-2 (COX-2) and Microsomal Prostaglandin E2 Synthase-1 (mPGES-1) catalyze isomerization of the cyclooxygenase product PGH2 into PGE2. Deletion of COX-2/mPGES-1 suppresses carotid artery atherogenesis and angiotensin II-induced aortic aneurysms formation, and attenuates neointimal hyperplasia after vascular injury in mice. The upregulation of COX-2/mPGES-1 in the wall of ruptured human cerebral aneurysms is not known. METHODS: Ten patients with intracranial aneurysms (5 ruptured and 5 nonruptured) underwent microsurgical clipping. During the procedure, a segment of the aneurysm dome was resected and immunostained with monoclonal antibodies for COX-1, COX-2, and mPGES-1. A segment of the superficial temporal artery was also removed and immunostained with monoclonal antibodies for COX-1, COX-2, and mPGES-1. RESULTS: All 10 aneurysm tissues stained positive for mPGES-1 monoclonal antibody. Expression of mPGES-1 was more abundant in ruptured aneurysm tissue than in nonruptured aneurysms, based on a semiquantitative grading. None of the superficial temporal artery specimens expressed mPGES-1. COX-2 was upregulated in the same distribution as was mPGES-1. COX-1 was present constitutively in all tissues. CONCLUSIONS: COX-2/mPGES-1 are expressed in the wall of human cerebral aneurysms and more abundantly so in ruptured aneurysms than in nonruptured. We speculate that the protective effect of aspirin against rupture of cerebral aneurysms may be mediated in part by inhibition of COX-2/mPGES-1.

Early change in ferumoxytol-enhanced magnetic resonance imaging signal suggests unstable human cerebral aneurysm: a pilot study.

BACKGROUND AND PURPOSE: The clinical significance of early (ie, within the first 24 hours) uptake of ferumoxytol by macrophages in the wall of human cerebral aneurysms is not clear. The purpose of this study was to determine whether early uptake of ferumoxytol suggests unstable cerebral aneurysm. METHODS: Thirty unruptured aneurysms in 22 patients were imaged with magnetic resonance imaging 24 hours after infusion of ferumoxytol. Eighteen aneurysms were also imaged 72 hours after infusion of ferumoxytol. Aneurysm dome tissue was collected from 4 patients with early magnetic resonance imaging signal changes, 5 patients with late signal changes, and 5 other patients with ruptured aneurysms. The tissue was immunostained for expression of cyclooxygenase-1, cyclooxygenase-2, microsomal prostaglandin E2 synthase-1, and macrophages. RESULTS: In 23% (7/30) of aneurysms, there was pronounced early uptake of ferumoxytol. Four aneurysms were clipped. The remaining 3 aneurysms were managed conservatively; all 3 ruptured within 6 months. In 53% (16 of 30) of aneurysms, there was pronounced uptake of ferumoxytol at 72 hours. Eight aneurysms were surgically clipped, and 8 were managed conservatively; none ruptured or increased in size after 6 months. Expression of cyclooxygenase-2, microsomal prostaglandin E2 synthase-1, and macrophages was similar in unruptured aneurysms with early uptake of ferumoxytol and ruptured aneurysms. Expression of these inflammatory molecules was significantly higher in aneurysms with early uptake of ferumoxytol versus aneurysms with late uptake. CONCLUSIONS: Uptake of ferumoxytol in aneurysm walls within the first 24 hours strongly suggests aneurysm instability and probability of rupture within 6 months, and may warrant urgent intervention.

Recurrent vasospasm after endovascular treatment in subarachnoid hemorrhage.

OBJECTIVES: the frequency and predictors of recurrent symptomatic and angiographic vasospasm after angioplasty or intra-arterial chemical vasodilatation (IACV) in patients with subarachnoid hemorrhage (SAH) are not well characterized. METHODS: a retrospective review of serial clinical and angiographic data was conducted between 7/2001-6/2008 on spontaneous SAH patients who underwent endovascular therapy for symptomatic vasospasm. RESULTS: of 318 SAH patients, symptomatic vasospasm occurred in 80 (25%) and endovascular intervention was performed on 69 (22%) patients. Of these 69 patients, all received IACV in 274 vessels and 33 also underwent angioplasty in a total of 76 vessels. Recurrent angiographic vasospasm occurred in the same vessel segment in 9/23 (39%) patients who received both angioplasty + IACV compared to 40/49 (82%) of patients who received IACV alone (P < 0.001). Recurrent symptomatic vasospasm occurred in 10/26 (38%) angioplasty + IACV patients compared to 28/37 (76%) patients who received IACV alone (P = 0.003). The modified-Fisher Score, A1 spasm, distal and multi-vessel vasospasm predicted recurrent angiographic spasm after IACV alone (P < 0.05). Procedural complications occurred in 4% of IACV alone patients and 6% of angioplasty + IACV patients (P = 0.599). CONCLUSIONS: recurrent angiographic or symptomatic vasospasm is not uncommon after angioplasty + IACV, but appears to occur significantly less than after IACV alone, without any increase in procedural complications.

The relationship between oxygen and adenosine in astrocytic cultures.

Brain tissue oxygenation affects cerebral function and blood flow (CBF). Adenosine (Ado), a purine nucleoside, moderates neuronal activity, and arterial diameter. The cellular source of Ado in brain remains elusive; however, astrocytes are a logical site of production. Using astrocytic cultures, we tested the hypothesis that astrocytic derived Ado reflects cerebral oxygenation. We found that during alterations in pO(2), extracellular levels of Ado [Ado](e) changed rapidly. Graded reductions of oxygen tension revealed that[Ado](e) reached 10(-7) M to 10(-6) M with a pO(2) of 30-10mmHg, comparable with [Ado](e) and oxygen levels found in brain tissue during normoxemia. Higher O(2) levels were associated with a depression of [Ado](e). Under conditions of low pO(2) (pO(2)

Intracranial tumors: cisternal angle as a measure of midbrain compression for assessing risk of postembolization clinical deterioration.

PURPOSE: To identify objective imaging characteristics that are predictors of clinical deterioration after embolization of large intracranial tumors. MATERIALS AND METHODS: This HIPAA-compliant retrospective study was approved by the institutional review board, and informed consent was waived. The records of twelve patients with large intracranial tumors who underwent embolization were analyzed for imaging characteristics that would portend acute neurologic deterioration following embolization. The degree of midbrain compression was calculated by using the cisternal angle (the angle formed at the intersection of a line drawn along the midsagittal plane and a line drawn along the anterior aspect of the cerebral peduncle). Angiograms were evaluated for the degree of pre- and postembolization tumor blush. Neurologic status before and after embolization was evaluated. The Wilcoxon signed rank test was used to compare the cisternal angles ipsilateral and contralateral to the tumor. The cisternal angle was measured in 100 control subjects with no mass lesions to evaluate its normal distribution. RESULTS: Of the 12 patients, three experienced acute clinical deterioration after embolization. A feature common to these patients was substantial preprocedure midbrain compression, as indicated by a cisternal angle of less than 25 degrees , which was significantly less than the mean angle in the control group. Another consistent risk factor was a strong initial tumor blush pattern and a major blush reduction following embolization. CONCLUSION: Cisternal angle is an objective measure of midbrain compression. The presence of a cisternal angle less than 25 degrees (indicating severe midbrain compression), strong tumor blush, and major postprocedure blush reduction are predictors of clinical deterioration after embolization.

The role of adenosine in hypercarbic hyperemia: in vivo and in vitro studies in adenosine 2(A) receptor knockout and wild-type mice.

OBJECT: The authors tested the hypothesis that adenosine, acting through the A(2A) receptor, is not involved in hypercarbic hyperemia by assessing the effects of increased PaCO(2) on cerebral blood flow (CBF) in vivo in wild-type and A(2A) receptor knockout mice. In addition, they evaluated the effect of abluminal pH changes in vitro on the diameter of isolated perfused penetrating arterioles harvested from wild-type and A(2A) receptor knockout mice. METHODS: The authors evaluated in a blinded fashion the CBF response during transient (60-second) hypercapnic (7% CO(2)) hypercarbia in anesthetized, ventilated C57Bl/6 wild-type and adenosine A(2A) receptor knockout mice. They also evaluated the hypercarbic response in the absence and presence of the nonselective and selective adenosine antagonists. RESULTS: Cerebral blood flow was measured using laser Doppler flowmetry. There were no differences between the CBF responses to hypercarbia in the wild-type and the knockout mice. Moreover, the hypercarbic hyperemia response was not affected by the adenosine receptor antagonists. The authors also tested the response to alteration in abluminal pH in isolated perfused, pressurized, penetrating arterioles (average diameter 63.3 +/- 3.6 microm) harvested from wild-type (6 mice) and knockout (5 mice) animals. Arteriolar dilation in response to a decrease in abluminal pH, simulating the change in vivo during hypercarbia, was similar in wild-type (15.9 +/- 2.6%) and A(2A) receptor knockout (17.7 +/- 1.3%) mice. With abluminal application of CGS 21680 (10(-6) M), an A(2A) receptor agonist, wild-type arterioles dilated in an expected manner (9.8 +/- 0.7%), whereas A(2A) receptor knockout vessels had minimal response. CONCLUSIONS: The results of the in vivo and in vitro studies in wild-type and A(2A) receptor knockout mice support the authors' hypothesis that hypercarbic vasodilation does not involve an adenosine A(2A) receptor-related mechanism.

Regulation of cerebral vasculature in normal and ischemic brain.

We outline the mechanisms currently thought to be responsible for controlling cerebral blood flow (CBF) in the physiologic state and during ischemia, focusing on the arterial pial and penetrating microcirculation. Initially, we categorize the cerebral circulation and then review the vascular anatomy. We draw attention to a number of unique features of the cerebral vasculature, which are relevant to the microcirculatory response during ischemia: arterial histology, species differences, collateral flow, the venous drainage, the blood-brain barrier, astrocytes and vascular nerves. The physiology of the arterial microcirculation is then assessed. Lastly, we review the changes during ischemia which impact on the microcirculation. Further understanding of the normal cerebrovascular anatomy and physiology as well as the pathophysiology of ischemia will allow the rational development of a pharmacologic therapy for human stroke and brain injury.

Correlation of intrinsic optical signal, cerebral blood flow, and evoked potentials during activation of rat somatosensory cortex.

OBJECT: This study was undertaken to test the hypothesis that cerebral blood flow (CBF) and the intrinsic optical signal could be dissociated by altering adenosine receptor activity and to uncover the origin of the optic signal using a cranial window in the anesthetized rat. METHODS: In anesthetized, ventilated, and temperature-controlled rats with closed cranial windows, the authors evaluated simultaneously the alterations in pial arteriolar diameter, intrinsic optical signals (690 nm), and somatosensory evoked potentials during cortical activation evoked by contralateral sciatic nerve stimulation (SNS). To dissociate the vascular and intrinsic signal, they topically applied the adenosine receptors antagonists theophylline (5 microM), which affects A1 and A2A receptors, and 8-cyclopentyl-1,3-dipropylxanthine (CPX, 1 microM), which blocks the A(1) receptor. The former interacts primarily with the vasculature whereas the latter influences the parenchyma exclusively. RESULTS: During 20 seconds of contralateral SNS, pial arterioles in the hindlimb somatosensory cortex dilated in a characteristic peak and shoulder pattern. As compared with mock cerebrospinal fluid alone, theophylline significantly (p<0.05) attenuated SNS-induced vasodilation (mean+/-standard deviation 8.1+/-2.5% vs 21.7+/-1.9%; 4 rats in each group). In contrast, CPX potentiated vasodilation significantly (p<0.05) during SNS (54.7+/-15.8% for the CPX group vs 20.1+/-1.9% for the controls; 5 rats in each group). The change in optical signal persisted after cessation of SNS in all the animals. Thus, the pattern of change of the optical signal was distinctly different from the pattern of changes in arteriolar diameter (which returned rapidly to baseline). Moreover, the optical signal during SNS was increased by 50% by theophylline and by almost 5-fold by CPX (p<0.05). The area of change of the intrinsic signal was also increased by the topical application of theophylline and CPX. The somatosensory evoked potential recordings revealed no significant changes after theophylline application, but CPX caused a small diminution of the N1 wave (p<0.01). CONCLUSIONS: The noncongruent temporal profiles of the changes in pial arteriolar diameter and optical signal, imaged at 690 nm, indicate that the optical signal at 690 nm is not related to CBF. Alteration of adenosine receptor activity independently changed cortical activity, as measured by the optical signal, and CBF, as determined by pial arteriolar diameter. Manipulation of the adenosine receptor activity during increased cortical activity confirmed the temporal dissociation of optical signal and CBF and provided further evidence for the role of adenosine in regulating CBF.

The Incidence and Impact of Secondary Cerebral Insults on Outcome After Aneurysmal Subarachnoid Hemorrhage.

INTRODUCTION: Secondary cerebral insults can adversely affect patients with traumatic brain injury. By contrast, the incidence of secondary cerebral insults after aneurysmal subarachnoid hemorrhage (SAH) and their impact on outcome have been less well studied. METHODS: Four hundred and twenty-one patients with SAH who underwent surgical occlusion of their ruptured aneurysm and who received intensive care unit care for ≥48 hours were retrospectively identified from a prospective observational database. Patients were managed according to standard recommendations for SAH. Three secondary cerebral insults were examined: hypotension (<90 mmHg systolic), hypoxia (Pao2 <60 mm Hg), and hyperglycemia (>200 mg/dL). RESULTS: A secondary cerebral insult was observed in 309 (73.4%) patients including 135 (32.1%) who had multiple insults. There was an association between worse clinical grade and development of secondary insults (P = 0.0002), particularly multiple insults (P < 0.0001). When stratified by clinical grade, single (adjusted odds ratio [OR], 2.23; 95% confidence interval [CI], 1.10-4.51; P = 0.026) and multiple (adjusted OR, 4.37; 95% CI, 2.14-8.93; P < 0.0001) secondary cerebral insults were associated with worse outcome. In multivariate analysis and controlling for age, admission clinical grade, severity of SAH on computed tomography, intracerebral hematoma, increased intracranial pressure (>20 mm Hg), rebleed, intraoperative rupture, and hydrocephalus, secondary cerebral insults were independently associated with poor outcome (adjusted OR, 2.45; 95% CI, 1.20-5.02; P = 0.014). CONCLUSIONS: Secondary cerebral insults (hypoxia, hypotension, and hyperglycemia) are common after SAH, including among patients with a good clinical grade. These insults after SAH are associated with worse outcome. These data suggest that prevention of secondary cerebral insults may provide an opportunity to improve patient outcome after SAH.

Time-dependent alterations in functional and pharmacological arteriolar reactivity after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Disturbances in cerebral arteriolar function, in addition to large vessel vasospasm, may be responsible for ischemia after subarachnoid hemorrhage. The purpose of this study was to test the hypothesis that subarachnoid hemorrhage alters cerebral microvascular reactivity. METHODS: An endovascular filament model was used to induce subarachnoid hemorrhage in halothane-anesthetized male Sprague-Dawley rats. We evaluated pial arteriolar responses to sciatic nerve stimulation, topically applied vasoactive agents (adenosine or sodium nitroprusside), and CO(2) inhalation in rats subjected to subarachnoid hemorrhage at 1 to 5 days after insult. RESULTS: In sham-operated rats, sciatic nerve stimulation evoked a 23.5+/-1.8% increase in arteriolar diameter, which was significantly attenuated to 13.7+/-0.9%, 12.8+/-2.5%, and 18.8+/-2.9% at 24, 48, and 72 hours after subarachnoid hemorrhage, respectively (P<0.05; n> or =7). At 96 and 120 hours after subarachnoid hemorrhage, sciatic nerve stimulation-induced dilation recovered to sham levels. Somatosensory-evoked potentials were unaltered by subarachnoid hemorrhage. Pial vasodilatation to adenosine (10 micromol/L) and sodium nitroprusside (1 micromol/L) were significantly impaired, by 47% and 41%, respectively, at 48 hours after subarachnoid hemorrhage (P<0.05; n=7). In contrast, CO(2) reactivity was unaffected by subarachnoid hemorrhage. CONCLUSIONS: Pial arteriolar responses to cortical activation may be decreased in the initial 2 to 3 days after experimental subarachnoid hemorrhage.

Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial.

BACKGROUND: Traumatic brain injuries represent an important and costly health problem. Supplemental magnesium positively affects many of the processes involved in secondary injury after traumatic brain injury and consistently improves outcome in animal models. We aimed to test whether treatment with magnesium favourably affects outcome in head-injured patients. METHODS: In a double-blind trial, 499 patients aged 14 years or older admitted to a level 1 regional trauma centre between August, 1998, and October, 2004, with moderate or severe traumatic brain injury were randomly assigned one of two doses of magnesium or placebo within 8 h of injury and continuing for 5 days. Magnesium doses were targeted to achieve serum magnesium ranges of 1.0-1.85 mmol/L or 1.25-2.5 mmol/L. The primary outcome was a composite of mortality, seizures, functional measures, and neuropsychological tests assessed up to 6 months after injury. Analyses were done according to the intention-to-treat principle. This trial is registered with , number . FINDINGS: Magnesium showed no significant positive effect on the composite primary outcome measure at the higher dose (mean=55 average percentile ranking on magnesium vs 52 on placebo, 95% CI for difference -7 to 14; p=0.70). Those randomly assigned magnesium at the lower dose did significantly worse than those assigned placebo (48 vs 54, 95% CI -10.5 to -2; p=0.007). Furthermore, there was higher mortality with the higher magnesium dose than with placebo. Other major medical complications were similar between groups, except for a slight excess of pulmonary oedema and respiratory failure in the lower magnesium target group. No subgroups were identified in which magnesium had a significantly positive effect. INTERPRETATION: Continuous infusions of magnesium for 5 days given to patients within 8 h of moderate or severe traumatic brain injury were not neuroprotective and might even have a negative effect in the treatment of significant head injury.

Effect of time, injury, age and ethanol on interpatient variability in valproic acid pharmacokinetics after traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) results in an increase in hepatic metabolism. The increased metabolism is in significant contrast to a large body of in vitro and in vivo data demonstrating that activation of the host-defence response downregulates hepatic metabolism. Theoretically, this occurs because of activation of the pro-inflammatory cytokines tumour necrosis factor-alpha, interferon-gamma, interleukin (IL)-1 and IL-6. As part of a large double-blind, placebo-controlled clinical trial evaluating the use of valproic acid for prophylaxis of post-traumatic seizures, we obtained extensive valproic acid concentration-time data. Valproic acid is a hepatically metabolised, low extraction-ratio drug. Therefore, unbound clearance (CL(u)) is equal to intrinsic or metabolic clearance. OBJECTIVE: The objective of this study was to evaluate the time-dependent effects of TBI on the pharmacokinetics of total and unbound valproic acid with the goal of identifying patient factors that may predict changes in total clearance (CL) and CL(u). In addition, by determining the factors that influence the magnitude and time course of induction of hepatic metabolism and understanding their interaction with the host-defence mediators, we can further our insight into the mechanism(s) responsible for the changes in CL and CL(u). STUDY DESIGN: Valproic acid plasma concentration data were obtained from 158 TBI patients. Unbound valproic acid plasma concentrations were estimated using total valproic acid plasma and albumin concentrations following a Scatchard equation binding model previously developed in a subset of TBI patients. The effect of 13 patient factors on CL and CL(u) was evaluated initially in a univariate analysis. The significant factors were then included in a multiple linear regression analysis by use of step-wise selection and forward selection procedures. RESULTS: CL and CL(u) were significantly increased after TBI in a time-dependent manner. The average increase was >75% by weeks 2 and 3 post-injury. The magnitude of the induction of CL was increased with decreased albumin concentrations, in addition to the presence of ethanol on admission, increased severity of head injury, tube feeding and total parenteral nutrition (TPN). The magnitude of induction of CL(u) was increased by older age, presence of ethanol on admission, increased severity of head injury, tube feeding, TPN, and if the patient had a post-injury neurosurgical procedure. The time to normalisation of CL(u) was significantly longer in patients with head injury plus other injuries compared with those with head injury alone. CONCLUSIONS: As has been reported with other drugs, TBI results in a significant increase in the metabolism of valproic acid. The patient factors identified in this study that resulted in an increase in the magnitude and time course of the induction of CL(u) (ethanol, older age, presence of a neurosurgical procedure, severity of TBI and presence of multiple non-TBI injuries) have all been reported to cause a shift to the anti-inflammatory mediators IL-4 and IL-10. This suggests that the increase in hepatic metabolism after TBI may be due to the increased presence of anti-inflammatory mediators in contrast to the inhibition effect of the pro-inflammatory mediators in non-TBI inflammation and infection.

The Effects of Red Blood Cell Transfusion on Functional Outcome after Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: The optimal red blood cell transfusion (RBCT) trigger for patients with aneurysmal subarachnoid hemorrhage (SAH) is unknown. In patients with cerebral vasospasm, anemia may increase susceptibility to ischemic injury; conversely, RBCT may worsen outcome given known deleterious effects. OBJECTIVE: To examine the association between RBCT, delayed cerebral ischemia (DCI), vasospasm, and outcome after SAH. METHODS: A total of 421 consecutive patients with SAH, admitted to a neurocritical care unit at a university-affiliated hospital and who underwent surgical occlusion of their ruptured aneurysm were retrospectively identified from a prospective observational database. Propensity score methods were used to reduce the bias associated with treatment selection. RESULTS: Two hundred and sixty-one patients (62.0%) received an RBCT. Angiographic vasospasm (odds ratio [OR] 1.6; 95% confidence interval [CI], 1.1-2.3; P = 0.025) but not severe angiographic spasm, DCI, or delayed infarction was associated with RBCT. A total of 283 patients (67.2%) experienced a favorable outcome, defined as good or moderately disabled on the Glasgow Outcome Scale; 47 (11.2%) were severely disabled or vegetative and 91 patients (21.6%) were dead at 6-month follow-up. Among patients who survived ≥2 days, RBCT was associated with unfavorable outcome (OR, 2.6; 95% CI, 1.6-4.1). Transfusion of ≥3 units of blood was associated with an increased incidence of unfavorable outcome. Propensity analysis to control for the probability of exposure to RBCT conditional on observed covariates measured before RBCT indicates that RBCT is associated with unfavorable outcome in the absence of DCI (OR, 2.17; 95% CI, 1.56-3.01; P < 0.0001) but not when DCI is present (OR, 0.82; 95% CI, 0.35-1.92; P = 0.65). CONCLUSIONS: Blood transfusions are associated with unfavorable outcome after SAH particularly when DCI is absent. Propensity analysis suggests that RBCT may be associated with poor outcome rather than being a marker of disease severity. However, when DCI is present, RBCT may help improve outcome.

Effect of caffeine on cerebral blood flow response to somatosensory stimulation.

Despite caffeine's wide consumption and well-documented psychoactive effects, little is known regarding the effects of caffeine on neurovascular coupling. In the present study, we evaluated the effects of caffeine, an adenosine receptor antagonist, on intracerebral arterioles in vitro and subsequently, on the pial circulation in vivo during cortical activation induced by contralateral sciatic nerve stimulation (SNS). In our in vitro studies, we utilized isolated intracerebral arterioles to determine the effects of caffeine (10 or 50 micromol/L) on adenosine-induced vasodilatation. At the lower concentration, caffeine was without effect, but at the higher concentration, caffeine produced significant attenuation. In our in vivo studies, we determined the cerebrospinal fluid (CSF) caffeine concentrations at 15, 30, and 60 mins after intravenous administration of 5, 10 and 40 mg/kg. At the latter two concentrations, CSF levels exceeded 10 micromol/L. We then evaluated the pial arteriolar response during cortical activation caused by contralateral SNS after administering caffeine intravenously (0, 5, 10, 20 30, and 40 mg/kg). The pial circulation was observed through a closed cranial window in chloralose-anesthetized Sprague-Dawley rats. The contralateral sciatic nerve was isolated, positioned on silver electrodes and stimulated for 20 secs (0.20 V, 0.5 ms, and 5 Hz). Arteriolar diameter was quantified using an automated video dimension analyzer. Contralateral SNS resulted in a 23.8% +/-3.9% increase in pial arteriolar diameter in the hindlimb sensory cortex under control conditions. Intravenous administration of caffeine at the lowest dose studied (5 mg/kg) had no effect on either resting arteriolar diameter or SNS-induced vasodilatation. However, at higher doses (10, 20, 30, and 40 mg/kg, intravenously), caffeine significantly (P < 0.05; n = 6) attenuated both resting diameter and cerebral blood flow (CBF) responses to somatosensory stimulation. Intravenous administration of theophylline (10, 20, and 40 mg/kg), another adenosine receptor antagonist, also significantly reduced SNS-induced vasodilatation in a dose-dependent manner. Hypercarbic vasodilatation was unaffected by either caffeine or theophylline. The results of the present study show that caffeine significantly reduces cerebrovascular responses to both adenosine and to somatosensory stimulation and supports a role of adenosine in the regulation of CBF during functional neuronal activity.

Methods for isolation and characterization of intracerebral arterioles in the C57/BL6 wild-type mouse.

Vascular control mechanisms have been studied extensively in mice. However, an in vitro characterization of penetrating intracerebral arterioles has not been reported. We describe methods for isolation and cannulation for mouse intracerebral arterioles. This technique allows analysis of mouse cerebral arteriolar physiology and pharmacology without the confounding influences of the surrounding brain elements. Penetrating intracerebral arterioles from adult C57/BL6 wild-type (WT) mice were isolated at 4 degrees C, transferred to an inverted microscope and cannulated at both ends using a dual glass micropipette system, wherein intraluminal flow (0.2 microl/min) and pressure (60 mmHg) were maintained. The arterioles developed spontaneous tone when the chamber was warmed to 37 degrees C, with the resulting diameter reaching 68.4+/-0.9% of passive diameter (29.8+/-1.1 microm). After the development of spontaneous tone, incremental changes in luminal pressure from 20 to 140 mmHg induced myogenic responses. Acidosis (pH 6.8) and alkalosis (pH 7.6) caused dilation (20.0+/-1.4%) and constriction (17.2+/-1.4%), respectively. Extraluminal adenosine (ADO (10 microM); 24.3+/-3.6%) and sodium nitroprusside (SNP (10 microM); 28.6+/-4.1%) and intraluminal adenosine 5'-triphosphate (ATP (10 microM); 20.0+/-3.9%) resulted in vasodilation similar in magnitude to that observed in rat arterioles. This information provides a foundation for elucidating cerebral vascular control mechanisms in genetically engineered mice.

Systemic theophylline augments the blood oxygen level-dependent response to forepaw stimulation in rats.

BACKGROUND AND PURPOSE: Functional MR imaging with blood oxygen level-dependent (BOLD) contrast enhancement is believed to rely on changes in cerebral blood flow and deoxyhemoglobin level to estimate the location and degree of neural activation. We studied the relationship between neural activation and the observed BOLD response by using theophylline, an antagonist of the inhibitory neurotransmitter adenosine and a potent inhibitor of the vasodilatory response to neural activation. METHODS: Using a rat model with electrical forepaw stimulation, we performed fMRI measurements before and after the systemic injection of either theophylline (0.1 mmol/kg) or an equivalent volume of saline. Changes in the BOLD response were quantified by determining the number of activated voxels and the amplitude of the BOLD response for each animal in the theophylline and saline groups. RESULTS: The theophylline group had a significantly Tincreased BOLD response (70-150% increased activated voxel count and 60-65% increased BOLD response amplitude) at 45 and 60 minutes after systemic injection compared with baseline. The response of the saline-injected control group did not change significantly. CONCLUSION: The administration of systemic theophylline significantly augmented the BOLD response due to either an elevation of resting deoxyhemoglobin levels or the neuroexcitatory effect of theophylline. This effect potentially could be used in human fMRI studies to increase the sensitivity of the BOLD response.

Accurate intraoperative localization of spinal dural arteriovenous fistulae with embolization coil: technical note.

Spinal dural arteriovenous fistulae represent a potentially curable cause of a progressive myelopathy and therefore should be treated aggressively by either endovascular or surgical methods. In the surgical treatment of these lesions, intraoperative radiographic localization of the site of the fistula can be problematic. We describe an endovascular technique in which radiopaque microcoils are placed in the major feeding artery(ies) after completion of spinal angiography, which then provides a marker that is easily visualized with intraoperative x-rays, allowing effective localization of the site of the fistula.

Bilateral multiple cervical root avulsions without skeletal or ligamentous damage resulting from blast injury: case report.

OBJECTIVE AND IMPORTANCE: We describe a unique case of multiple bilateral cervical root injuries without ligamentous or bony injury secondary to a sandblast accident. CLINICAL PRESENTATION: A 19-year-old man sustained a sandblast injury to his face, neck, chest, and upper extremities, with immediate loss of motor and sensory function occurring in both of his upper extremities. Cervical spine x-rays, computed tomography, and magnetic resonance imaging demonstrated no fracture, soft tissue abnormality, or malalignment. The restriction of deficits to the patient's upper extremities suggested a central cervical spinal cord injury, bilateral brachial injuries, or a conversion disorder. INTERVENTION: Cervical computed tomographic myelography revealed multiple bilateral nerve root injuries. CONCLUSION: This case report is unique in the literature in that it describes a patient with multiple cervical nerve root injuries secondary to sandblast injury without ligamentous or bony injury. Although magnetic resonance imaging remains the diagnostic modality of choice in patients with acute spinal cord injury, it is deficient in demonstrating cervical root injury in the acute setting. In this setting, computed tomographic myelography is superior.