Christoph Leithner

No evidence for early decrease in blood oxygenation in rat whisker cortex in response to functional activation.

Using optical methods through a closed cranial window over the rat primary sensory cortex in chloralose/urethane-anesthetized rats we evaluated the time course of oxygen delivery and consumption in response to a physiological stimulus (whisker deflection). Independent methodological approaches (optical imaging spectroscopy, single fiber spectroscopy, oxygen-dependent phosphorescence quenching) were applied to different modes of whisker deflection (single whisker, full whisker pad). Spectroscopic data were evaluated using different algorithms (constant pathlength, differential pathlength correction). We found that whisker deflection is accompanied by a significant increase of oxygenated hemoglobin (oxy-Hb), followed by an undershoot. An early increase in deoxygenated hemoglobin (deoxy-Hb) proceeded hyperoxygenation when spectroscopic data were analyzed by constant pathlength analysis. However, correcting for the wavelength dependence of photon pathlength in brain tissue (differential pathlength correction) completely eliminated the increase in deoxy-Hb. Oxygen-dependent phosphorescence quenching did not reproducibly detect early deoxygenation. Together with recent fMRI data, our results argue against significant early deoxygenation as a universal phenomenon in functionally activated mammalian brain. Interpreted with a diffusion-limited model of oxygen delivery to brain tissue our results are compatible with coupling between neuronal activity and cerebral blood flow throughout stimulation, as postulated 110 years ago by C. Roy and C. Sherrington (1890, J. Physiol. 11:85--108).

Does hypothermia influence the predictive value of bilateral absent N20 after cardiac arrest

Background: Bilateral absent N20 responses of median nerve somatosensory evoked potentials (SEPs) reliably predict poor prognosis after cardiac arrest. However, the studies supporting this fact were carried out before hypothermia was established as standard treatment. Recent evidence suggests that hypothermia treatment affects the predictive value of clinical findings in cardiac arrest patients, raising the question whether the predictive value of N20 responses has changed as well. Methods: We retrospectively studied 185 consecutive patients treated with hypothermia after cardiac arrest. SEP recordings were available for 112 patients. SEPs were classified as bilateral absent N20, pathologic N20, or normal. Baseline and follow-up information were obtained from our database. Results: We identified 36 patients with bilateral absent N20, 35 (97%) of whom had poor outcome. One patient had prolonged high amplitude peripheral SEP, but bilaterally absent N20 3 days after cardiac arrest and regained consciousness with normal cognitive functions and reproducible N20 responses. One further patient had minimally detectable N20 at day 3 and recovered consciousness and normal N20 responses on follow-up. Conclusions: Our data indicate that recovery of consciousness and cognitive functions is possible in spite of absent or minimally present N20 responses more than 24 hours after cardiac arrest in a very small proportion of patients. N20 responses may recover beyond this time window. The predictive value of bilateral absent N20 responses needs to be reevaluated in larger prospective studies. Until these studies are available, decisions to stop therapy in cardiac arrest survivors should not be based on N20 responses alone.

Intravenous Rosuvastatin for Acute Stroke Treatment: An Animal Study

Background and Purpose— Statins exert rapid cholesterol-independent vasoprotective effects. Here, we tested whether postevent treatment with intravenously (i.v.) administered rosuvastatin improves acute stroke outcome in mice. Methods— 129/SV wild-type mice were subjected to 1-hour filamentous middle cerebral artery occlusion (MCAo), followed by reperfusion, and were postevent treated with i.v. or intraperitoneal (i.p.) rosuvastatin given up to 6 hours after MCAo (dose range 0.02 to 20 mg kg−1 body weight). Results— Rosuvastatin, when administered i.v., significantly reduced lesion size when given up to 4 hours after MCAo and in doses as low as 0.2 mg kg−1. In contrast, i.p. administration provided protection only when given directly on reperfusion at a dose of 20 mg kg−1 but not at lower doses or later time points. Lesion protection was evident as late as 5 days after brain ischemia and was associated with functional improvements in the pole-test and wire-hanging test (2.0 mg kg−1 dose). Neuroprotection with i.v. rosuvastatin was achieved with peak plasma concentrations <0.5 ng ml−1 (ie, with 0.2 mg kg−1) and was associated with increased levels of phosphorylated Akt kinase and endothelial nitric oxide synthase in the vasculature. Conclusions— Rosuvastatin, given intravenously at pharmacologically relevant concentrations, protects from focal brain ischemia up to 4 hours after an event. In our opinion, the development of an intravenous statin formulation is warranted for acute stroke trials with statins in humans.

Pharmacological uncoupling of activation induced increases in CBF and CMRO2.

Neurovascular coupling provides the basis for many functional neuroimaging techniques. Nitric oxide (NO), adenosine, cyclooxygenase, CYP450 epoxygenase, and potassium are involved in dilating arterioles during neuronal activation. We combined inhibition of NO synthase, cyclooxygenase, adenosine receptors, CYP450 epoxygenase, and inward rectifier potassium (Kir) channels to test whether these pathways could explain the blood flow response to neuronal activation. Cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) of the somatosensory cortex were measured during forepaw stimulation in 24 rats using a laser Doppler/spectroscopy probe through a cranial window. Combined inhibition reduced CBF responses by two-thirds, somatosensory evoked potentials and activation-induced CMRO2 increases remained unchanged, and deoxy-hemoglobin (deoxy-Hb) response was abrogated. This shows that in the rat somatosensory cortex, one-third of the physiological blood flow increase is sufficient to prevent microcirculatory increase of deoxy-Hb concentration during neuronal activity. The large physiological CBF response is not necessary to support small changes in CMRO2. We speculate that the CBF response safeguards substrate delivery during functional activation with a considerable ‘safety factor’. Reduction of the CBF response in pathological states may abolish the BOLD–fMRI signal, without affecting underlying neuronal activity.

Neurovascular coupling in rat brain operates independent of hemoglobin deoxygenation

Recently, a universal, simple, and fail-safe mechanism has been proposed by which cerebral blood flow (CBF) might be coupled to oxygen metabolism during neuronal activation without the need for any tissue-based mechanism. According to this concept, vasodilation occurs by local erythrocytic release of nitric oxide or ATP wherever and whenever hemoglobin is deoxygenated, directly matching oxygen demand and supply in every tissue. For neurovascular coupling in the brain, we present experimental evidence challenging this view by applying an experimental regime operating without deoxy-hemoglobin. Hyperbaric hyperoxygenation (HBO) allowed us to prevent hemoglobin deoxygenation, as the oxygen that was physically dissolved in the tissue was sufficient to support oxidative metabolism. Regional CBF and regional cerebral blood oxygenation were measured using a cranial window preparation in anesthetized rats. Hemodynamic and neuronal responses to electrical forepaw stimulation or cortical spreading depression (CSD) were analyzed under normobaric normoxia and during HBO up to 4 ATA (standard atmospheres absolute). Inconsistent with the proposed mechanism, during HBO, CBF responses to functional activation or CSD were unchanged. Our results show that activation-induced CBF regulation in the brain does not operate through the release of vasoactive mediators on hemoglobin deoxygenation or through a tissue-based oxygen-sensing mechanism.

The oxygen paradox of neurovascular coupling

The coupling of cerebral blood flow (CBF) to neuronal activity is well preserved during evolution. Upon changes in the neuronal activity, an incompletely understood coupling mechanism regulates diameter changes of supplying blood vessels, which adjust CBF within seconds. The physiologic brain tissue oxygen content would sustain unimpeded brain function for only 1 second if continuous oxygen supply would suddenly stop. This suggests that the CBF response has evolved to balance oxygen supply and demand. Surprisingly, CBF increases surpass the accompanying increases of cerebral metabolic rate of oxygen (CMRO2). However, a disproportionate CBF increase may be required to increase the concentration gradient from capillary to tissue that drives oxygen delivery. However, the brain tissue oxygen content is not zero, and tissue pO2 decreases could serve to increase oxygen delivery without a CBF increase. Experimental evidence suggests that CMRO2 can increase with constant CBF within limits and decreases of baseline CBF were observed with constant CMRO2. This conflicting evidence may be viewed as an oxygen paradox of neurovascular coupling. As a possible solution for this paradox, we hypothesize that the CBF response has evolved to safeguard brain function in situations of moderate pathophysiological interference with oxygen supply.

Dizziness in the Emergency Room: Diagnoses and Misdiagnoses

Background: Dizziness is among the most frequent neurological chief complaints in emergency room (ER) patients. Although the majority of underlying disorders are benign, serious causes that require immediate in-hospital treatment may occur that are difficult to identify clinically. Methods: Retrospective study of 475 consecutive ER neurological consultations with dizziness as the chief complaint. Results: Of all ER dizziness patients, 73% were initially assigned to benign and 27% to serious diagnoses. The two most frequent disorders were benign paroxysmal positional vertigo (22%) and stroke (20%). On follow-up (available in 124 patients), 43% of all ER diagnoses were corrected: 6% of benign ER diagnoses were corrected to serious diagnoses, 23% of serious ER diagnoses were revised to benign. The most frequent corrections concerned patients with an ER diagnosis of stroke or vestibular neuronitis. Conclusions: In the patient sample studied here, serious causes of dizziness were more prevalent than can be expected from population-based surveys or data from specialized outpatient departments. However, inappropriate assignment of dizziness patients to benign diagnoses still occurred in a relevant proportion of patients. ER clinical pathways, planning of imaging resources and follow-up of patients in- and outside the hospital must take these points into consideration.

Pathophysiological interference with neurovascular coupling - when imaging based on hemoglobin might go blind

Assessing neuronal activity by non-invasive functional brain imaging techniques which are based on the hemodynamic response depends totally on the physiological cascade of metabolism and blood flow. At present, functional brain imaging with near infrared spectroscopy (NIRS) or BOLD-fMRI is widely used in cognitive neuroscience in healthy subjects where neurovascular coupling and cerebrovascular reactivity can be assumed to be intact. Local activation studies as well as studies investigating functional connectivity between brain regions of the resting brain provide a rapidly increasing body of knowledge on brain function in humans and animals. Furthermore, functional NIRS and MRI techniques are increasingly being used in patients with severe brain diseases and this use might gain more and more importance for establishing their use in the clinical routine. However, more and more experimental evidence shows that changes in baseline physiological parameters, pharmacological interventions, or disease-related vascular changes may significantly alter the normal response of blood flow and blood oxygenation and thus may lead to misinterpretation of neuronal activity. In this article we present examples of recent experimental findings on pathophysiological changes of neurovascular coupling parameters in animals and discuss their potential implications for functional imaging based on hemodynamic signals such as fNIRS or BOLD-fMRI. To enable correct interpretation of neuronal activity by vascular signals, future research needs to deepen our understanding of the basic mechanisms of neurovascular coupling and the specific characteristics of disturbed neurovascular coupling in the diseased brain.

Serial measurement of neuron specific enolase improves prognostication in cardiac arrest patients treated with hypothermia: A prospective study

BackgroundNeuron specific enolase (NSE) has repeatedly been evaluated for neurological prognostication in patients after cardiac arrest. However, it is unclear whether current guidelines for NSE cutoff levels also apply to cardiac arrest patients treated with hypothermia. Thus, we investigated the prognostic significance of absolute NSE levels and NSE kinetics in cardiac arrest patients treated with hypothermia.MethodsIn a prospective study of 35 patients resuscitated from cardiac arrest, NSE was measured daily for four days following admission. Outcome was assessed at ICU discharge using the CPC score. All patients received hypothermia treatment for 24 hours at 33°C with a surface cooling device according to current guidelines.ResultsThe cutoff for absolute NSE levels in patients with unfavourable outcome (CPC 3-5) 72 hours after cardiac arrest was 57 μg/l with an area under the curve (AUC) of 0.82 (sensitivity 47%, specificity 100%). The cutoff level for NSE kinetics in patients with unfavourable outcome (CPC 3-5) was an absolute increase of 7.9 μg/l (AUC 0.78, sensitivity 63%, specificity 100%) and a relative increase of 33.1% (AUC 0.803, sensitivity 67%, specificity 100%) at 48 hours compared to admission.ConclusionIn cardiac arrest patients treated with hypothermia, prognostication of unfavourable outcome by NSE kinetics between admission and 48 hours after resuscitation may be superior to prognostication by absolute NSE levels.

Regional cerebral oxygen saturation after cardiac arrest in 60 patients—A prospective outcome study

INTRODUCTION Non-invasive near-infrared spectroscopy (NIRS) offers the possibility to determine regional cerebral oxygen saturation (rSO2) in patients with cardiac arrest. Limited data from recent studies indicate a potential for early prediction of neurological outcome. METHODS Sixty cardiac arrest patients were prospectively enrolled, 22 in-hospital cardiac arrest (IHCA) and 38 out-of-hospital cardiac arrest (OHCA) patients respectively. NIRS of frontal brain was started after return of spontaneous circulation (ROSC) during admission to ICU and was continued until normothermia. Outcome was determined at ICU discharge by the Pittsburgh Cerebral Performance Category (CPC) and 6 months after cardiac arrest. RESULTS A good outcome (CPC 1-2) was achieved in 23 (38%) patients, while 37 (62%) had a poor outcome (CPC 3-5). Patients with good outcome had significantly higher rSO2 levels (CPC 1-2: rSO2 68%; CPC 3-5: rSO2 58%; p<0.01). For good and poor outcome median rSO2 within the first 24h period was 66% and 59% respectively and for the following 16h period 68% and 59% (p<0.01). Outcome prediction by area of rSO2 below a critical threshold of rsO2=50% within the first 40h yielded 70% specificity and 86% sensitivity for poor outcome. CONCLUSION On average, rSO2 within the first 40h after ROSC is significantly lower in patients with poor outcome, but rSO2 ranges largely overlap between outcome groups. Our data indicate limited potential for prediction of poor outcome by frontal brain rSO2 measurements.