Long-range temporal correlations in epileptogenic and non-epileptogenic human hippocampus.

Epileptogenic human hippocampus generates spontaneous energy fluctuations with a wide range of amplitude and temporal variation, which are often assumed to be entirely random. However, the temporal dynamics of these fluctuations are poorly understood, and the question of whether they exhibit persistent long-range temporal correlations (LRTC) remains unanswered. In this paper we use detrended fluctuation analysis (DFA) to show that the energy fluctuations in human hippocampus show LRTC with power-law scaling, and that these correlations differ between epileptogenic and non-epileptogenic hippocampus. The analysis shows that the energy fluctuations exhibit slower decay of the correlations in the epileptogenic hippocampus compared with the non-epileptogenic hippocampus. The DFA-derived scaling exponents demonstrate that there are LRTC of energy fluctuations in human hippocampus, and that the temporal persistence of energy fluctuations is characterized by a bias for large (small) energy fluctuations to be followed by large (small) energy fluctuations. Furthermore, we find that in the period of time leading up to seizures there is no change in the scaling exponents that characterize the LRTC of energy fluctuations. The fact that the LRTC of energy fluctuations do not change as seizures approach provides evidence that the local neuronal network dynamics do not change in the period before seizures, and that seizures in mesial temporal lobe epilepsy may be triggered by an influence that is external to the hippocampus. The presence of LRTC with power-law scaling does not imply a specific mechanism, but the finding that temporal correlations decay more slowly in epileptogenic hippocampus provides electrophysiologic evidence that the underlying neuronal dynamics are different within the epileptogenic hippocampus compared with contralateral hippocampus. We briefly discuss possible neurobiological mechanisms for LRTC of the energy fluctuations in hippocampus.

Continuous measurements of intra-vascular pO2 in the pig optic nerve head.

BACKGROUND: The measurement of oxygen concentration in the microvasculature of a tissue is important for the understanding of oxygen delivery. MATERIAL AND METHODS: A technique was developed to measure in a continuous manner the partial pressure of oxygen (pO2) in the optic nerve microvasculature of the minipig. This technique is based on the quenching by oxygen of the phosphorescence emitted by a dye that is injected intravenously. It provides measurements of the intra-vascular pO2 and was applied simultaneously with measurements of the extra-vascular pO2 with microelectrodes and blood flow by laser Doppler flowmetry. RESULTS: We demonstrate for the first that the optic nerve head intra-vascular pO2 increases during dark adaptation. Furthermore no change in extra-vascular pO2 and blood flow could be detected. CONCLUSIONS: Based on Krogh's model, these results suggest that oxygen consumption by the optic nerve head tissue increases during dark adaptation.

[Measuring leukocyte velocity in macular capillaries using a miniaturized blue field simulator: effect of aperture of the pupil]. / Messung der Leukozytengeschwindigkeit in makulären Kapillaren mittels eines miniaturisierten Blaufeldsimulators: Effekt der Blendengrösse in der Pupille.

BACKGROUND: In this paper we present a miniaturized blue field simulator (BFS) which allows the measurement of the velocity (V) pulsatility (P) and number (D) of leukocytes in the macular retinal capillaries. A study on the effect of the aperture size of the blue light source at the subject's pupil on the measured flow parameters was performed. METHODS: A blue field entoptoscope with a small halogen lamp was used to induce the perception of the "flying corpuscles" and a flat color screen was selected to display a computer simulation of this entoptic phenomenon. The aperture of the blue light source at the pupil was varied by a diaphragm placed at a conjugate pupil plane while the size and retinal irradiance of the blue field stimulus at the fundus was held constant. RESULTS: The results show significant correlations between log pupil area and both V (-18% per log unit) and D (+42% per log unit). When the retinal illuminance is expressed in Log Trolands, V shows no dependency, but D is strongly correlated (+40% per log Troland). CONCLUSIONS: When applying the BFS technique, the size of the blue light stimulus at the pupil, if undilated, must be well controlled to minimize instrument-related variations of the blood flow measurements.

[Autoregulation in ischemia of the optic nerve in the human]. / Autoregulation du débit sanguin du nerf optique chez l'homme.

BACKGROUND: Autoregulation is defined as the maintenance of constant blood flow in a vascular system in spite of changes in perfusion pressure (PPm). MATERIALS AND METHODS: PPm was decreased by increasing the intraocular pressure (IOP) with a suction cup and optic nerve blood flow was measured with the laser Doppler flowmetry technique (LDF) in 9 normal volunteers. RESULTS: The blood flow was autoregulated down to a PPm of 13 mm Hg (IOP = 47 mm Hg). CONCLUSIONS: These results confirm previous studies in cats and monkeys. The mechanism of autoregulation is probably a decrease in resistance due to capillary recruitment.

[Effect of changes in ocular perfusion pressure on choroid ischemia in man]. / Effet des changements de la pression de perfusion oculaire sur le débit sanguin choroïdien chez l'homme.

BACKGROUND: The effect of changes in ocular perfusion pressure (PPm) on the choroidal blood flow (ChBF) in man was studied with the laser Doppler flowmetry (LDF) technique. MATERIALS AND METHODS: We changed the PPm by increasing the intraocular pressure (IOP) or by increasing the blood pressure (BP) with isometric exercises. RESULTS: We observed that a) ChBF was not significantly different from baseline up to an IOP of 27 mm Hg and b) ChBF remained constant even if PPm increased by as much as 72%. CONCLUSION: Our results suggest that ChBF is autoregulated in response to an increase in IOP up to about 27 mm Hg. ChBF remains also constant in spite of an increase in systemic BP, probably due to a vasoconstriction induced by increased sympathetic activity.

Effect of decreased ocular perfusion pressure on blood flow and the flicker-induced flow response in the cat optic nerve head.

The effect of decreased ocular mean perfusion pressure (PPm), defined as mean arterial blood pressure minus intraocular pressure (IOP), on optic nerve head blood flow (Fonh) and on the response of this flow (RFonh) to diffuse luminance flicker was investigated in 19 anesthetized cats using laser Doppler flowmetry. PPm was decreased by increasing the IOP. The flicker stimulus consisted of 20-msec flashes delivered at 10 Hz for 30-60 sec. It illuminated a 30 degrees diameter area of the fundus, centered at the optic disk. Decreasing PPm by 10-35% from its resting value resulted in a 23% increase in RFonh (supranormal RFonh). With further decreases in PPm, RFonh decreased, reaching zero at a PPm below 20 mmHg. Fonh remained constant until PPm was < 40 mmHg and then decreased thereafter. When PPm was brought back to resting value after having been decreased for approximately 45 min, Fonh first increased by approximately 380% and then returned to its value at rest within approximately 4.5 min. At low PPm, hyperoxia decreased Fonh by 23% and restored the attenuated RFonh back to the value at resting PPm and hypoxia did not increase Fonh, as it did at normal PPm. This study confirms that the optic nerve head circulation is autoregulated over a wide range of PPm and reveals, for the first time, a hyperemic response to a prolonged decrease in PPm. It suggests that hypoxia plays a role in abolishing RFonh at low PPm and that the supranormal RFonh at moderately decreased PPm is due to an increase in the flicker-induced ganglion cell activity.

Nitric oxide has a vasodilatory role in cat optic nerve head during flicker stimuli.

The role of nitric oxide (NO) in the regulation of optic nerve head (ONH) blood flow was investigated from direct electrochemical measurements of NO and simultaneous measurements of ONH blood flow by laser Doppler flowmetry during increased neuronal activity with diffuse luminance flickering light stimuli. For normal physiological conditions, there was a consistent increase in ONH blood flow with each flicker stimulus (n = 10 cats). Simultaneous NO measurements were made in the vitreous humor immediately in front of the ONH (n = 6 cats). During flicker, NO increased by 88 +/- 23 nM (P < 0.05) above basal NO levels. Measurements were repeated after inhibiting NO synthase by intravenous infusion of either NG-nitro-L-arginine (n = 5 cats) or NG-nitro-L-arginine methyl ester (n = 5 cats). After inhibition, NO levels were significantly reduced and both ONH blood flow and NO responses to flicker were significantly attenuated. We conclude that NO plays a key vasodilatory role in the ONH, modulating blood flow during greater neuronal activity with flicker stimuli.

Effects of endothelin-1 on optic nerve head blood flow in cats.

We determined the effects of endothelin-1 on optic nerve head (ONH) blood flow in anesthetized cats. Endothelin-1 (50-2500 pmol) injected into the vitreous produced a dose-related and sustained decrease (22 +/- 6% by 500 pmol and 36 +/- 11% by 2500 pmol) in the ONH blood flow. Blood pressure (BP) and heart rate (HR) remained, however, unchanged. In contrast, intravenous (i.v.) injected endothelin-1 (0.004-0.4 nmol kg-1) produced a dose-related and short-lasting increase in the ONH blood flow; its maximum increase by 0.4 nmol kg-1 was 135 +/- 34%. Endothelin-1, at 0.4 nmol kg-1, i.v., produced a transient decrease followed by a more sustained increase in BP, but had no remarkable effect on HR. The increase in ONH blood flow by i.v. injection of endothelin-1 was abolished by N(G)-nitro-L-arginine methyl ester (L-NAME, 5 mg kg-1 min-1, i.v.). The suppression of blood flow by L-NAME was reversed by the addition of L-arginine (50 mg kg-1 min-1). Pressor responses to endothelin-1 (0.4 nmol kg-1, i.v.) were augmented in the presence of L-NAME, but reversed in combination with L-arginine. These findings suggest that i.v. injection of endothelin-1 causes NO release from endothelial cells which increases ONH blood flow, whereas intravitreal injection of endothelin-1 decreases ONH blood flow by its vasoconstrictive effect. Different populations of ET receptors on vascular smooth muscles or endothelial cells would reflect the opposing effects of endothelin-1.

Frequency and luminance-dependent blood flow and K+ ion changes during flicker stimuli in cat optic nerve head.

PURPOSE: The purpose of this study was to investigate whether blood flow in the cat optic nerve head (ONH) is related to increased neuronal activity elicited by diffuse luminance flickering light stimulation. METHODS: ONH blood flow was measured by laser Doppler flowmetry in anesthetized cats during 1 to 3 minutes of flickering light stimulation at controlled luminance and frequency (n = 227 measurements in 18 cats) using either a conventional visual stimulator (repetitive short flashes) or a sinusoidally varying light stimulator. Potassium ion concentration ([K+]) changes in the vitreous humor immediately in front of the optic disk were measured with neutral carrier K+ ionophore liquid membrane microelectrodes. Effects of varying flicker frequency (2 to 80 Hz) at constant luminance were quantified. Effects of luminance were quantified by varying the modulation depth of the stimulus at constant frequency. RESULTS: Both ONH blood flow and [K+] increased during flicker stimulus with an average slope of 0.305% +/- 0.064% (SE)/microM [K+] (257 measurements in 18 cats). The peak ONH blood flow increase was 59% +/- 11% above baseline at 33.3 +/- 3.1 Hz. The peak [K+] increase was 188 +/- 42 microM above baseline at 38.3 +/- 3.3 Hz. Both ONH blood flow and [K+] changes had similar bandpass characteristics with frequency, first increasing, then dropping off at higher frequencies (122 measurements in 10 cats). Both frequency responses were described by power law functions (y = af"). Luminance responses for both ONH blood flow and [K+] changes could be fit by a modified Hill model and were 50% of maximum at light modulation depths of 21.2% +/- 4.6% and 22.5% +/- 3.7%, respectively (53 measurements in 5 cats). CONCLUSIONS: Increases in ONH blood flow were correlated with changes in [K+]. Both responses were remarkably similar, with no significant differences in the frequency for peak responses in ONH blood flow or [K+], in low- and high-frequency power law exponents of the two responses, or in the 50% response to light modulation. The results are consistent with close coupling of neuronal activity and ONH blood flow.

Effects of adenosine on ocular blood flow.

PURPOSE: To determine the effect of intravascular adenosine on blood flow in the ocular fundus and to examine indirectly whether the blood-brain barrier to adenosine, which exists in the cerebrovasculature of the cat, is present in the eye of this animal. METHODS: The noninvasive techniques of laser Doppler flowmetry and velocimetry along with fundus photography were used to measure the change in optic nerve head and choroidal and retinal blood flow during intravenous infusions of 0.18 and 0.6 mg/kg per minute of adenosine. RESULTS: Infusions of adenosine induced significant increases in choroidal blood flow (60% with 0.6 mg/kg per minute) but not in optic nerve head or retinal blood flows. CONCLUSIONS: The lack of effect of intravenously infused adenosine on the optic nerve and retinal circulations is most likely caused by the tight junctions in the vessels of these vascular beds, which prevent adenosine from reaching its receptors. Perivascular adenosine in the choroid most likely accounts for the increase in blood flow in this tissue.

Nitric oxide and choroidal blood flow regulation.

PURPOSE: Nitric oxide (NO) has been found to be an endothelial-derived relaxing factor mediating the vasodilatation that results from the stimulation of muscarinic endothelial receptors. It also has been identified as a putative neurotransmitter of parasympathetic origin in choroidal perivascular autonomic fibers. The authors investigated a potential role of NO in choroidal blood flow (ChBF) regulation. METHODS: Local ChBF in the tapetal region of 26 anesthetized cats was measured by laser Doppler flowmetry. Cats were infused through the femoral vein with increasing dosages of acetylcholine (ACh); N omega-nitro-L-arginine (NNL-A), a specific inhibitor of NO synthesis; L-arginine; and D-arginine. ChBF and mean arterial pressure (MAP) were continuously recorded. RESULTS: Infusion of 20 micrograms/minute ACh induced a 68% increase in ChBF despite a 9% decrease in MAP. Infusion of 16 mg/minute NNL-A attenuated the ACh-induced increase in ChBF by 46% and increased MAP by 40%. Infusion of different dosages of NNL-A without prior administration of ACh caused ChBF to fall below and MAP to rise above baseline in a dose-dependent fashion. Infusion of L-arginine prior to ACh infusion enhanced by 27% the ACh-induced increase in ChBF, whereas D-arginine had no effect on this increase. CONCLUSIONS: These findings suggest the presence of a local vasodilatory cholinergic mechanism in the choroid, inducing the release of NO. They also suggest that release of NO in the choroid may maintain basal blood flow to this tissue.

Choroidal blood flow in the foveal region of the human ocular fundus.

PURPOSE: To develop a noninvasive method for the investigation of choroidal blood flow (ChBF) and its regulation in the foveal region of the human ocular fundus. METHODS: Measurement of ChBF was based on the technique of laser Doppler flowmetry (LDF). Sixteen normal subjects (age range, 20 to 64 years), with normal eye examination results, were asked to fixate on a diode laser beam (wavelength = 811 nm, 60 microW at the cornea) delivered to the undilated eye through a fundus camera. Light scattered by red blood cells in the tissue volume sampled by the incident laser beam was detected at the fundus image plane of the camera by an optical fiber. The diameter of the beam at the fundus of the emmetropic eye was about 300 microns. Relative ChBF was measured in both eyes by analyzing the Doppler signal with commercial skin blood flowmeters. The average pulsatile component of ChBF, ChBFP, was determined over the cardiac cycle, and its value was compared to the average total ChBF, ChBFAV. Responses of ChBF to various physiological stimuli, such as increased blood O2 and CO2 concentrations, rapid increases in intraocular pressure, and valsalva maneuvers, were documented. RESULTS: Significant correlations were obtained between the ChBFAV values measured with both flowmeters (P < 0.001) and between the ChBFAV values measured in the right and left eye (P < 0.001). ChBFP represented less than 23% of ChBFAV. ChBFAV was not significantly affected by 5 minutes of breathing 100% oxygen. Raising end-tidal CO2 in one subject from 37 to 59 mm Hg increased ChBFAV by approximately 40%. Acute elevation of the intraocular pressure by suction cup or finger pressure on the globe reduced ChBFAV by as much as 90%. Valsalva maneuvers induced reproducible responses that were very different from those recorded from the skin microcirculation. CONCLUSIONS: Although LDF of the choroidal circulation is still at an early stage of development, this noninvasive method appears to provide continuous and sensitive measurements of relative choroidal blood flow in the foveal region of the human fundus. Near-infrared laser diodes enable measurements through undilated pupils. Examples of responses suggest new avenues in the investigation by LDF of the effect of various physiological stimuli, pharmacologic agents, and pathologic processes on the choroidal circulation in man.

Local choroidal blood flow in the cat by laser Doppler flowmetry.

PURPOSE: To develop a procedure using a noninvasive technique that will allow the investigation of choroidal blood flow (ChBF) regulation in discrete regions of the cat eye. Validation of this procedure will provide a method to study intrinsic, neural, and pharmacologic factors that regulate regional ChBF. METHODS: The technique to measure ChBF is based on laser Doppler flowmetry. However, in contrast to conventional laser Doppler flowmetry, which uses fiber-optic probes in direct contact with the tissue to deliver the laser beam and detect the scattered light, with this technique the beam is delivered through a fundus camera and the scattered light is detected in the retinal image plane of the camera. Measurements were made in 34 anesthetized cats under conditions that would ensure that the flow measured represented ChBF in the choriocapillaris: the laser beam was aimed at retinal intervascular sites in the tapetal region of the fundus; the Doppler shift power spectrum of the light scattered by the red blood cells had the shape and frequency range typical for a microvascular bed; and the recorded flow did not decrease by more than 5% when the cat was given 100% O2 to breathe for 4 minutes. The responses to various physiologic and pharmacologic stimuli were tested and compared with those obtained from retinal vessels. RESULTS: Intravenous infusions of acetylcholine increased ChBF in a dose-response fashion, whereas sympathetic nerve stimulation at various frequencies decreased ChBF as predicted by previous studies. By comparison, retinal blood flow was negligibly affected by these two stimuli. In contrast to retinal blood flow, ChBF was unaffected by diffuse luminance flicker. ChBF was found to be pulsatile. The mean of the pulsatile component of ChBF represented approximately 34% of mean ChBF, a value similar to those derived from ChBF measurements in minipigs and retinal blood flow in the cat. CONCLUSIONS: This study demonstrates that laser Doppler flowmetry is a valid technique for obtaining local, noninvasive, and continuous recordings of relative ChBF. Tested under steady-state conditions for blood pressure, heart rate, and acid-base balance, ChBF is stable for long periods of time, allowing the investigation of the effect of various physiologic stimuli and pharmacologic agents on this flow.

O2 gradients and countercurrent exchange in the cat vitreous humor near retinal arterioles and venules.

Recessed cathode O2 microelectrodes were used to measure spatially detailed oxygen tension (PO2) gradients in the vitreous humor near the cat retina. Measurement sites (n = 41 in 8 cats) included single arterioles and venules and parallel vessel pairs. Mean vitreous PO2 was 37.9 +/- 1.5 (SE) Torr. Close to the retinal surface (approximately 200 microns), PO2 was found to be both higher and lower than the vitreous PO2, depending on the proximity of the microelectrode tip to retinal vessels. Both positive (inward) and negative (outward) O2 fluxes (JO2) were measured, consistent with the anatomy and expected boundary conditions in the eye. The PO2 at the closest approach above arterioles was 55.2 +/- 2.3 Torr, significantly higher than in the vitreous (P < 0.0001). All arterioles had outward JO2 with an overall mean of -2.58.10(-6) ml O2/sec/cm2. Some of the venules were also losing O2, but at much lower rates than arterioles. Several venules were gaining O2. Countercurrent transport (A-V shunting) was also seen between vessel pairs. Our experimental results allow theoretical predictions to be made for the axial drop in blood PO2 along an arteriole as a function of blood flow.

Effect of acute increases in intraocular pressure on intravascular optic nerve head oxygen tension in cats.

A newly developed phosphorescence imaging technique was used to generate two-dimensional maps of intravascular oxygen tension (PO2) in the optic nerve head (ONH) and retina of the cat to study the effects of acute moderate increases in intraocular pressure (IOP) on the ONH and retinal PO2. Both the ONH and retinal PO2 were remarkably well maintained as the IOP increased; hypoxia developed only after the blood flow to the eye was stopped. Because ONH hypoxia was not observed during IOP elevation, a lack of oxygen may not be a major cause of glaucomatous damage, although the effects of chronically elevated IOP on the PO2 remain to be evaluated. Because this imaging technique was noninvasive and required only a small bolus injection of a nontoxic oxygen probe, the authors anticipate that it will find significant application in the study of many ocular vascular diseases and glaucoma.