Background and objectives: Hemorrhagic insult is a major source of morbidity and mortality in both adults and newborn babies in the developed countries. The mechanisms underlying the non-traumatic rupture of cerebral vessels are not fully clear, but there is strong evidence that stress, which is associated with an increase in arterial blood pressure, plays a crucial role in the development of acute intracranial hemorrhage (ICH), and alterations in cerebral blood flow (CBF) may contribute to the pathogenesis of ICH. The problem is that there are no effective diagnostic methods that allow for a prognosis of risk to be made for the development of ICH. Therefore, quantitative assessment of CBF may significantly advance the understanding of the nature of ICH. The aim of this study was to determine the particularities of alterations in arterial and venous cerebral circulation in hypertensive rats at different stages of stress-related development of ICH using three-dimensional Doppler optical coherence tomography (DOCT).
Material and methods: Experiments were performed in mongrel adult rats. To induce ICH, hypertensive rats underwent stress (effect of severe sound, 120 dB during 2 h). To induce the renal hypertension (two kidneys, one clip) the rats were clipped at the left renal artery with a silver clip. Seven weeks after clipping, the hypertensive rats were used in the experiment. The monitoring of CBF was performed in anesthetized rats with fixed heads using a commercially available swept source OCT system (OCS1300SS; Thorlabs) in the masked period of ICH (4 h after stress) and during ICH (24 h after stress).
Results: It could be shown that in stressed rats, compared with non-stressed animals, the latent stage of stress-induced ICH (4 h after stress-off) is characterized by an increase in diameter of the superior sagittal vein with decrease in speed of the blood flow in the venous network, whereas no changes in the CBF in the arterial tree were found in this period. These facts suggest that the masked period of ICH is accompanied by decreasing venous outflow and the development of venous insufficiency. The incidence of ICH, 24 h after stress, is associated with progression of pathological alterations in cerebral venous circulation. All hypertensive rats with ICH demonstrated a greater increase in the diameter of the superior sagittal vein than stressed rats at the latent stage of ICH (in 2.5-fold, p<0.05) and healthy animals (in 3.7-fold, p<0.05). The velocity of blood flow in the dilated sagittal vein of rats with ICH decreased more than stressed rats without ICH and healthy animals. The progression of venous insufficiency was accompanied by relaxation of cerebral arteries with a fall in the speed of blood flow in the arterial tree, reflecting the development of intracranial hypotension.
Conclusion: In summary, using DOCT we have shown that the latent stage of stress-induced ICH is characterized by a decrease in venous outflow. The incidence of ICH is associated with the progression of pathological alterations in cerebral venous circulation that is accompanied by a decrease in blood flow in the arterial tree. The evaluation of cerebral venous insufficiency is an important diagnostic approach for the prognosis of the risk of developing cerebral hypotension and ICH.
Hintergrund und Zielsetzung: Schlaganfälle sind in den entwickelten Ländern eine der Hauptursachen für Morbidität und Mortalität bei Erwachsenen und Neugeborenen. Die Mechanismen, die zur nicht-traumatischen Ruptur von Hirngefäßen führen, sind nicht vollständig klar. Doch gibt es starke Hinweise darauf, dass Spannungen, die mit einer Erhöhung des arteriellen Blutdrucks einhergehen, eine entscheidende Rolle bei der Entwicklung akuter intrakranieller Hirnblutungen spielen und Änderungen des zerebralen Blutflusses zur Pathogenese beitragen können. Das Problem ist, dass es bislang keine effektive diagnostische Methode gibt, mit der sich das Risiko für die Entwicklung intrakranieller Hirnblutungen vorhersagen lässt. Daher kann eine quantitative Beurteilung des zerebralen Blutflusses erheblich zum besseren Verständnis beitragen. Das Ziel dieser Studie war es daher, die Besonderheiten der Veränderungen in der arteriellen und venösen zerebralen Durchblutung in hypertensiven Ratten in verschiedenen Stadien der Stress-Entwicklung mittels dreidimensionaler Doppler-OCT (3D-DOCT) zu untersuchen.
Material und Methoden: Die Experimente wurden an erwachsenen Mischlingsratten durchgeführt. Um interkranielle Hirnblutungen zu induzieren, wurden die hypertensiven Ratten Stress ausgesetzt (Beschallung mit 120 dB über eine Zeit von 2 h). Um eine renale Hypertonie zu erzeugen, wurde bei den Ratten die linke Nierenarterie mit einem Silberclip abgeklemmt. Nach 7 Wochen wurden die hypertensiven Ratten im Experiment verwendet. Die Messung des zerebralen Blutflusses erfolgte 4 h und 24 h nach Stress-Belastung mittels eines kommerziellen OCT-Systems (OCS1300SS; Thorlabs), wobei die narkotisierten Ratten am Kopf fixiert wurden.
Ergebnisse: Im Vergleich zu nicht gestressten Tieren war bei den gestressten Ratten die latente Stufe der Stress-induzierten intrakraniellen Hirnblutung (4 h nach Stressende) durch eine Zunahme des Durchmessers der Hirnvene bei gleichzeitiger Verlangsamung des Blutflusses im venösen Gefäßsystem gekennzeichnet. Im arteriellen Gefäßbaum wurde hingegen keine Veränderung des zerebralen Blutflusses festgestellt. Dies legt nahe, dass die latente Phase einer intrakraniellen Hirnblutung mit einer Verringerung des venösen Abflusses und der Entwicklung einer Veneninsuffizienz einhergeht. 24 h nach Belastung kommt es zu einem Fortschreiten der pathologischen Veränderungen im zerebralen venösen Blutkreislauf. Alle hypertensiven Ratten mit akuter intrakranieller Hirnblutung zeigten eine größere Zunahme des Durchmessers der Hirnvene als die gestressten Ratten im latenten Stadium (um das 2,5fache, p<0,05) bzw. als die gesunden Tiere (um das 3,7fache; p<0,05). Die Geschwindigkeit des Blutflusses in der dilatierten sagittalen Vene von Ratten mit akuter intrakranieller Hirnblutung verringerte sich mehr als bei Ratten ohne Hirnblutung und bei gesunden Tieren. Das Fortschreiten der Veneninsuffizienz ging mit einer Entspannung der zerebralen Arterien bei gleichzeitigem Rückgang der Geschwindigkeit des Blutflusses in den arteriellen Gefäßen einher, was die Entwicklung der intrakraniellen Hypotonie widerspiegelte.
Fazit: Es lässt sich schlussfolgern, dass unter Verwendung der DOCT gezeigt werden konnte, dass die latente Phase der Stress-induzierten interkraniellen Hirnblutung durch eine Abnahme des venösen Abflusses gekennzeichnet ist. Die Inzidenz einer interkraniellen Hirnblutung ist mit dem Fortschreiten von pathologischen Veränderungen in der zerebralen venösen Zirkulation assoziiert und wird durch eine Verringerung des Blutflusses im arteriellen Gefäßbaum begleitet. Die Auswertung der zerebralen venösen Insuffizienz ist ein wichtiges diagnostisches Vorgehen für die Prognose des Risikos der Entwicklung von zerebraler Hypotonie und intrakranieller Hirnblutung.
Stress plays a crucial role in development of acute intracranial hemorrhage (ICH) [1–3]. In 1988, Caplan  reviewed reports of primary (i.e., non-traumatic) ICH occurring in unusual circumstances, most frequently in patients with no signs of prior hypertension, suggesting that acute elevations in blood pressure or cerebral blood flow (CBF) could cause vessel rupture. He pointed out that such uncommon examples might shed light on the pathogenesis of the majority of primary ICH cases. Altered cerebral vasomotor reactivity or autoregulatory control, which may accompany the aging process and chronic hypertension, could therefore predispose an individual to stress-induced vessel rupture, as could genetically determined variability in vessel responsiveness .
The mechanisms responsible for development of ICH are not well understood, but there is strong evidence that alterations in CBF may contribute to the pathogenesis of ICH and strokes [4, 5]. Therefore, quantitative assessment of CBF may significantly advance the understanding of the nature of ICH and major cerebrovascular diseases. It is of note that there is limited information regarding the particularities of arterial and venous alterations which are associated with the risk of developing ICH .
The standard for measurement of regional blood flow is autoradiography. However, although autoradiographic methods provide three-dimensional (3D) spatial information, they contain no information about the temporal evolution of CBF changes . Therefore, studies of dynamics of the pathological changes in cerebral vasculature cannot be performed with these methods. Magnetic resonance imaging [8–11] and positron emission tomography  are the first imaging techniques for the evaluation of hemorrhage volume to provide spatial maps of CBF but they are limited in their temporal and spatial resolution. Laser speckle imaging  has recently been applied for high spatiotemporal resolution relative measurements of CBF . However, it is difficult to relate correlation times (laser speckle) or the width of the power spectral density (laser Doppler) to absolute velocities and flow of red blood cells. Recent developments in the semiconductor industry have enabled the use of system-on-chip capabilities for constructing two-dimensional (2D) blood flow maps . On the contrary, laser speckle imaging is essentially a full-field technique. However, laser Doppler flowmetry and laser speckle analysis even in their up-to-date implementations are still “en-face” techniques and they are unable to provide sufficient in-depth resolution and 3D imaging of the vasculature. Instead, they provide a projection of the vasculature on the surface from within the entire measurable tissue volume. An adequate combination of spatial resolution (both in-depth and lateral) and penetration depth is achieved in Doppler optical coherence tomography (DOCT) [16–18], optical angiography [19, 20] or correlation-mapping OCT . Correlation-mapping OCT produces high-quality 3D images of vascular networks owing efficient separation of the signals from the static part of the sample and from the moving one. These images give sufficient information about dynamic changes in cerebral and peripheral vasculature under different physiological conditions [16, 17, 22–26].
The aim of this study was to determine the particularities of alterations in arterial and venous cerebral circulation in hypertensive rats at different stages of stress-related development of ICH using 3D-DOCT.
2 Methods and materials
Experiments were carried out in mongrel male rats with a body weight of 200–250 g. All procedures were performed in accordance with the “Guide for the Care and Use of Laboratory Animals” . The rats were housed at 25±2°C, 55% humidity, and 12:12 h light/dark cycle.
Chronic hypertension is regarded as the main cause of ICH . Therefore, to induce the renal hypertension (two kidneys, one clip) the rats were clipped at the left renal artery with a silver clip, having an inner gap of 0.25 mm under anesthesia with ketamine (40 mg/kg, intraperitoneal injection). Seven weeks after clipping, the hypertensive rats were used in the experiment. Details of the technique have been published earlier . To induce ICH, hypertensive rats were subjected to severe stress by means of a combination of immobilization for 120 min together with loud intermittent sounds at 120 dB .
2.2 Surgical procedure
The epicranium was exposed by a parieto-occipital midline skin incision in all animals. With the use of a microsurgical technique, the periosteum was pushed back, and biparietal parasagittal groove-shaped trephinations (1.5×4 mm) were performed with a microdrill (Mikroton; Aesculap, USA) accompanied by continuous irrigation with saline to prevent heating of the tissue. Special care was taken to prevent penetration of the dura mater.
2.3 CBF measuring
The monitoring of CBF was performed in the anesthetized rats with fixed heads. In total, n=17 healthy rats (control group), n=14 stressed hypertensive rats without ICH and n=14 with ICH (experimental groups) were examined. Measurements focused on the cerebral arteries of cortex and sagittal vein which is a superficial venous vessel, i.e., its topography can easily be detected and it is therefore a good object for optical measurements. To monitor the cortical microcirculation a commercially available swept source OCT system (OCS1300SS; Thorlabs, Inc., USA) was used, operating at 1325 nm central wavelength and 100 nm bandwidth. The longitudinal resolution (in air) was about 12 μm. The software package supplied with this system allows one to recover Doppler phase maps out of the complex form of the interference signal resulting from the Fourier transform. The Doppler phase map depicts spatial distribution of moving particles and their velocity. Thus, the occurrence of the Doppler shift indicates the vessels themself while the magnitude of this shift reveals the velocity distribution within these vessels. Because of interferometric data processing, the system implements phase-resolved technique for Doppler frequency shift measurements and phase values are wrapped modulo π. This wrapped phase map is produced by the out-of-the-box system software. To solve this problem, we have developed customized home-made software using the LabVIEW Development System (National Instruments Corporation, USA) for further processing of original phase maps. The processing algorithm is made up of the following steps:
unwrapping phase distribution;
translation of the phase values into the frequency shift according to the system specification (axial scan rate) and
translation of the frequency shift into the velocity according to the experimental arrangement specification (central wavelength of swept source, incident angle and sample refractive index).
The velocity of moving cells was calculated using the following equation:
where λ0 is the central wavelength of radiation (in vacuum), fD is the Doppler frequency shift, n is the refractive index which is assumed to be equal to 1.4, and θ is the angle between directions of incident radiation and of cell movement. Eq. (1) shows that for particles moving at equal velocities, the major contribution to the Doppler signal is given by the particles that move at a lesser angle against the incident wave. At the same time, the incident wave, scattered by particles moving perpendicularly to the direction of incidence, does not adopt Doppler shift at all. According to the above, we assume that waves propagating close to aperture angle of the illuminating lens generate a major part of the Doppler signal (if the particles move perpendicularly to the optical axis of that lens). Since vasculature in the tissue is plexiform this assumption is quite rough, but it allows us to make a simplified preliminary analysis of the expected results. The aperture angle of output lens LSM03 mounted in the used OCT system is 7.5° according to specifications. This value was used in estimation.
The Doppler frequency shift fD is calculated as the OCT signal phase change rate:
Here Δφ is the phase difference that can be retrieved from the phase maps produced by the Thorlabs software, fA is the axial scan rate, which is equal to 16 kHz. Since Δφ is wrapped modulo π, fD and V are also wrapped terms, actual values of fD and V can be recovered using the unwrapping procedure.
2.4 Statistical analysis
Results were presented as mean±standard error of the mean (SEM). The differences between groups were evaluated by Student’s test using Statistics for Windows 5.0. Significance levels were set at p<0.05 for all data.
We analyzed the particularities of alterations in the cerebral arteries of cortex and superior sagittal vein which drains into the superior sagittal sinus in hypertensive rats at the different stages of development of stress-induced cerebral hemorrhage, i.e., 4 h (latent stage without ICH) and 24 h (the incidence of ICH) after effects of severe stress. These stages have been confirmed using the histological assay of brain tissue in rats .
The latent period of development of ICH (4 h after stress-off) was characterized by a significant alteration in the venous but not in arterial CBF. This meant that the diameter of the superior sagittal vein increased more in stressed rats than in non-stressed animals (0.67±0.03 mm vs. 0.37±0.02 mm, p<0.05). Figure 1 shows the Doppler phase map of superior sagittal vein (left and right branches) in the normal state (Figure 1B) and 4 h after stress-off (Figure 1C) in rats. The phase values Δj can be translated to the velocity distribution using Eqs. (1) and (2).
The relaxation of the superior sagittal vein was accompanied by a decrease in the speed of blood flow (3.01±0.13 mm/s vs. 4.98±0.34 mm/s, p<0.05) reflecting a decrease in cerebral venous outflow.
The diameter and speed of blood flow of the cerebral arteries of the cortex did not change significantly. For example, in healthy rats the lumen of small cerebral arteries were 0.12±0.04 mm, the velocity of blood flow was 5.51±0.09 mm/s and in stressed rats they were 0.14±0.03 mm and 5.65±0.95 mm/s, respectively.
Twenty-four hours after stress, all rats demonstrated development of ICH with progression of cerebral vein dilation. Here the diameter of superior sagittal vein was 3.7-fold greater in rats with ICH compared with the control group (1.38±0.07 mm vs. 0.37±0.02 mm, p<0.05) and was 2.0-fold higher vs. stressed rats without ICH (1.38±0.07 mm vs. 0.67±0.03 mm, p<0.05). The velocity of the blood flow in the dilated sagittal vein decreased in rats with ICH compared with rats without ICH by 1.4-fold (2.05±0.17 mm/s vs. 3.01±0.13 mm/s, p<0.05) and by 2.4-fold in comparison with healthy animals (2.05±0.17 mm/s vs. 4.98±0.34 mm/s, p<0.05). The decrease of venous outflow was associated with impairment of arterial brain circulation. Indeed, the diameter of small cerebral arteries of cortex increased (0.22±0.02 mm vs. 0.12±0.04 mm, p<0.05) with a decrease in the speed of the blood flow (2.11±0.03 mm/s vs. 5.51±0.09 mm/s, p<0.05).
Therefore the pathological changes in CBF associated with ICH in rats developed within 24 h after stress influences, and the time of appearance of these changes was different in the sagittal vein and in the arteries of cortex. The stress-reactivity of the sagittal vein was higher than the sensitivity to stress of the cerebral arteries. Indeed, the deleterious effect of stress on venous circulation (the increase of diameter of sagittal vein with a decrease in blood flow) could already be observed 4 h after stress and they progressed throughout the next day of the experiment (Figures 2 and 3). Comparable pathological changes in the cerebral arterial circulation were only found in the rats 24 h after stress, whereas during the first 4 h of stress-off period both the diameter of cerebral arteries and the blood flow in them remained unchanged.
In this study using 3D-DOCT, we examined the particularities of venous and arterial pathological alterations which are associated with different stages of development of ICH in hypertensive rats. The results show that masked period of ICH (the first 4 h after stress) are characterized by dilation of superior sagittal vein reflecting impaired venous outflow and development of venous insufficiency. Others have also demonstrated that a decrease in cerebral venous outflow is implicated in contributing to the occurrence of ICH . It is important to note that the latent period of the deleterious effect of severe stress on brain circulation is not accompanied by any changes in cerebral arterial blood flow. In fact between stressed rats without ICH and healthy animals there were no significant differences in the diameter and velocity of blood flow in the arterial network. Therefore a decrease of cerebral venous outflow is the first marker of pathological changes in the brain which is associated with the risk of developing ICH. A number of investigators have shown that the ICH is primarily venous .
The incidence of ICH (24 h after stress) is accompanied by a progressive increase in the pathological changes in cerebral circulation i.e., the dilation of the sagittal vein increases with concurrent relaxation of cerebral arteries and the fall of the blood flow speed in the arterial tree reflects the development of intracranial hypotension. These results are consistent with the findings of other researchers who have showed that hypotension and low cerebral perfusion pressure are associated with ICH and that systemic hypotension predisposes subjects to ICH have both been shown in clinical studies [32–35]. The prevention of cerebral hypotension is the major therapy during the early phases after traumatic brain injury [36–38].
It is hypothesized that decreased CBF with loss of cerebrovascular regulation after ICH impairs brain tissue oxygenation . In patients with subarachnoid hemorrhage, investigators demonstrated that the fall in CBF with oxygen desaturation is associated with a poor neurological outcome . A progressive decrease in CBF has been reported in patients with subarachnoid hemorrhage for 3 weeks after bleeding, and the decrease in blood flow is related to a worsening in the clinical grade . The same results have been obtained from animal data with experimental models of ICH . Thus, our results show that the decrease in cerebral arterial and venous blood flow is related to the severity of the deleterious effect of stress on brain hemodynamics. The early stage of ICH was characterized by the decrease in venous outflow without any changes in cerebral arteries. The progression of venous insufficiency in rats with the incidence of ICH provokes secondary pathological changes in cerebral arterial circulation via the decrease in arterial blood flow and subsequent development of cerebral hypotension. These facts allow us to suggest that stress-induced changes in cerebral venous circulation is a more sensitive and informative component of brain hemodynamics for diagnostics of the risk of developing ICH than the alterations in cerebral arterial blood flow.
We suggest that the application of DOCT in the study of CBF is an effective optical method for the analysis of cortical cerebral circulation under normal and pathological conditions. The evaluation of stress-reactivity of cerebral veins with DOCT could be a new diagnostic approach to the analysis of the pathological changes in cerebrovascular circulation associated with ICH. Our findings are consistent with results of other researchers who have demonstrated that rapid volumetric OCT angiography of cortex surface is an important method in the study of cerebrovascular reactivity and may be used to quantitatively measure changes in vessel tone providing qualitative information on perfusion .
In summary, using DOCT we have shown that the latent stage of stress-induced ICH is characterized by decrease of venous outflow. The incidence of ICH is associated with progression of pathological alterations in cerebral venous circulation that is accompanied by a decrease in blood flow in the arterial tree. Thus, the evaluation of cerebral venous insufficiency is an important diagnostic approach for the prognosis of the risk of developing cerebral hypotension and ICH.
This work was supported in part by RF Governmental contracts 11.519.11.2035, 14.B37.21.0728, 14.B37.21.0563; 14.B37.21.0216 and grants FiDiPro, TEKES Program (40111/11), Finland; SCOPES EC, Uzb/Switz/RF, Swiss NSF, IZ74ZO_137423/1; RF President’s grant “Scientific Schools”, 1177.2012.2., Russian Foundation for Basic Research Grant No. 12-02-31204 mol-a and No. a-11-02-00560.
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