Directional connectivity between frontal and posterior brain regions is altered with increasing concentrations of propofol.

Recent studies using electroencephalography (EEG) suggest that alteration of coherent activity between the anterior and posterior brain regions might be used as a neurophysiologic correlate of anesthetic-induced unconsciousness. One way to assess causal relationships between brain regions is given by renormalized partial directed coherence (rPDC). Importantly, directional connectivity is evaluated in the frequency domain by taking into account the whole multichannel EEG, as opposed to time domain or two channel approaches. rPDC was applied here in order to investigate propofol induced changes in causal connectivity between four states of consciousness: awake (AWA), deep sedation (SED), loss (LOC) and return of consciousness (ROC) by gathering full 10/20 system human EEG data in ten healthy male subjects. The target-controlled drug infusion was started at low rate with subsequent gradual stepwise increases at 10 min intervals in order to carefully approach LOC (defined as loss of motor responsiveness to a verbal stimulus). The direction of the causal EEG-network connections clearly changed from AWA to SED and LOC. Propofol induced a decrease (p = 0.002-0.004) in occipital-to-frontal rPDC of 8-16 Hz EEG activity and an increase (p = 0.001-0.040) in frontal-to-occipital rPDC of 10-20 Hz activity on both sides of the brain during SED and LOC. In addition, frontal-to-parietal rPDC within 1-12 Hz increased in the left hemisphere at LOC compared to AWA (p = 0.003). However, no significant changes were detected between the SED and the LOC states. The observed decrease in back-to-front EEG connectivity appears compatible with impaired information flow from the posterior sensory and association cortices to the executive prefrontal areas, possibly related to decreased ability to perceive the surrounding world during sedation. The observed increase in the opposite (front-to-back) connectivity suggests a propofol concentration dependent association and is not directly related to the level of consciousness per se.

Capacity and hypoxic response of subcutaneous adipose tissue blood flow in humans.

BACKGROUND: The blood flow capacity in subcutaneous adipose tissue in humans remains largely unknown, and therefore the aim of this study was to determine the physiological range of blood flow in this tissue. METHODS AND RESULTS: The subcutaneous adipose tissue blood flow (ATBF) was measured in 9 healthy young men by positron emission tomography using radiowater tracer. Subcutaneous ATBF was determined in regions adjacent to knee extensors at rest and during dynamic knee extensor exercise, and with 2 physiological perturbations: while breathing moderate systemic hypoxic air (14% O2) at rest and during exercise, and during intra-femoral artery infusion of high-dose adenosine infusion. ATBF was 1.3±0.6ml·100g(-1)·min(-1) at rest and increased with exercise (8.0±3.0ml·100g(-1)·min(-1), P<0.001) and adenosine infusion (10.5±4.9ml·100g(-1)·min(-1), P=0.001), but not when breathing moderate systemic hypoxic air (1.5±0.4ml·100g(-1)·min(-1)). ATBF was similar during exercise and adenosine infusion, but vascular conductance was lower during adenosine infusion. Finally, ATBF during exercise in moderate systemic hypoxia was reduced (6.3±2.2ml·100g(-1)·min(-1)) compared to normoxic exercise (P=0.004). CONCLUSIONS: The vasodilatation capacity of human subcutaneous adipose blood flow appears to be comparable to, or even higher, than that induced by moderate intensity exercise. Furthermore, the reduced blood flow response in subcutaneous adipose tissue during systemic hypoxia is likely to contribute, in part, to the redistribution of blood flow to exercising muscle in a condition of reduced oxygen availability.

Positron emission tomography detects greater blood flow and less blood flow heterogeneity in the exercising skeletal muscles of old compared with young men during fatiguing contractions.

The purpose of this study was to investigate blood flow and its heterogeneity within and among the knee muscles in five young (26 ± 6 years) and five old (77 ± 6 years) healthy men with similar levels of physical activity while they performed two types of submaximal fatiguing isometric contraction that required either force or position control. Positron emission tomography (PET) and [(15)O]-H2O were used to determine blood flow at 2 min (beginning) and 12 min (end) after the start of the tasks. Young and old men had similar maximal forces and endurance times for the fatiguing tasks. Although muscle volumes were lower in the older subjects, total muscle blood flow was similar in both groups (young men: 25.8 ± 12.6 ml min(-1); old men: 25.1 ± 15.4 ml min(-1); age main effect, P = 0.77) as blood flow per unit mass of muscle in the exercising knee extensors was greater in the older (12.5 ± 6.2 ml min(-1) (100 g)(-1)) than the younger (8.6 ± 3.6 ml min(-1) (100 g)(-1)) men (age main effect, P = 0.001). Further, blood flow heterogeneity in the exercising knee extensors was significantly lower in the older (56 ± 27%) than the younger (67 ± 34%) men. Together, these data show that although skeletal muscles are smaller in older subjects, based on the intact neural drive to the muscle and the greater, less heterogeneous blood flow per gram of muscle, old fit muscle achieves adequate exercise hyperaemia.

Inhibition of α-adrenergic tone disturbs the distribution of blood flow in the exercising human limb.

The role of neuronal regulation of human cardiovascular function remains incompletely elucidated, especially during exercise. Here we, by positron emission tomography, monitored tissue-specific blood flow (BF) changes in nine healthy young men during femoral arterial infusions of norepinephrine (NE) and phentolamine. At rest, the α-adrenoceptor agonist NE reduced BF by ~40%, similarly in muscles (from 3.2 ± 1.9 to 1.4 ± 0.3 ml·min(-1)·100 g(-1) in quadriceps femoris muscle), bone (from 1.1 ± 0.4 to 0.5 ± 0.2 ml·min(-1)·100 g(-1)) and adipose tissue (AT) (from 1.2 ± 0.7 to 0.7 ± 0.3 ml·min(-1)·100 g(-1)). During exercise, NE reduced exercising muscle BF by ~16%. BF in AT was reduced similarly as rest. The α-adrenoceptor antagonist phentolamine increased BF similarly in the different muscles and other tissues of the limb at rest. During exercise, BF in inactive muscle was increased 3.4-fold by phentolamine compared with exercise without drug, but BF in exercising muscles was not influenced. Bone and AT (P = 0.055) BF were also increased by phentolamine in the exercise condition. NE increased and phentolamine decreased oxygen extraction in the limb during exercise. We conclude that inhibition of α-adrenergic tone markedly disturbs the distribution of BF and oxygen extraction in the exercising human limb by increasing BF especially around inactive muscle fibers. Moreover, although marked functional sympatholysis also occurs during exercise, the arterial NE infusion that mimics the exaggerated sympathetic nerve activity commonly seen in patients with cardiovascular disease was still capable of directly limiting BF in the exercising leg muscles.

Squeezing the muscle: compression clothing and muscle metabolism during recovery from high intensity exercise.

The purpose of this experiment was to investigate skeletal muscle blood flow and glucose uptake in m. biceps (BF) and m. quadriceps femoris (QF) 1) during recovery from high intensity cycle exercise, and 2) while wearing a compression short applying ~37 mmHg to the thigh muscles. Blood flow and glucose uptake were measured in the compressed and non-compressed leg of 6 healthy men by using positron emission tomography. At baseline blood flow in QF (P = 0.79) and BF (P = 0.90) did not differ between the compressed and the non-compressed leg. During recovery muscle blood flow was higher compared to baseline in both compressed (P<0.01) and non-compressed QF (P<0.001) but not in compressed (P = 0.41) and non-compressed BF (P = 0.05; effect size = 2.74). During recovery blood flow was lower in compressed QF (P<0.01) but not in BF (P = 0.26) compared to the non-compressed muscles. During baseline and recovery no differences in blood flow were detected between the superficial and deep parts of QF in both, compressed (baseline P = 0.79; recovery P = 0.68) and non-compressed leg (baseline P = 0.64; recovery P = 0.06). During recovery glucose uptake was higher in QF compared to BF in both conditions (P<0.01) with no difference between the compressed and non-compressed thigh. Glucose uptake was higher in the deep compared to the superficial parts of QF (compression leg P = 0.02). These results demonstrate that wearing compression shorts with ~37 mmHg of external pressure reduces blood flow both in the deep and superficial regions of muscle tissue during recovery from high intensity exercise but does not affect glucose uptake in BF and QF.

Bone blood flow and metabolism in humans: effect of muscular exercise and other physiological perturbations.

Human bone blood flow and metabolism during physical exercise remains poorly characterized. In the present study we measured femoral bone blood flow and glucose uptake in young healthy subjects by positron emission tomography in three separate protocols. In 6 women, blood flow was measured in femoral bone at rest and during one-leg intermittent isometric exercise with increasing exercise intensities. In 9 men, blood flow in the femur was determined at rest and during dynamic one-leg exercise and two other physiological perturbations: moderate systemic hypoxia (14 O2 ) at rest and during exercise, and during intrafemoral infusion of high-dose adenosine. Bone glucose uptake was measured at rest and during dynamic one-leg exercise in 5 men. The results indicate that isometric exercise increased femoral bone blood flow from rest (1.8 ± 0.6 mL/100 g/min) to low intensity exercise (4.1 ± 1.5 mL/100 g/min, p = 0.01), but blood flow did not increase further with increasing intensity. Resting femoral bone blood flow in men was similar to that of women and dynamic one-leg exercise increased it to 4.2 ± 1.2 mL/100 g/min, p < 0.001. Breathing of hypoxic air did not change femoral bone blood flow at rest or during exercise, but intra-arterial infusion of adenosine during resting conditions increased bone blood flow to 5.7 ± 2.4 mL/100 g/min, to the level of moderate-intensity dynamic exercise. Dynamic one-leg exercise increased femoral bone glucose uptake 4.7-fold compared to resting contralateral leg. In conclusion, resting femoral bone blood flow increases by physical exercise, but appears to level off with increasing exercise intensities. Moreover, although moderate systemic hypoxia does not change bone blood flow at rest or during exercise, intra-arterially administered adenosine during resting conditions is capable of markedly enhancing bone blood flow in humans. Finally, bone glucose uptake also increases substantially in response to exercise.

Returning from oblivion: imaging the neural core of consciousness.

One of the greatest challenges of modern neuroscience is to discover the neural mechanisms of consciousness and to explain how they produce the conscious state. We sought the underlying neural substrate of human consciousness by manipulating the level of consciousness in volunteers with anesthetic agents and visualizing the resultant changes in brain activity using regional cerebral blood flow imaging with positron emission tomography. Study design and methodology were chosen to dissociate the state-related changes in consciousness from the effects of the anesthetic drugs. We found the emergence of consciousness, as assessed with a motor response to a spoken command, to be associated with the activation of a core network involving subcortical and limbic regions that become functionally coupled with parts of frontal and inferior parietal cortices upon awakening from unconsciousness. The neural core of consciousness thus involves forebrain arousal acting to link motor intentions originating in posterior sensory integration regions with motor action control arising in more anterior brain regions. These findings reveal the clearest picture yet of the minimal neural correlates required for a conscious state to emerge.

Heart rate variability dynamics during low-dose propofol and dexmedetomidine anesthesia.

Heart rate variability (HRV) has been observed to decrease during anesthesia, but changes in HRV during loss and recovery of consciousness have not been studied in detail. In this study, HRV dynamics during low-dose propofol (N = 10) and dexmedetomidine (N = 9) anesthesia were estimated by using time-varying methods. Standard time-domain and frequency-domain measures of HRV were included in the analysis. Frequency-domain parameters like low frequency (LF) and high frequency (HF) component powers were extracted from time-varying spectrum estimates obtained with a Kalman smoother algorithm. The Kalman smoother is a parametric spectrum estimation approach based on time-varying autoregressive (AR) modeling. Prior to loss of consciousness, an increase in HF component power indicating increase in vagal control of heart rate (HR) was observed for both anesthetics. The relative increase of vagal control over sympathetic control of HR was overall larger for dexmedetomidine which is in line with the known sympatholytic effect of this anesthetic. Even though the inter-individual variability in the HRV parameters was substantial, the results suggest the usefulness of HRV analysis in monitoring dexmedetomidine anesthesia.

Effects of adenosine, exercise, and moderate acute hypoxia on energy substrate utilization of human skeletal muscle.

Glucose metabolism increases in hypoxia and can be influenced by endogenous adenosine, but the role of adenosine for regulating glucose metabolism at rest or during exercise in hypoxia has not been elucidated in humans. We studied the effects of exogenous adenosine on human skeletal muscle glucose uptake and other blood energy substrates [free fatty acid (FFA) and lactate] by infusing adenosine into the femoral artery in nine healthy young men. The role of endogenous adenosine was studied by intra-arterial adenosine receptor inhibition (aminophylline) during dynamic one-leg knee extension exercise in normoxia and acute hypoxia corresponding to ∼3,400 m of altitude. Extraction and release of energy substrates were studied by arterial-to-venous (A-V) blood samples, and total uptake or release was determined by the product of A-V differences and muscle nutritive perfusion measured by positron emission tomography. The results showed that glucose uptake increased from a baseline value of 0.2 ± 0.2 to 2.0 ± 2.2 µmol·100 g(-1)·min(-1) during adenosine infusion (P < 0.05) at rest. Although acute hypoxia enhanced arterial FFA levels, it did not affect muscle substrate utilization at rest. During exercise, glucose uptake was higher (195%) during acute hypoxia compared with normoxia (P = 0.058), and aminophylline had no effect on energy substrate utilization during exercise, despite that arterial FFA levels were increased. In conclusion, exogenous adenosine at rest and acute moderate hypoxia during low-intensity knee-extension exercise increases skeletal muscle glucose uptake, but the increase in hypoxia appears not to be mediated by adenosine.

Consciousness lost and found: subjective experiences in an unresponsive state.

Anesthetic-induced changes in the neural activity of the brain have been recently utilized as a research model to investigate the neural mechanisms of phenomenal consciousness. However, the anesthesiologic definition of consciousness as "responsiveness to the environment" seems to sidestep the possibility that an unresponsive individual may have subjective experiences. The aim of the present study was to analyze subjective reports in sessions where sedation and the loss of responsiveness were induced by dexmedetomidine, propofol, sevoflurane or xenon in a nonsurgical experimental setting. After regaining responsiveness, participants recalled subjective experiences in almost 60% of sessions. During dexmedetomidine sessions, subjective experiences were associated with shallower "depth of sedation" as measured by an electroencephalography-derived anesthesia depth monitor. Results confirm that subjective experiences may occur during clinically defined unresponsiveness, and that studies aiming to investigate phenomenal consciousness under sedative and anesthetic effects should control the subjective state of unresponsive participants with post-recovery interviews.

Regulation of human skeletal muscle perfusion and its heterogeneity during exercise in moderate hypoxia.

Although many effects of both acute and chronic hypoxia on the circulation are well characterized, the distribution and regulation of blood flow (BF) heterogeneity in skeletal muscle during systemic hypoxia is not well understood in humans. We measured muscle BF within the thigh muscles of nine healthy young men using positron emission tomography during one-leg dynamic knee extension exercise in normoxia and moderate physiological systemic hypoxia (14% O(2) corresponding to approximately 3,400 m of altitude) without and with local adenosine receptor inhibition with femoral artery infusion of aminophylline. Systemic hypoxia reduced oxygen extraction of the limb but increased muscle BF, and this flow increment was confined solely to the exercising quadriceps femoris muscle. Exercising muscle BF heterogeneity was reduced from rest (P = 0.055) but was not affected by hypoxia. Adenosine receptor inhibition had no effect on capillary BF during exercise in either normoxia or hypoxia. Finally, one-leg exercise increased muscle BF heterogeneity both in the resting posterior hamstring part of the exercising leg and in the resting contralateral leg, whereas mean BF was unchanged. In conclusion, the results show that increased BF during one-leg exercise in moderate hypoxia is confined only to the contracting muscles, and the working muscle hyperemia appears not to be directly mediated by adenosine. Increased flow heterogeneity in noncontracting muscles likely reflects sympathetic nervous constraints to curtail BF increments in areas other than working skeletal muscles, but this effect is not potentiated in moderate systemic hypoxia during small muscle mass exercise.

Comparison of exogenous adenosine and voluntary exercise on human skeletal muscle perfusion and perfusion heterogeneity.

Adenosine is a widely used pharmacological agent to induce a "high-flow" control condition to study the mechanisms of exercise hyperemia, but it is not known how well an adenosine infusion depicts exercise-induced hyperemia, especially in terms of blood flow distribution at the capillary level in human muscle. Additionally, it remains to be determined what proportion of the adenosine-induced flow elevation is specifically directed to muscle only. In the present study, we measured thigh muscle capillary nutritive blood flow in nine healthy young men using PET at rest and during the femoral artery infusion of adenosine (1 mg min(-1) l thigh volume(-1)), which has previously been shown to induce a maximal whole thigh blood flow of approximately 8 l/min. This response was compared with the blood flow induced by moderate- to high-intensity one-leg dynamic knee extension exercise. Adenosine increased muscle blood flow on average to 40 +/- 7 ml x min(-1) x 100 g muscle(-1) with an aggregate value of 2.3 +/- 0.6 l/min for the whole thigh musculature. Adenosine also induced a substantial change in blood flow distribution within individuals. Muscle blood flow during the adenosine infusion was comparable with blood flow in moderate- to high-intensity exercise (36 +/- 9 ml x min(-1) x 100 g muscle(-1)), but flow heterogeneity was significantly higher during the adenosine infusion than during voluntary exercise. In conclusion, a substantial part of the flow increase in the whole limb blood flow induced by a high-dose adenosine infusion is conducted through the physiological non-nutritive shunt in muscle and/or also through tissues of the limb other than muscle. Additionally, an intra-arterial adenosine infusion does not mimic exercise hyperemia, especially in terms of muscle capillary flow heterogeneity, while the often-observed exercise-induced changes in capillary blood flow heterogeneity likely reflect true changes in nutritive flow linked to muscle fiber and vascular unit recruitment.

Bispectral index, entropy, and quantitative electroencephalogram during single-agent xenon anesthesia.

BACKGROUND: The aim was to evaluate the performance of anesthesia depth monitors, Bispectral Index (BIS) and Entropy, during single-agent xenon anesthesia in 17 healthy subjects. METHODS: After mask induction with xenon and intubation, anesthesia was continued with xenon only. BIS, State Entropy and Response Entropy, and electroencephalogram were monitored throughout induction, steady-state anesthesia, and emergence. The performance of BIS, State Entropy, and Response Entropy were evaluated with prediction probability, sensitivity, and specificity analyses. The power spectrum of the raw electroencephalogram signal was calculated. RESULTS: The mean (SD) xenon concentration during anesthesia was 66.4% (2.4%). BIS, State Entropy, and Response Entropy demonstrated low prediction probability values at loss of response (0.455, 0.656, and 0.619) but 1 min after that the values were high (0.804, 0.941, and 0.929). Thereafter, equally good performance was demonstrated for all indices. At emergence, the prediction probability values to distinguish between steady-state anesthesia and return of response for BIS, State Entropy, and Response Entropy were 0.988, 0.892, and 0.992. No statistical differences between the performances of the monitors were observed. Quantitative electroencephalogram analyses showed generalized increase in total power (P < 0.001), delta (P < 0.001) and theta activity (P < 0.001), and increased alpha activity (P = 0.003) in the frontal brain regions. CONCLUSIONS: Electroencephalogram-derived depth of sedation indices BIS and Entropy showed a delay to detect loss of response during induction of xenon anesthesia. Both monitors performed well in distinguishing between conscious and unconscious states during steady-state anesthesia. Xenon-induced changes in electroencephalogram closely resemble those induced by propofol.