The effects of ketamine-xylazine anesthesia on cerebral blood flow and oxygenation observed using nuclear magnetic resonance perfusion imaging and electron paramagnetic resonance oximetry

Ketamine-xylazine is a commonly used anesthetic for laboratory rats. Previous results showed that rats anesthetized with ketamine-xylazine can have a much lower cerebral partial pressure of oxygen (P(t)O(2)), compared to unanesthetized and isoflurane anesthetized rats. The underlying mechanisms for the P(t)O(2) reduction need to be elucidated. In this study, we measured regional cerebral blood flow (CBF) using nuclear magnetic resonance (NMR) perfusion imaging and cortical P(t)O(2) using electron paramagnetic resonance (EPR) oximetry in the forebrain of rats under isoflurane, ketamine, ketamine-xylazine and isoflurane-xylazine anesthesia. The results show that in ventilated rats ketamine at a dose of 50 mg/kg does not induce significant changes in CBF, compared to isoflurane. Ketamine-xylazine in combination causes 25-65% reductions in forebrain CBF in a region-dependent manner. Adding xylazine to isoflurane anesthesia results in similar regional reductions in CBF. EPR oximetry measurements show ketamine increases cortical P(t)O(2) while xylazine decreases cortical P(t)O(2). The xylazine induced reduction in CBF could explain the reduced brain oxygenation observed in ketamine-xylazine anesthetized rats.     

Effects of ketamine/xylazine and isoflurane on rat brain glucose metabolism measured by 18F‐fluorodeoxyglucose‐positron emission tomography

The aim of the present study was to investigate changes in glucose metabolism in male Wistar rats induced by the anesthetics isoflurane and ketamine combined with xylazine via ¹⁸F‐fluorodeoxyglucose‐positron emission tomography. We analyzed the differential effects of the anesthetics on ¹⁸F‐fluorodeoxyglucose uptake and pharmacokinetics in 33 rats using quantification methods: (a) the standardized uptake value, (b) voxel‐based analyses, and (c) kinetic analysis. Both anesthetics reduced glucose uptake in the entire brain. The voxel‐based analyses detected smaller uptake reductions in the bilateral primary somatosensory system cortex and part of the limbic system in the ketamine‐xylazine (KX) group and in the vestibular nucleus in the isoflurane group. Through kinetic analysis, we found that the volume of distribution and the membrane transport rate K₁ were reduced in the KX group. Through various methods of ¹⁸F‐fluorodeoxyglucose‐positron emission tomography quantification, the present study found that anesthesia with the ketamine‐xylazine combination induced a global reduction of glucose metabolism compared with isoflurane; this reduction of metabolism was relatively lower in the primary somatosensory cortex and part of the limbic system. The volume of distribution of ¹⁸F‐fluorodeoxyglucose and its Glut1‐mediated transport across the brain membranes (K₁) were decreased in the KX group.     

Differential effects of anesthetics on cocaine's pharmacokinetic and pharmacodynamic effects in brain

Most studies of the effect of cocaine on brain activity in laboratory animals are preformed under anesthesia, which could potentially affect the physiological responses to cocaine. Here we assessed the effects of two commonly used anesthetics [α‐chloralose (α‐CHLOR) and isofluorane (ISO)] on the effects of acute cocaine (1 mg/kg i.v.) on cerebral blood flow (CBF), cerebral blood volume (CBV), and tissue hemoglobin oxygenation (S_tO₂) using optical techniques and cocaine’s pharmacokinetics (PK) and binding in the rat brain using (PET) and [¹¹C]cocaine. We showed that acute cocaine at a dose abused by cocaine abusers decreased CBF, CBV and S_tO₂ in rats anesthetized with ISO, whereas it increased these parameters in rats anesthetized with α‐CHLOR. Importantly, in ISO‐anesthetized animals cocaine‐induced changes in CBF and S_tO₂ were coupled, whereas for α‐CHLOR these measures were uncoupled. Moreover, the clearance of [¹¹C]cocaine from the brain was faster for ISO (peak half‐clearance 15.8 ± 2.8 min) than for α‐CHLOR (27.5 ± 0.6 min), and the ratio of specific to non‐specific binding of [¹¹C]cocaine in the brain was higher for ISO‐ (3.37 ± 0.32) than for α‐CHLOR‐anesthetized rats (2.24 ± 0.4). For both anesthetics, cocaine‐induced changes in CBF followed the fast uptake of [¹¹C]cocaine in the brain (peaking at ～2.5–4 min), but only for ISO did the duration of the CBV and S_tO₂ changes correspond to the rate of [¹¹C]cocaine’s clearance from the brain. These results demonstrate that anesthetics influence cocaine’s hemodynamic and metabolic changes in the brain, and its binding and PK, which highlights the need to better understand the interactions between anesthetics and pharmacological challenges in brain functional imaging studies.     

Neuroprotection of S(+) ketamine isomer in global forebrain ischemia

The non-competitive N-methyl- -aspartate (NMDA) receptor antagonist ketamine can block the action of excitotoxic amino acids in the central nervous system. S(+) ketamine has a 2–3 times higher anesthetic potency compared with the ketamine-racemate and also shows a higher neuroprotective efficacy in vitro. To determine the neuroprotective activity of S(+) ketamine compared with its R(−) stereoisomer in vivo, we examined the functional and neurohistological outcome in rats treated 15 min after global forebrain ischemia with S(+) ketamine in different dosages compared with R(−) ketamine. Influence of the treatment on regional cerebral blood flow (rCBF) and cortical oxygen saturation (HbO₂) was monitored over 1 h after the ischemia using laser doppler flowmetry and microphotospectrometry respectively. Sixty and ninety mg/kg of S(+) ketamine but not R(−) ketamine significantly reduced neuronal cell loss in the cortex compared with the saline treated group. No significant neuroprotection was observed in the hippocampus. Although no significant change in rCBF was found, S(+) ketamine restored the cortical HbO₂ to preischemic values. These results indicate that S(+) ketamine in higher dosages can reduce neuronal damage in the cortex after cerebral ischemia, possibly by improving the ratio of oxygen supply to consumption in the postischemic tissue.     

Method for rapid MRI quantification of global cerebral metabolic rate of oxygen

A recently reported quantitative magnetic resonance imaging (MRI) method denoted OxFlow has been shown to be able to quantify whole-brain cerebral metabolic rate of oxygen (CMRO₂) by simultaneously measuring oxygen saturation (S_vO₂) in the superior sagittal sinus and cerebral blood flow (CBF) in the arteries feeding the brain in 30 seconds, which is adequate for measurement at baseline but not necessarily in response to neuronal activation. Here, we present an accelerated version of the method (referred to as F-OxFlow) that quantifies CMRO₂ in 8 seconds scan time under full retention of the parent method''s capabilities and compared it with its predecessor at baseline in 10 healthy subjects. Results indicate excellent agreement between both sequences, with mean bias of 2.2% (P=0.18, two-tailed t-test), 3.4% (P=0.08, two-tailed t-test), and 2.0% (P=0.56, two-tailed t-test) for S_vO₂, CBF, and CMRO₂, respectively. F-OxFlow''s potential to monitor dynamic changes in S_vO₂, CBF, and CMRO₂ is illustrated in a paradigm of volitional apnea applied to five of the study subjects. The sequence captured an average increase in S_vO₂, CBF, and CMRO₂ of 10.1±2.5%, 43.2±9.2%, and 7.1±2.2%, respectively, in good agreement with literature values. The method may therefore be suited for monitoring alterations in CBF and S_vO₂ in response to neurovascular stimuli.     

Capillary dysfunction is associated with symptom severity and neurodegeneration in Alzheimer's disease

Introduction

We examined whether cortical microvascular blood volume and hemodynamics in Alzheimer's disease (AD) are consistent with tissue hypoxia and whether they correlate with cognitive performance and the degree of cortical thinning.

Cerebral functional, metabolic and circulatory effects of intravenous infusion of adrenaline in the rat

Cerebral functional, metabolic and circulatory effects of intravenous infusion of adrenaline (8 μg/kg/min) were evaluated in paralyzed, artificially ventilated and lightly anesthetized rats. At 5, 10 and 15 min following the start of infusion cerebral oxygen consumption (CMR_O2) increased 1.6- to 2-fold and cerebral blood flow (CBF) 3- to 4-fold. If the increase in arterial blood pressure was prevented or minimized, adrenaline infusion had no effect on CMR_O2 or CBF. In the absence of adrenaline infusion, a precipitous rise in blood pressure (induced by cross-clamping the aorta) likewise failed to alter CMR_O2 or CBF. It is concluded that the cerebral metabolic and circulatory effects required the presence of both high concentrations of adrenaline and a marked rise in pressure, the latter presumably allowing translocation of the amine from blood to cerebral extracellular fluids.Changes in EEG were recorded in animals in which the blood pressure was allowed to rise and in those in which it was servo-controlled. In the former, 5 of 6 animals showed an increased incidence of slow (4–5 Hz) waves, but the records failed to show signs of EEG arousal. In servo-controlled animals, 5 of 6 animals showed similar changes but with longer latency and shorter duration.Measurements of tissue metabolites failed to show alterations in cerebral cortical concentrations of glycogen, lactate, ATP, ADP, AMP or cyclic AMP. The lack of perturbation of cerebral metabolic state in spite of a doubling of CMR_O2 hints at the operation of an unusual metabolic effect of adrenaline on brain cells.     

The effect of head cooling on the physiological responses and resultant neural damage to global hemispheric hypoxic ischemia in prostaglandin E2 treated rats

The study determined if head cooling would reduce the augmented increase in neural damage of global hemispheric hypoxic ischemia (GHHI) of prostaglandin E₂ (PGE₂) treated rats. Halothane anesthetized, male, Long–Evans rats (9–11 weeks of age), kept at 37°C colonically (T_c) had (a) systemic core (colonic, T_c), temporalis muscle temperatures ipsilateral (T_ipsi) and contralateral (T_contra) to the side of right common carotid artery (RCCA) ligation, (b) mean arterial pressure (MAP) and (c) ipsilateral cortical capillary blood flow (CBF) measured simultaneously after intracerebroventricular (i.c.v.) injection (2.5 μl) of sterile (SS) or 25 ng PGE₂ then GHHI (35 min of 12% O₂, balance N₂ after RCCA ligation) followed by a 10 min normoxic recovery period. Head cooling (10°C cool air over the head region) occurred in one PGE₂ subgroup 10 min post-injection until the end of the hypoxic period. Icv-PGE₂ treated rats, maintained at 37°C (no head cooling) had increased T_c, T_ipsi, T_contras and MAPs from respective pre-injection control values; this group showed increased ipsilateral hemispheric neural damage to GHHI assessed 7 days later, compared to i.c.v.-SS treated group given the same GHHI insult. Cooling the head region of rats previously given PGE₂ decreased T_ipsi and T_contras from respective control temperatures but did not change MAP or CBF from respective pre-injection values. Hemispheric damage of the PGE₂ cooled group was reduced from damage of non-cooled PGE₂ treated rats and was similar to i.c.v.-SS treated rats. Results demonstrate that the heightened core temperatures induced by PGE₂ administration (major endogenous mediator of bacterial fever induction) play a significant role in escalating the neural damage to global ischemia.     

Tissue oxygen is reduced in white matter of spontaneously hypertensive-stroke prone rats: a longitudinal study with electron paramagnetic resonance

Small vessel disease is associated with white-matter (WM) magnetic resonance imaging (MRI) hyperintensities (WMHs) in patients with vascular cognitive impairment (VCI) and subsequent damage to the WM. Although WM is vulnerable to hypoxic-ischemic injury and O₂ is critical in brain physiology, tissue O₂ level in the WM has not been measured and explored in vivo. We hypothesized that spontaneously hypertensive stroke-prone rat (SHR/SP) fed a Japanese permissive diet (JPD) and subjected to unilateral carotid artery occlusion (UCAO), a model to study VCI, would lead to reduced tissue oxygen (pO₂) in the deep WM. We tested this hypothesis by monitoring WM tissue pO₂ using in vivo electron paramagnetic resonance (EPR) oximetry in SHR/SP rats over weeks before and after JPD/UCAO. The SHR/SP rats experienced an increase in WM pO₂ from 9 to 12 weeks with a maximal 32% increase at week 12, followed by a dramatic decrease in WM pO₂ to near hypoxic conditions during weeks 13 to 16 after JPD/UCAO. The decreased WM pO₂ was accompanied with WM damage and hemorrhages surrounding microvessels. Our findings suggest that changes in WM pO₂ may contribute to WM damage in SHR/SP rat model, and that EPR oximetry can monitor brain pO₂ in the WM of small animals.     

Repeated assessment of orthotopic glioma pO(2) by multi-site EPR oximetry: a technique with the potential to guide therapeutic optimization by repeated measurements of oxygen

Tumor hypoxia plays a vital role in therapeutic resistance. Consequently, measurements of tumor pO₂ could be used to optimize the outcome of oxygen-dependent therapies, such as, chemoradiation. However, the potential optimizations are restricted by the lack of methods to repeatedly and quantitatively assess tumor pO₂ during therapies, particularly in gliomas. We describe the procedures for repeated measurements of orthotopic glioma pO₂ by multi-site electron paramagnetic resonance (EPR) oximetry. This oximetry approach provides simultaneous measurements of pO₂ at more than one site in the glioma and contralateral cerebral tissue.The pO₂ of intracerebral 9L, C6, F98 and U251 tumors, as well as contralateral brain, were measured repeatedly for five consecutive days. The 9L glioma was well oxygenated with pO₂ of 27-36 mm Hg, while C6, F98 and U251 glioma were hypoxic with pO₂ of 7-12 mm Hg. The potential of multi-site EPR oximetry to assess temporal changes in tissue pO₂ was investigated in rats breathing 100% O₂. A significant increase in F98 tumor and contralateral brain pO₂ was observed on day 1 and day 2, however, glioma oxygenation declined on subsequent days.In conclusion, EPR oximetry provides the capability to repeatedly assess temporal changes in orthotopic glioma pO₂. This information could be used to test and optimize the methods being developed to modulate tumor hypoxia. Furthermore, EPR oximetry could be potentially used to enhance the outcome of chemoradiation by scheduling treatments at times of increase in glioma pO₂.     

Role of nitric oxide in regulation of cerebral microvascular tone and autoregulation of cerebral blood flow in cats

The role of nitric oxide in the regulation of cerebrocortical microvascular tone and autoregulation of cerebral blood flow (CBF) was examined in 24 anesthetized cats. The local cerebral blood volume (CBV), mean transit time of blood (MTT), and CBF in the cortex were measured by our photoelectric method. CBV represents the cumulative dimensions of the cerebral microvessels. Intravenous injection of 0.35–0.7 mg/kg/minN^G-monomethyl-l-arginine (l-NMMA), an inhibitor of nitric oxide synthesis, significantly increased mean arterial blood pressure (MABP; 8.4–14.1%,P < 0.01), decreased CBV (15.2–28.7%,P < 0.01), and decreased CBF (20.0–29.8%,P < 0.01) in a dose-related manner. The changes in MABP, CBV, and CBF elicited byl-NMMA were inhibited (P < 0.05) by simultaneous infusion of 35 mg/kg/minl-arginine. Autoregulation of CBF was examined during controlled hypotension of −30 to −40 mmHg (artificial bleeding) and recovery of blood pressure (reinfusion of blood). Although CBF remained constant with blood pressure changes in the control state (ΔCBF/ΔMABP of 0.037±0.155 with hypotension), CBF became dependent on blood pressure changes (ΔCBF/ΔMABP of 0.478±0.135, P < 0.05) during infusion of 0.35 mg/kg/minl-NMMA. It is concluded that nitric oxide participates in both the regulation of basal tone of cerebral microvessels and the autoregulation of CBF.     

Microvascular oxygen tension and flow measurements in rodent cerebral cortex during baseline conditions and functional activation

Measuring cerebral oxygen delivery and metabolism microscopically is important for interpreting macroscopic functional magnetic resonance imaging (fMRI) data and identifying pathological changes associated with stroke, Alzheimer''s disease, and brain injury. Here, we present simultaneous, microscopic measurements of cerebral blood flow (CBF) and oxygen partial pressure (pO₂) in cortical microvessels of anesthetized rats under baseline conditions and during somatosensory stimulation. Using a custom-built imaging system, we measured CBF with Fourier-domain optical coherence tomography (OCT), and vascular pO₂ with confocal phosphorescence lifetime microscopy. Cerebral blood flow and pO₂ measurements displayed heterogeneity over distances irresolvable with fMRI and positron emission tomography. Baseline measurements indicate O₂ extraction from pial arterioles and homogeneity of ascending venule pO₂ despite large variation in microvessel flows. Oxygen extraction is linearly related to flow in ascending venules, suggesting that flow in ascending venules closely matches oxygen demand of the drained territory. Oxygen partial pressure and relative CBF transients during somatosensory stimulation further indicate arteriolar O₂ extraction and suggest that arterioles contribute to the fMRI blood oxygen level dependent response. Understanding O₂ supply on a microscopic level will yield better insight into brain function and the underlying mechanisms of various neuropathologies.     

Cerebral blood flow and BOLD fMRI responses to hypoxia in awake and anesthetized rats

This study investigated the functional MRI responses to graded hypoxia in awake/restrained and anesthetized animals by measuring cerebral blood flow (CBF) and blood oxygenation (BOLD) changes and estimating changes in cerebral metabolic rate of oxygen (CMRO2). Hypoxia in isoflurane anesthetized rats reduced blood pressure but did not change heart rate and respiration rate. In contrast, hypoxia in awake animals showed compensatory responses by sustaining blood pressure, increasing heart rate and respiration rate. Basal CBF was higher under isoflurane anesthesia than awake state because isoflurane is a vasodilator. Graded hypoxia decreased BOLD signals. Surprisingly, hypoxia also decreased CBF likely because hypoxia induced hypocapnia. Hypoxia-induced CBF and BOLD decreases were smaller in awake, relative to anesthetized, rats at low pO2, but similar at high pO2. CBF leveled off with decreasing hypoxia-induced pCO2 in awake rats, but monotonically decreased in anesthetized rats. CMRO2 estimated using a biophysical BOLD model did not change under mild hypoxia but was reduced under severe hypoxia relative to baseline. These results showed that isoflurane attenuated autonomic responses to hypoxia, hypoxia-induced hypocapnia dominated CBF changes, tissues in awake conditions appeared better oxygenated, and severe hypoxia reduced oxygen metabolism. This study underscored the marked differences in BOLD and CBF MRI responses to hypoxia in vivo between awake and anesthetized conditions and has implications for functional MRI studies of hypoxia in anesthetized animal models.     

Baseline CBF,and BOLD,CBF, and CMRO2 fMRI of visual and vibrotactile stimulations in baboons

Neurovascular coupling associated with visual and vibrotactile stimulations in baboons anesthetized sequentially with isoflurane and ketamine was evaluated using multimodal functional magnetic resonance imaging (fMRI) on a clinical 3-Tesla scanner. Basal cerebral blood flow (CBF), and combined blood-oxygenation-level-dependent (BOLD) and CBF fMRI of visual and somatosensory stimulations were measured using pseudo-continuous arterial spin labeling. Changes in stimulus-evoked cerebral metabolic rate of oxygen (CMRO₂) were estimated using calibrated fMRI. Arterial transit time for vessel, gray matter (GM), and white matter (WM) were 250, 570, and 823 ms, respectively. Gray matter and WM CBF, respectively, were 107.8±7.9 and 47.8±3.8 mL per 100 g per minute under isoflurane, and 108.8±10.3 and 48.7±4.2 mL per 100 g per minute under ketamine (mean±s.e.m., N=8 sessions, five baboons). The GM/WM CBF ratio was not statistically different between the two anesthetics, averaging 2.3±0.1. Hypercapnia evoked global BOLD and CBF increases. Blood-oxygenation-level-dependent, CBF, and CMRO₂ signal changes by visual and vibrotactile stimulations were 0.19% to 0.22%, 18% to 23%, and 4.9% to 6.7%, respectively. The CBF/CMRO₂ ratio was 2.9 to 4.7. Basal CBF and fMRI responses were not statistically different between the two anesthetics. This study establishes a multimodal fMRI protocol to probe clinically relevant functional, physiological and metabolic information in large nonhuman primates.     

[11C]Raclopride binding in the striatum of minimally restrained and free‐walking awake mice in a positron emission tomography study

Anesthesia and restraint stress have profound impacts on brain functions, including neural activity and cerebrovascular function, possibly influencing functional and neurochemical positron emission tomography (PET) imaging data. For circumventing this effect, we developed an experimental system enabling PET imaging of free‐walking awake mice with minimal restraints by fixing the head to a holder. The applicability of this system was investigated by performing PET imaging of D₂ dopamine receptors with [¹¹C]raclopride under the following three different conditions: (1) free‐walking awake state; (2) 1.5% isoflurane anesthesia; and (3) whole‐body restraint without anesthesia. [¹¹C]raclopride binding potential (BP_ND) values under isoflurane anesthesia and restrained awake state were significantly lower than under free‐walking awake state (P < 0.01). Heart rates in restrained awake mice were significantly higher than those in free‐walking awake mice (P < 0.01), suggesting that free‐walking awake state minimized restraint stress during the PET scan. [¹¹C] raclopride‐PET with methamphetamine (METH) injection was also performed in awake and anesthetized mice. METH‐induced reduction of [¹¹C]raclopride BP_ND in anesthetized mice showed a trend to be less than that in free‐walking awake mice, implying that pharmacological modulation of dopaminergic transmissions could be sensitively captured by PET imaging of free‐walking awake mice. We concluded that our system is of utility as an in vivo assaying platform for studies of brain functions and neurotransmission elements in small animals, such as those modeling neuropsychiatric disorders. Synapse 69:600–606, 2015 . © 2015 Wiley Periodicals, Inc.     

The effect of racemic ketamine on the large conductance Ca-activated potassium (BK) channels in GH3 cells

Recently, inhalation anesthetics have been reported to block BK channels in adrenal chromaffin cells. To determine if BK block was characteristic only of inhalation anesthetics or was also a property of other general anesthetics we examined the effects of ketamine, an intravenous general anesthetic which is structurally different than inhalation anesthetics. Cell-attached and excised patch single channel and standard whole cell recording techniques were used to examine the effect of racemic ketamine on the BK channel activity in GH₃ cells. When solutions containing 150 mM KCl are used in both the pipette and bath, the BK channels are characterized as a voltage-dependent channel with a unit conductance of 150–300 pS. Racemic ketamine (at clinically relevant concentrations; 2–500 μM) selectively blocked BK channels in a dose-dependent, reversible manner as evidenced by decreases in NP_o (number of channels × open probability). This decrease was due to both a decrease in mean open time and an increase in the mean closed time but without a decrease in single-channel current amplitude. Ketamine shifts the P_o vs voltage curve to higher potentials without a change in the slope of the voltage dependence. Ketamine also shifts the P_o vs [Ca⁺²] relationship to higher Ca⁺² concentrations. The IC₅₀ for the single-channel block by ketamine is 20.3 ± 15.9 μM. In an effort to confirm that the effect of ketamine was predominantly due to a block of the BK channels, standard whole cell techniques were utilized. As with the single-channel experiments, ketamine (2–500 μM) produced a dose-dependent, voltage-independent and reversible decrease in outward current with an IC₅₀ of 23.7 ± 11.5 μM. Addition of 100 μM ketamine to cells pretreated with the BK channel blocker, charybdotoxin (ChTX), did not result in a further decrease in outward current. These results demonstrate a selective effect of ketamine at clinically relevant concentrations which is consistent with results reported for inhalation anesthetics.     

Comparison of cerebral blood flow acquired by simultaneous [15O]water positron emission tomography and arterial spin labeling magnetic resonance imaging

Until recently, no direct comparison between [¹⁵O]water positron emission tomography (PET) and arterial spin labeling (ASL) for measuring cerebral blood flow (CBF) was possible. With the introduction of integrated, hybrid magnetic resonance (MR)-PET scanners, such a comparison becomes feasible. This study presents results of CBF measurements recorded simultaneously with [¹⁵O]water and ASL. A 3T MR-BrainPET scanner was used for the simultaneous acquisition of pseudo-continuous ASL (pCASL) magnetic resonance imaging (MRI) and [¹⁵O]water PET. Quantitative CBF values were compared in 10 young healthy male volunteers at baseline conditions. A statistically significant (P<0.05) correlation was observed between the two modalities; the whole-brain CBF values determined with PET and pCASL were 43.3±6.1 mL and 51.9±7.1 mL per 100 g per minute, respectively. The gray/white matter (GM/WM) ratio of CBF was 3.0 for PET and 3.4 for pCASL. A paired t-test revealed differences in regional CBF between ASL and PET with higher ASL-CBF than PET-CBF values in cortical areas. Using an integrated, hybrid MR-PET a direct simultaneous comparison between ASL and [¹⁵O]water PET became possible for the first time so that temporal, physiologic, and functional variations were avoided. Regional and individual differences were found despite the overall similarity between ASL and PET, requiring further detailed investigations.     

Effect of Isoflurane (Forane) on Intraoperative Electrocorticogram

Isoflurane, an inhalation agent often used for general anesthesia during craniotomy, has been reported to suppress spike activity in the intraoperative electrocor-ticogram (ECoG) during epilepsy surgery. We studied the effect of isoflurane concentrations of 0.25, 0.5, 0.75, 1, and 1.25% on the number of spike bursts per 5-min epochs in 15 patients undergoing ECoG during epilepsy surgery. N₂O in O₂ was maintained at 50% in 10 patients, at 60% in 2, and at 70% in 3. End tidal CO₂ concentration was maintained in the hypocarbic range, and analgesia was maintained with the narcotic alfentanil in the range of 0.5–2 μg/kg/min. The median number of spikes for each isoflurane concentration was 29 (range 3–107) at 0.25%, 27 (range 2–73) at 0.5%; 29 (range 5–90) at 0.75%, 33 (range 2–100) at 1%, and 40 (range 32–140) in 5 patients who tolerated 1.25% without occurrence of burst suppression pattern. No significant difference (Student's paired t test) was noted in the number of spikes for each isoflurane concentration. Therefore, if isoflurane concentrations are maintained between 0.25 and 1.25% or before burst suppression pattern occurs and N₂O/O₂ is maintained in the 50–70% range, isoflurane has no significant effect on spike activity.     

Difference in response of D2 receptor binding between11C-N-methylspiperone and11C-raclopride against anesthetics in rhesus monkey brain

Summary The effects of anesthesia on dopamine D₂ receptor binding in the rhesus monkey brain were examined using positron emission tomography. The bindings of¹¹C-N-methylspiperone (NMSP) and¹¹C-raclopride (RAC) were measured under controlled ketamine or isoflurane anesthesia. The binding of¹¹C-NMSP was significantly lower in the striatum anesthetized with isoflurane than with ketamine. There was a smaller change in the binding of¹¹C-RAC than of¹¹C-NMSP. These findings suggest that changes in¹¹C-NMSP or¹¹C-RAC binding induced by anesthetics were not due solely to changes in the competition of endogenous dopamine.     

Low neuronal metabolism during isoflurane-induced burst suppression is related to synaptic inhibition while neurovascular coupling and mitochondrial function remain intact

Deep anaesthesia may impair neuronal, vascular and mitochondrial function facilitating neurological complications, such as delirium and stroke. On the other hand, deep anaesthesia is performed for neuroprotection in critical brain diseases such as status epilepticus or traumatic brain injury. Since the commonly used anaesthetic propofol causes mitochondrial dysfunction, we investigated the impact of the alternative anaesthetic isoflurane on neuro-metabolism. In deeply anaesthetised Wistar rats (burst suppression pattern), we measured increased cortical tissue oxygen pressure (p_tiO₂), a ∼35% drop in regional cerebral blood flow (rCBF) and burst-associated neurovascular responses. In vitro, 3% isoflurane blocked synaptic transmission and impaired network oscillations, thereby decreasing the cerebral metabolic rate of oxygen (CMRO₂). Concerning mitochondrial function, isoflurane induced a reductive shift in flavin adenine dinucleotide (FAD) and decreased stimulus-induced FAD transients as Ca²⁺ influx was reduced by ∼50%. Computer simulations based on experimental results predicted no direct effects of isoflurane on mitochondrial complexes or ATP-synthesis. We found that isoflurane-induced burst suppression is related to decreased ATP consumption due to inhibition of synaptic activity while neurovascular coupling and mitochondrial function remain intact. The neurometabolic profile of isoflurane thus appears to be superior to that of propofol which has been shown to impair the mitochondrial respiratory chain.