The characterization of topological architecture of complex brain networks is one of the most challenging issues in neuroscience. Slow (<0.1 Hz), spontaneous fluctuations of the blood oxygen level dependent (BOLD) signal in functional magnetic resonance imaging are thought to be potentially important for the reflection of spontaneous neuronal activity. Many studies have shown that these fluctuations are highly coherent within anatomically or functionally linked areas of the brain. However, the underlying topological mechanisms responsible for these coherent intrinsic or spontaneous fluctuations are still poorly understood. Here, we apply modern network analysis techniques to investigate how spontaneous neuronal activities in the human brain derived from the resting-state BOLD signals are topologically organized at both the temporal and spatial scales. We first show that the spontaneous brain functional networks have an intrinsically cohesive modular structure in which the connections between regions are much denser within modules than between them. These identified modules are found to be closely associated with several well known functionally interconnected subsystems such as the somatosensory/motor, auditory, attention, visual, subcortical, and the “default” system. Specifically, we demonstrate that the module-specific topological features can not be captured by means of computing the corresponding global network parameters, suggesting a unique organization within each module. Finally, we identify several pivotal network connectors and paths (predominantly associated with the association and limbic/paralimbic cortex regions) that are vital for the global coordination of information flow over the whole network, and we find that their lesions (deletions) critically affect the stability and robustness of the brain functional system. Together, our results demonstrate the highly organized modular architecture and associated topological properties in the temporal and spatial brain functional networks of the human brain that underlie spontaneous neuronal dynamics, which provides important implications for our understanding of how intrinsically coherent spontaneous brain activity has evolved into an optimal neuronal architecture to support global computation and information integration in the absence of specific stimuli or behaviors.
Oxygen transport to and substrate turnover in leg muscle were studied at rest and during light and heavy upright bicycle exercise in two brothers with a hereditary hemoglobinopathy associated with high oxygen affinity (P50 = 13 mmHg). Femoral venous oxygen tension was below normal and femoral venous oxygen saturation above normal at rest and during exercise. Thus, the arterial-femoral venous oxygen saturation difference was decreased. Despite a compensatory increase in hemoglobin concentration, the arterial-femoral venous oxygen content difference tended to be below normal at heavy exercise. Approximately 25% of the oxygen was delivered via the abnormal hemoglobin at relative heavy exercise. Arterial lactate levels, lactate release, and muscle lactate concentration were not increased at any level of exercise. Glucose, alanine, pyruvate, and glycerol turnover were essentially normal, but the glycogen and creatine phosphate stores were abnormally depleted at the termination of heavy exercise. The exercise electrocardiogram (ECG) was normal, indicating that myocardial oxygenation was adequate. Muscle-surface oxygen pressure fields were normal at rest (not investigated during exercise). It is concluded that the high oxygen affinity of the hemoglobin in our two subjects did not lead to heart or skeletal muscle hypoxia during heavy exercise, as judged from the ECG and from the leg lactate turnover. Despite the lack of evidence for muscle hypoxia, the subjects experienced leg muscle fatigue and the creatine phosphate and glycogen stores were depleted more than normally.
Functional magnetic resonance imaging (fMRI) has revealed that the human brain undergoes prominent, regional hemodynamic fluctuations when a subject is at rest. These ongoing fluctuations exhibit distinct patterns of spatiotemporal synchronization that have been dubbed “resting state functional connectivity”, and which currently serve as a principal tool to investigate neural networks in the normal and pathological human brain. Despite the wide application of this approach in human neuroscience, the neural mechanisms that give rise to spontaneous fMRI correlations are largely unknown. Here we review results of recent electrophysiological studies in the cerebral cortex of humans and nonhuman primates that link neural activity to ongoing fMRI fluctuations. We begin by describing results obtained with simultaneous fMRI and electrophysiological measurements that allow for the identification of direct neural correlates of resting state functional connectivity. We next highlight experiments that investigate the correlational structure of spontaneous neural signals, including the spatial variation of signal coherence over the cortical surface, across cortical laminae, and between the two hemispheres. In the final section we speculate on the origins and potential consequences of ongoing signals for normal brain function, and point out inherent limitations of the fMRI correlation approach.
Slow (<0.1Hz), spontaneous fluctuations in the fMRI blood oxygen level-dependent (BOLD) signal have been shown to exhibit phase coherence within functionally related areas of the brain. Surprisingly, this phenomenon appears to transcend levels of consciousness. The genesis of coherent BOLD fluctuations remains to be fully explained. We present a resting state functional connectivity study of a six-year old child with radiologically normal brain imaged both before and after complete section of the corpus callosum for the treatment of intractable epilepsy. Post-operatively, there was a striking loss of interhemispheric BOLD correlations with preserved intrahemispheric correlations. These unique data provide important insights into the relationship between connectional anatomy and functional organization of the human brain. Such observations have the potential to increase our understanding of large-scale brain systems in health and disease as well as improve the treatment of neurologic disorders.
synchrony; functional connectivity; corpus callosotomy; epilepsy; fMRI; resting state
1. A procedure is devised whereby cutaneous blood (so called capillary blood) from a finger-tip can be obtained for gas analyses without coming in contact with the air. 2. Determination was made of the oxygen content of the arterial, cutaneous, and venous blood respectively from a normal resting individual, the arterial and cutaneous blood showing the same oxygen content (97.5 and 96.6 per cent of the total oxygen-combining power of the blood). Venous blood drawn simultaneously was 75 per cent saturated. 3. Using the fact that there is a maximum value for the oxygen-combining power of the blood, we have shown, without doing arterial puncture, that under different conditions (normal and pathological individuals, resting and after exercise) the cutaneous blood and the arterial blood are almost identical as far as the oxygen content is concerned. 4. We think that we are justified in extending the identity, found between the oxygen content of the arterial and cutaneous blood, to other substances in the blood, for instance sugar, salt, uric acid, etc., and also to the reaction of the blood. 5. We are unable to say whether this identity between cutaneous and arterial blood is always true; for example, in a patient with increased venous pressure. 6. In all the experiments we have discarded the first drop of blood, which in some instances was darker than the rest, and always used at least 2 cc. of cutaneous blood. Whether the same results would be obtained with a very small amount of blood, for instance 0.2 to 0.4 cc., we do not know. 7. The experiments show that unless the perfusion of the skin has been extremely great during the experiment, samples of blood obtained from an incision in the skin (of the finger) cannot represent the true capillary blood. The neutral expression cutaneous blood seems therefore for the present preferable to the term capillary blood for samples of blood obtained by cutaneous incisions.
The resting brain is not silent; rather, it is characterized by organized resting-state networks showing spontaneous and coherent neuronal activities, which can be mapped using the spatiotemporal correlation of blood oxygenation level-dependent (BOLD) signal fluctuations measured by functional magnetic resonance imaging (fMRI). However, it remains elusive whether the similar fMRI approach is able to image the coherent network in a working brain, and if yes, whether there is a distinction between the resting- and working-state coherent networks. This study aimed to address these questions in the human visual cortex with a desired activation paradigm using continuous, sustained visual stimuli. It was found that the resting-state coherent network covering the human visual cortex was spatially reorganized during the stimulation into two coherent networks with distinct temporal characteristics of BOLD fluctuations: one covering the activated visual cortical region and the other covering the remaining (nonactivated) visual cortex. The stimulus-specific reorganization of the coherent network observed in the present fMRI study in human is consistent with previous electrophysiological findings from animal studies, and may suggest an essential mechanism for brain functioning. Finally, a similar fMRI experiment was also conducted under brief, short stimulation to examine how the stimulation paradigm can affect the observations.
coherent neural network; functional MRI (fMRI); reorganization of neural network; resting-state fMRI (rs-fMRI); resting-state network; working-state network
Spontaneous hemodynamic signals fluctuate coherently within many resting-brain functional networks not only in awake humans and lightly anesthetized primates but also in animals under deep anesthesia characterized by burst–suppression electroencephalogram (EEG) activity and unconsciousness. To understand the neural origin of spontaneous hemodynamic fluctuations under such a deep anesthesia state, epidural EEG and cerebral blood flow (CBF) were simultaneously recorded from the bilateral somatosensory cortical regions of rats with isoflurane-induced burst–suppression EEG activity. Strong neurovascular coupling was observed between spontaneous EEG “bursts” and CBF “bumps,” both of which were also highly synchronized across the 2 hemispheres. Functional magnetic resonance imaging (fMRI) was used to image spontaneous blood oxygen level–dependent (BOLD) signals under the same anesthesia conditions and showed similar BOLD “bumps” and dependence on anesthesia depth as the CBF signals. The spatiotemporal BOLD correlations indicate a strong but less-specific coherent network covering a wide range of cortical regions. The overall findings reveal that the spontaneous CBF/BOLD fluctuations under unconscious burst–suppression anesthesia conditions originate mainly from underlying neural activity. They provide insights into the neurophysiological basis for the use of BOLD- and CBF-based fMRI signals for noninvasively imaging spontaneous and synchronous brain activity under various brain states.
burst–suppression anesthesia; functional MRI; hemodynamic fluctuation; neurovascular coupling; spontaneous brain activity
Although possible sources and functions of the resting state networks (RSN) of the brain have been proposed, most evidence relies on circular logic and reverse inference. We propose that autonomic arousal provides an objective index of psychophysiological states during rest that may also function as a driving source of the activity and connectivity of RSN. Recording blood oxygenation level-dependent (BOLD) signal using functional magnetic resonance imaging and skin conductance simultaneously during rest in human subjects, we found that the spontaneous fluctuations of BOLD signals in key nodes of RSN are associated with changes in non-specific skin conductance response, a sensitive psychophysiological index of autonomic arousal. Our findings provide evidence of an important role for the autonomic nervous system to the spontaneous activity of the brain during ‘rest’.
resting-state functional connectivity MRI; autonomic arousal; skin conductance response; interoception; consciousness
Spontaneous low-frequency fluctuations in the blood oxygen level–dependent (BOLD) functional magnetic resonance imaging (MRI) signal have been shown to reflect neural synchrony between brain regions. A “default network” of spontaneous low-frequency fluctuations has been described in healthy volunteers during stimulus-independent thought. Negatively correlated with this network are regions activated during attention-demanding tasks. Both these networks involve brain regions and functions that have been linked with schizophrenia in previous research. The present study examined spontaneous slow fluctuations in the BOLD signal at rest, as measured by correlation with low-frequency oscillations in the posterior cingulate, in 17 schizophrenic patients, and 17 comparable healthy volunteers. Healthy volunteers demonstrated correlation between spontaneous low-frequency fluctuations of the BOLD signal in the posterior cingulate and fluctuations in the lateral parietal, medial prefrontal, and cerebellar regions, similar to previous reports. Schizophrenic patients had significantly less correlation between spontaneous slow activity in the posterior cingulate and that in the lateral parietal, medial prefrontal, and cerebellar regions. Connectivity of the posterior cingulate was found to vary with both positive and negative symptoms in schizophrenic patients. Because these data suggest significant abnormalities in resting-state neural networks in schizophrenia, further investigations of spontaneous slow fluctuations of the BOLD signal seem warranted in this population.
anticorrelated networksdefault network; schizophrenia; functional MRI; spontaneous slow fluctuations; posterior cingulate; medial prefrontal cortex
1. The oxygen content of venous and of arterial blood from fifteen essentially normal individuals at rest in bed has been determined. 2. The percentage saturation of the arterial blood has varied between 100 and 94.3. The average is 95.5 per cent. 3. The oxygen consumption has varied between 2.6 and 8.3 volumes per cent. 4. The oxygen content and the percentage saturation of arterial blood taken at close intervals from three different peripheral arteries of a normal individual have shown values agreeing within the limits of error. Analyses of the blood gases of a normal individual, at rest and after exercise, have shown a lowering of the percentage oxygen saturation of the arterial blood and a diminished carbon dioxide content after exercise. 5. In three persons with severe anemia the saturation of the arterial blood has not differed from the normal. Very low absolute values were found for the oxygen content of the venous blood, but the normal oxygen consumption has been maintained. 6. The carbon dioxide content of the arterial blood from ten normal individuals has varied between 54.7 and 44.6 volumes per cent. That of the venous blood has varied between 60.4 and 48.3 volumes per cent. 7. No deviations from the normal values for oxygen and carbon dioxide were found in venous and arterial blood from cardiac patients without arrhytiunias, well compensated, and at rest in bed. 8. A series of determinations has been made upon nine cardiac patients with varying degrees of decompensation. The percentage oxygen saturation of the arterial blood on admission was abnormally low in seven of these cases. With the return to compensation and with the clearing up of pulmonary symptoms, the percentage saturation of the arterial blood returned to normal in four of them. 9. In a case of long standing mitral endocarditis with auricular fibrillation it remained low over a period of I month of observation. 10. In a case of chronic myocarditis secondary to emphysema and chronic bronchitis, it remained low over the period of observation. 11. Normal values for the percentage saturation of the arterial blood were found in two individuals with decompensated aortic disease but without physical signs of extensive pulmonary involvement. 12. The oxygen consumption tended to be high in individuals with cardiac disease during the periods of marked decompensation and to be lower as compensation was regained. 13. The data presented indicate that at least in many circulatory diseases during decompensation, particularly when there are physical signs of pulmonary congestion, there is a disturbance of the pulmonary exchange, as indicated by the lowering of the percentage saturation of the arterial blood with oxygen.
Cardiovascular complications are common in fibrosing alveolitis, but there have been few physiological studies of the pulmonary circulation in this condition, and those that have been carried out have usually depended on right heart catheterisation. This paper reports non-invasive measurements of effective pulmonary blood flow, oxygen uptake, pulmonary arteriovenous oxygen content differences, and estimates of mixed venous oxygen saturation in 20 patients with histologically proved cryptogenic fibrosing alveolitis at rest and while exercising on a motorized treadmill. Results were compared with those of 20 age and sex matched normal subjects, at rest and at an arbitrarily chosen oxygen uptake of 0.75 l/min. The latter results were obtained by linear interpolation. Effective pulmonary blood flow was normal at rest, but oxygen dispatch to the tissues (blood flow x blood oxygen content) was significantly reduced at rest (mean reduction 190 (SD 68) ml/l/min; p less than 0.01) and at an oxygen uptake of 0.75 l/min (mean reduction 128 (50) ml/l/min; p less than 0.02), reflecting the presence of systemic arterial hypoxaemia. Pulmonary arteriovenous oxygen content differences were similar in patients and normal subjects, but mixed venous saturation was lower in the patients at rest (mean % reduction 6.8 (2.6); p less than 0.02) and at an oxygen uptake of 0.75 l/min (mean % reduction 9.6 (2.9); p less than 0.002). It is concluded that the supply of oxygen potentially available to the tissues is reduced at rest and during exercise in patients with fibrosing alveolitis and hence, by analogy with normal people exercising under hypoxic conditions, that pulmonary blood flow is inappropriately low in this condition. The low mixed venous oxygen saturation may contribute to the development of pulmonary hypertension in some patients. The rebreathing technique used in this study may be of use in monitoring treatment; it could be applied many times to the same patient, and might be a suitable way of following the response to pulmonary vasodilators.
Resting-state investigations based on the evaluation of intrinsic low-frequency fluctuations of the BOLD fMRI signal have been extensively utilized to map the structure and dynamics of large-scale functional network organization in humans. In addition to increasing our knowledge of normal brain connectivity, disruptions of the spontaneous hemodynamic fluctuations have been suggested as possible diagnostic indicators of neurological and psychiatric disease states. Though the non-invasive technique has been received with much acclamation, open questions remain regarding the origin, organization, phylogenesis, as well as the basis of disease-related alterations underlying the signal patterns. Experimental work utilizing animal models, including the use of neurophysiological recordings and pharmacological manipulations, therefore, represents a critical component in the understanding and successful application of resting-state analysis, as it affords a range of experimental manipulations not possible in human subjects. In this article, we review recent rodent and non-human primate studies and based on the examination of the homologous brain architecture propose the latter to be the best-suited model for exploring these unresolved resting-state concerns. Ongoing work examining the correspondence of functional and structural connectivity, state-dependency and the neuronal correlates of the hemodynamic oscillations are discussed. We then consider the potential experiments that will allow insight into different brain states and disease-related network disruptions that can extend the clinical applications of resting-state fMRI (RS-fMRI).
resting-state; non-human primate; functional connectivity; macaque; animal model; spontaneous activity; functional MRI (fMRI)
Although the close regional coupling of resting cerebral blood flow (CBF) with both cerebral metabolic rate of oxygen (CMRO2) and cerebral metabolic rate of glucose (CMRglc) within individuals is well documented, there are few data regarding the coupling between whole brain flow and metabolism among different subjects. To investigate the metabolic control of resting whole brain CBF, we performed multivariate analysis of hemispheric CMRO2, CMRglc, and other covariates as predictors of resting CBF among 23 normal humans. The univariate analysis showed that only CMRO2 was a significant predictor of CBF. The final multivariate model contained two additional terms in addition to CMRO2: arterial oxygen content and oxygen extraction fraction. Notably, arterial plasma glucose concentration and CMRglc were not included in the final model. Our data demonstrate that the metabolic factor controlling hemispheric CBF in the normal resting brain is CMRO2 and that CMRglc does not make a contribution. Our findings provide evidence for compartmentalization of brain metabolism into a basal component in which CBF is coupled to oxygen metabolism and an activation component in which CBF is controlled by another mechanism.
cerebral blood flow; cerebral glucose metabolism; cerebral oxygen metabolism; positron emission tomography; flow–metabolism coupling
Spontaneous activity in the resting human brain has been studied extensively; however, how such activity affects the local processing of a sensory stimulus is relatively unknown. Here, we examined the impact of spontaneous activity in primary visual cortex on neuronal and behavioural responses to a simple visual stimulus, using functional MRI. Stimulus-evoked responses remained essentially unchanged by spontaneous fluctuations, combining with them in a largely linear fashion (i.e., with little evidence for an interaction). However, interactions between spontaneous fluctuations and stimulus-evoked responses were evident behaviourally; high levels of spontaneous activity tended to be associated with increased stimulus detection at perceptual threshold. Our results extend those found in studies of spontaneous fluctuations in motor cortex and higher order visual areas, and suggest a fundamental role for spontaneous activity in stimulus processing.
Spontaneous activity; Resting-state functional connectivity; Primary visual cortex; Psycho-physiological interaction; fMRI
An animal model was developed to describe respiratory muscle work output, blood flow, and oxygen consumption during mechanical ventilation, resting spontaneous ventilation, and the increased unobstructed ventilatory efforts induced by CO2 rebreathing. Almost all of the work of breathing was inspiratory work at all ventilatory levels; thus, only blood flows to the diaphragm and external intercostals increased in the transition from mechanical to spontaneous ventilation, and they further increased linearly as ventilatory work was incrementally augmented ninefold by CO2 rebreathing. No other muscles of inspiration manifest increased blood flows. A small amount of expiratory work was measured at high ventilatory volumes during which two expiratory muscles (transverse abdominal and intercostals) had moderate increases in blood flow. Blood pressure did not change, but cardiac output doubled. Arterial-venous oxygen content difference across the diaphragm increased progressively, so oxygen delivery was augmented by both increased blood flow and increased oxygen extraction at all work loads. Oxygen consumption increased linearly as work of breathing increased, so efficiency did not change significantly. The mean efficiency of the respiratory muscles was 15.5%. These results differ significantly from the patterns previously observed by us during increased work of breathing induced by inspiratory resistance, suggesting a different distribution of work load among the various muscles of respiration, a different fractionation of oxygen delivery between blood flow and oxygen extraction, and a higher efficiency when shortening, not tension development, of the muscle is increased.
During resting conditions the brain remains functionally and metabolically active. One manifestation of this activity that has become an important research tool is spontaneous fluctuations in the blood oxygen level-dependent (BOLD) signal of functional magnetic resonance imaging (fMRI). The identification of correlation patterns in these spontaneous fluctuations has been termed resting state functional connectivity (fcMRI) and has the potential to greatly increase the translation of fMRI into clinical care. In this article we review the advantages of the resting state signal for clinical applications including detailed discussion of signal to noise considerations. We include guidelines for performing resting state research on clinical populations, outline the different areas for clinical application, and identify important barriers to be addressed to facilitate the translation of resting state fcMRI into the clinical realm.
fMRI; fcMRI; neurological disease; psychiatric disease; brain; spontaneous activity; intrinsic activity
Correlations between spontaneous fluctuations in the blood oxygenation level dependent (BOLD) signal measured with functional MRI are finding increasing use as measures of functional connectivity in the brain, where differences can potentially predict cognitive performance and diagnose disease. Caffeine, which is a widely consumed neural stimulant and vasoactive agent, has been found to decrease the amplitude and correlation of resting-state BOLD fluctuations, and hence is an important factor to consider in functional connectivity studies. However, because the BOLD signal is sensitive to neural and vascular factors, the physiological mechanisms by which caffeine alters spontaneous BOLD fluctuations remain unclear. Resting-state functional connectivity has traditionally been assessed using stationary measures, such as the correlation coefficient between BOLD signals measured across the length of a scan. However, recent work has shown that the correlation of resting-state networks can vary considerably over time, with periods as short as 10 seconds. In this study, we used a sliding window correlation analysis to assess temporal variations in resting-state functional connectivity of the motor cortex before and after caffeine ingestion. We found that the temporal variability of BOLD correlation was significantly higher following a caffeine dose, with transient periods of strong correlation alternating with periods of low or negative correlation. This phenomenon was primarily due to increased variability in the phase difference between BOLD time courses in the left and right motor cortices. These results indicate that caffeine may cause underlying spontaneous neural fluctuations to go in and out of coherence more frequently, and emphasizes the need to consider non-stationary measures when studying changes in functional connectivity.
nonstationary; functional MRI; resting-state network; temporal dynamics; correlation; spectral decomposition
It has been proposed that adenosine triphosphate (ATP) released from red blood cells (RBCs) may contribute to the tight coupling between blood flow and oxygen demand in contracting skeletal muscle. To determine whether ATP may contribute to the vasodilatory response to exercise in the forearm, we measured arterialised and venous plasma ATP concentration and venous oxygen content in 10 healthy young males at rest, and at 30 and 180 seconds during dynamic handgrip exercise at 45% of maximum voluntary contraction (MVC).
Venous plasma ATP concentration was elevated above rest after 30 seconds of exercise (P < 0.05), and remained at this higher level 180 seconds into exercise (P < 0.05 versus rest). The increase in ATP was mirrored by a decrease in venous oxygen content. While there was no significant relationship between ATP concentration and venous oxygen content at 30 seconds of exercise, they were moderately and inversely correlated at 180 seconds of exercise (r = -0.651, P = 0.021). Arterial ATP concentration remained unchanged throughout exercise, resulting in an increase in the venous-arterial ATP difference.
Collectively these results indicate that ATP in the plasma originated from the muscle microcirculation, and are consistent with the notion that deoxygenation of the blood perfusing the muscle acts as a stimulus for ATP release. That ATP concentration was elevated just 30 seconds after the onset of exercise also suggests that ATP may be a contributing factor to the blood flow response in the transition from rest to steady state exercise.
Resting-state functional magnetic resonance imaging (fMRI) is widely used for exploring spontaneous brain activity and large-scale networks; however, the neural processes underlying the observed resting-state fMRI signals are not fully understood. To investigate the neural correlates of spontaneous low-frequency fMRI fluctuations and functional connectivity, we developed a rat model of simultaneous fMRI and multiple-site intracortical neural recordings. This allowed a direct comparison to be made between the spontaneous signals and interhemispheric connectivity measured with the two modalities. Results show that low-frequency blood oxygen level-dependent (BOLD) fluctuations (<0.1 Hz) correlate significantly with slow power modulations (<0.1 Hz) of local field potentials (LFPs) in a broad frequency range (1–100 Hz) under isoflurane anesthesia (1%–1.8%). Peak correlation occurred between neural and hemodynamic activity when the BOLD signal was delayed by ∼4 sec relative to the LFP signal. The spatial location and extent of correlation was highly reproducible across studies, with the maximum correlation localized to a small area surrounding the site of microelectrode recording and to the homologous area in the contralateral hemisphere for most rats. Interhemispheric connectivity was calculated using BOLD correlation and band-limited LFP (1–4, 4–8, 8–14, 14–25, 25–40, and 40–100 Hz) coherence. Significant coherence was observed for the slow power changes of all LFP frequency bands as well as in the low-frequency BOLD data. A preliminary investigation of the effect of anesthesia on interhemispheric connectivity indicates that coherence in the high-frequency LFP bands declines with increasing doses of isoflurane, whereas coherence in the low-frequency LFP bands and the BOLD signal increases. These findings suggest that resting-state fMRI signals might be a reflection of broadband LFP power modulation, at least in isoflurane-anesthetized rats.
anesthetic effects; broadband LFP; functional connectivity; neural correlates; resting-state fMRI
Synchronized low-frequency fluctuations in the resting state functional MRI (fMRI) signal have been suggested to be associated with functional connectivity in brain networks. However, the underlying mechanism of this connectivity is still poorly understood, with the synchronized fluctuations could either originate from hemodynamic oscillations or represent true neuronal signaling. To better interpret the resting signal, in the current work, we examined spontaneous fluctuations at the level of cerebral metabolic rate of oxygenation (CMRO2), an index reflecting regional oxygen consumption and metabolism, and thus less sensitive to vascular dynamics. The CMRO2 signal was obtained based on a biophysical model with data acquired from simultaneous blood oxygenation level dependent (BOLD) and perfusion signals. CMRO2-based functional connectivity maps were generated in three brain networks: visual, default-mode, and hippocampus. Experiments were performed on twelve healthy participants during ‘resting state’ and as a comparison, with a visual task. CMRO2 signals in each of the abovementioned brain networks showed significant correlations. Functional connectivity maps from the CMRO2 signal are, in general, similar to those from BOLD and perfusion. In addition, we demonstrated that the three parameters (M, α and β) in the biophysical model for calculating CMRO2 have negligible effects on the determination of the CMRO2-based connectivity strength. This study provides evidence that the spontaneous fluctuations in fMRI at rest likely originate from dynamic changes of cerebral metabolism reflecting neuronal activity.
Functional connectivity; BOLD; perfusion; CMRO2
We performed a pilot investigation of the cardiopulmonary baroreflex control of ventricular contractility in two conscious dogs. We specifically measured spontaneous beat-to-beat hemodynamic variability before and after the administration of propranolol. We then identified the transfer function relating beat-to-beat fluctuations in central venous pressure (CVP) to maximal ventricular elastance (Emax) to characterize the cardiopulmonary baroreflex control of ventricular contractility, while accounting for the influences of arterial blood pressure fluctuations on Emax via the arterial baroreflex and heart rate fluctuations on Emax via the force-frequency relation. Our major finding is that the cardiopulmonary baroreflex responds to an increase (decrease) in CVP by increasing (decreasing) Emax via the β-sympathetic nervous system.
Previous research indicates that venous emptying serves as a stimulus for vasodilation in the human forearm. This suggests the importance of recognizing the potential influence of venous volume on reactive hyperemic blood flow (RHBF) following occlusion. The purpose of this study was to examine the influence of venous emptying on forearm vascular function.
Forearm RHBF, venous capacitance and venous outflow were examined in 35 individuals (age = 22 ± 2 years), using mercury in-Silastic strain gauge plethysmography, at rest and following five minutes of upper arm occlusion using standard procedures (Control). In addition, the same measures were obtained following five minutes of upper arm occlusion preceded by two minutes of passive arm elevation (Pre-elevation).
Average resting arterial inflow was 2.42 ± 1.11 ml·100 ml-1·min-1. RHBF and venous capacitance were significantly greater during Pre-elevation compared to Control (RHBF; Pre-elevation: 23.76 ± 5.95 ml·100 ml-1 ·min-1 vs. Control: 19.33 ± 4.50; p = 0.001), (venous capacitance; Pre-elevation: 2.74 ± 0.89 % vs. Control: 2.19 ± 0.97, p = 0.001). Venous outflow did not differ between the two conditions.
Venous emptying prior to upper arm occlusion results in a significant greater RHBF response and venous capacitance. Recognition of the influence of venous volume on RHBF is particularly important in studies focusing on arterial inflow, and also provides further evidence for the interplay between the venous and arterial system.
In this study, we aimed to demonstrate whether spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal derived from resting state functional magnetic resonance imaging (fMRI) reflect spontaneous neuronal activity in pathological brain regions as well as in regions spared by epileptiform discharges. This is a crucial issue as coherent fluctuations of fMRI signals between remote brain areas are now widely used to define functional connectivity in physiology and in pathophysiology. We quantified functional connectivity using non-linear measures of cross-correlation between signals obtained from intracerebral EEG (iEEG) and resting-state functional MRI (fMRI) in 5 patients suffering from intractable temporal lobe epilepsy (TLE). Functional connectivity was quantified with both modalities in areas exhibiting different electrophysiological states (epileptic and non affected regions) during the interictal period. Functional connectivity as measured from the iEEG signal was higher in regions affected by electrical epileptiform abnormalities relative to non-affected areas, whereas an opposite pattern was found for functional connectivity measured from the BOLD signal. Significant negative correlations were found between the functional connectivities of iEEG and BOLD signal when considering all pairs of signals (theta, alpha, beta and broadband) and when considering pairs of signals in regions spared by epileptiform discharges (in broadband signal). This suggests differential effects of epileptic phenomena on electrophysiological and hemodynamic signals and/or an alteration of the neurovascular coupling secondary to pathological plasticity in TLE even in regions spared by epileptiform discharges. In addition, indices of directionality calculated from both modalities were consistent showing that the epileptogenic regions exert a significant influence onto the non epileptic areas during the interictal period. This study shows that functional connectivity measured by iEEG and BOLD signals give complementary but sometimes inconsistent information in TLE.
Hemodynamic data were obtained in 13 cirrhotic patients with severe portal hypertension, undergoing combined hepatic vein, umbilicoportal vein, and superior mesenteric artery catheterization. The relative clearance of indocyanine green, the portohepatic gradient (difference between the free portal venous pressure and the free hepatic venous pressure), and the estimated hepatic blood flow were measured. The portal fraction (PF) of total hepatic blood flow was calculated in all patients using indicator dilution curves obtained from the portal bifurcation, a right hepatic vein, and when possible a left hepatic vein (six cases) after injection of 51Cr-labeled red blood cells (51Cr RBC) into the superior mesenteric artery. Flows were overestimated because of loss of indicator through spontaneous portosystemic shunts; however, the ratio between hepatic and portal indicator dilution curves can be used to calculate the portal fraction of total hepatic blood flow since no extrahepatic shunts existed after the bifurcation of the portal vein (as shown on portography). In 10 patients, 15 series of curves were calculable and the PF varied between 30.1 and 100% (mean ± SE: 71.1 ± 6.2%). In the three other patients, only delayed activity from recirculation was detected from portal and hepatic vein samples and PF was 0%; in these three cases, portography and arteriography revealed spontaneous portacaval shunting with reverse and/or stagnant circulation in the portal vein. In the 13 patients, no correlation existed between PF and the relative clearance of indocyanine green or the portohepatic gradient, parameters generally used as indices of severity in cirrhosis. In 10 patients, no correlation was found between PF and the estimated hepatic blood flow.
These data indicate that 51Cr RBC dilution curves can be used for the estimation of the portal fraction of total hepatic blood flow in conscious cirrhotic patients before portacaval shunts. Using this methodology, it could be assessed whether any critical level of portal fraction exists above which poor clinical results occur after portacaval shunting. This measurement could eventually be helpful in determining the appropriate surgical procedure to be applied in individual cases.
In this study, we tested the hypothesis that Human Neutrophil α-Defensins (HNPs) inhibit hepatic glucose production through a signaling pathway distinct from insulin. The effect of HNP-1 on fasting blood glucose levels and expression of hepatic gluconeogenic genes was first examined. Using hyperinsulin-emiceuglycemic clamps, we determined the effect of HNP-1 on endogenous glucose production, hepatic expression of key gluconeogenic genes, and glucose uptake in skeletal muscle in Zucker Diabetic Fatty (ZDF) rats. In isolated primary hepatocytes, we studied the effect of HNP-1 and -2 on glucose production, expression of gluconeogenic genes, and phosphorylation of Akt, c-Src, and FoxO1. Our results show that HNP-1 reduced blood glucose levels of both normal mice and ZDF rats predominantly through suppression of hepatic glucose production. HNPs inhibited glycogenolysis and gluconeogenesis in isolated hepatocytes. HNPs also suppressed expression of key gluconeogenic genes including phosphoenoylpyruvate carboxy kinase (PEPCK) and glucose-6-phosphatase (G6Pase). To investigate the mechanism, we found that HNPs stimulated phosphorylation of Akt and FoxO1 without activating IRS1. Nevertheless, HNPs activated c-Src. Blockade of c-Src activity with either a chemical inhibitor PP2 or an alternative inhibitor CSK prevented the inhibitory effect of HNPs on gluconeogenesis. Together, our results support the hypothesis that HNPs can suppress hepatic glucose production through an intracellular mechanism distinct from the classical insulin signaling pathway.