Increase In Local Cerebral Blood Flow Research Articles

CO2 signaling mediates neurovascular coupling in the cerebral cortex

Neurovascular coupling is a fundamental brain mechanism that regulates local cerebral blood flow (CBF) in response to changes in neuronal activity. Functional imaging techniques are commonly used to record these changes in CBF as a proxy of neuronal activity to study the human brain. However, the mechanisms of neurovascular coupling remain incompletely understood. Here we show in experimental animal models (laboratory rats and mice) that the neuronal activity-dependent increases in local CBF in the somatosensory cortex are prevented by saturation of the CO2-sensitive vasodilatory brain mechanism with surplus of exogenous CO2 or disruption of brain CO2/HCO3− transport by genetic knockdown of electrogenic sodium-bicarbonate cotransporter 1 (NBCe1) expression in astrocytes. A systematic review of the literature data shows that CO2 and increased neuronal activity recruit the same vasodilatory signaling pathways. These results and analysis suggest that CO2 mediates signaling between neurons and the cerebral vasculature to regulate brain blood flow in accord with changes in the neuronal activity.

Prolonged/delayed cerebral hyperperfusion in adult patients with moyamoya disease with RNF213 gene polymorphism c.14576G>A (rs112735431) after superficial temporal artery-middle cerebral artery anastomosis.

Superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis is the standard surgical management for moyamoya disease (MMD), whereas cerebral hyperperfusion (CHP) is one of the potential complications of this procedure that can result in delayed intracerebral hemorrhage and/or neurological deterioration. Recent advances in perioperative management in the early postoperative period have significantly reduced the risk of CHP syndrome, but delayed intracerebral hemorrhage and prolonged/delayed CHP are still major clinical issues. The clinical implication of RNF213 gene polymorphism c.14576G>A (rs112735431), a susceptibility variant for MMD, includes early disease onset and a more severe form of MMD, but its significance in perioperative pathology is unknown. Thus, the authors investigated the role of RNF213 polymorphism in perioperative hemodynamics after STA-MCA anastomosis for MMD. Among 96 consecutive adult patients with MMD comprising 105 hemispheres who underwent serial quantitative cerebral blood flow (CBF) analysis by N-isopropyl-p-[123I]iodoamphetamine SPECT after STA-MCA anastomosis, 66 patients consented to genetic analysis of RNF213. Patients were routinely maintained under strict blood pressure control during and after surgery. The local CBF values were quantified at the vascular territory supplied by the bypass on postoperative days (PODs) 1 and 7. The authors defined the radiological CHP phenomenon as a local CBF increase of more than 150% compared with the preoperative values, and then they investigated the correlation between RNF213 polymorphism and the development of CHP. CHP at POD 1 was observed in 23 hemispheres (23/73 hemispheres [31.5%]), and its incidence was not statistically different between groups (15/41 [36.6%] in RNF213-mutant group vs 8/32 [25.0%] in RNF213-wild type (WT) group; p = 0.321). CHP on POD 7, which is a relatively late period of the CHP phenomenon in MMD, was evident in 9 patients (9/73 hemispheres [12.3%]) after STA-MCA anastomosis. This prolonged/delayed CHP was exclusively observed in the RNF213-mutant group (9/41 [22.0%] in the RNF213-mutant group vs 0/32 [0.0%] in the RNF213-WT group; p = 0.004). Multivariate analysis revealed that RNF213 polymorphism was significantly associated with CBF increase on POD 7 (OR 5.47, 95% CI 1.06-28.35; p = 0.043). Prolonged/delayed CHP after revascularization surgery was exclusively found in the RNF213-mutant group. Although the exact mechanism underlying the contribution of RNF213 polymorphism to the prolonged/delayed CBF increase in patients with MMD is unclear, the current study suggests that genetic analysis of RNF213 is useful for predicting the perioperative pathology of patients with MMD.

Optical manipulation of local cerebral blood flow in the deep brain of freely moving mice.

An artificial tool for manipulating local cerebral blood flow (CBF) is necessary for understanding how CBF controls brain function. Here, we generate vascular optogenetic tools whereby smooth muscle cells and endothelial cells express optical actuators in the brain. The illumination of channelrhodopsin-2 (ChR2)-expressing mice induces a local reduction in CBF. Photoactivated adenylyl cyclase (PAC) is an optical protein that increases intracellular cyclic adenosine monophosphate (cAMP), and the illumination of PAC-expressing mice induces a local increase in CBF. We target the ventral striatum, determine the temporal kinetics of CBF change, and optimize the illumination intensity to confine the effects to the ventral striatum. We demonstrate the utility of this vascular optogenetic manipulation in freely and adaptively behaving mice and validate the task- and actuator-dependent behavioral readouts. The development of vascular optogenetic animal models will help accelerate research linking vasculature, circuits, and behavior to health and disease.

Pre-operative higher hematocrit and lower total protein levels are independent risk factors for cerebral hyperperfusion syndrome after superficial temporal artery-middle cerebral artery anastomosis with pial synangiosis in adult moyamoya disease patients-case-control study.

Superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis is a standard treatment for adult moyamoya disease (MMD) patients. Cerebral hyperperfusion (CHP) syndrome is one of the most serious complications of this procedure that can result in deleterious outcomes, but predicting CHP before revascularization surgery remains challenging. Furthermore, the hematological/serological factors associated with CHP syndrome are unknown. To investigate the correlation between pre-operative hematological/serological factors and the development of CHP syndrome after STA-MCA anastomosis with encephalo-duro-myo-synangiosis (EDMS) for MMD., a pre-operative peripheral blood test was performed within 5 days before surgery. Local cerebral blood flow (CBF) at the site of anastomosis was quantified by N-isopropyl-p-[123I] iodoamphetamine single-photon emission computed tomography 1 and 7 days after surgery, and the pre-operative CBF value at the corresponding area was measured. We defined CHP syndrome as a local CBF increase over 150% compared with the pre-operative value, which was responsible for delayed intracranial hemorrhage, transient focal neurological deterioration, and/or seizure. Then, we retrospectively investigated the correlation between peripheral blood test results and the development of CHP syndrome. CHP syndrome 1 day after STA-MCA anastomosis with EDMS was observed in nine patients (9/114 hemispheres; 7.9%). Multivariate analysis with multiple imputation revealed that higher hematocrit value and lower total protein level were significantly associated with the development of CHP syndrome (p value: 0.028 and 0.043, respectively). Higher pre-operative hematocrit levels and lower pre-operative total protein levels are novel risk factors for CHP syndrome after direct revascularization surgery in adult MMD patients.

Prediction of Cerebral Hyperperfusion after Superficial Temporal Artery-Middle Cerebral Artery Anastomosis by Three-Dimensional-Time-of-Flight Magnetic Resonance Angiography in Adult Patients with Moyamoya Disease

Introduction: Superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis is an effective surgical procedure for adult patients with moyamoya disease (MMD) and is known to have the potential to prevent cerebral ischemia and/or hemorrhagic stroke. Cerebral hyperperfusion (CHP) syndrome is one of the serious complications of this procedure that can result in deleterious outcomes, such as delayed intracerebral hemorrhage, but the prediction of CHP before revascularization surgery remains challenging. The present study evaluated the diagnostic value of preoperative three-dimensional (3D)-time-of-flight (TOF) magnetic resonance angiography (MRA) for predicting CHP after STA-MCA anastomosis for MMD. Materials and Methods: The signal intensity of the peripheral portion of the intracranial major arteries, such as the anterior cerebral artery (ACA), MCA, and posterior cerebral artery (PCA) ipsilateral to STA-MCA anastomosis, on preoperative MRA was graded (0–2 in each vessel) according to the ability to visualize each vessel on 97 affected hemispheres in 83 adult MMD patients. Local cerebral blood flow (CBF) at the site of anastomosis was quantitatively measured by N-isopropyl-p-[¹²³I]-iodoamphetamine single-photon emission computed tomography 1 and 7 days after surgery, in addition to the preoperative CBF value at the corresponding area. Then, we investigated the correlation between the preoperative MRA score and the development of CHP. Results: The CHP phenomenon 1 day after STA-MCA anastomosis (local CBF increase over 150% compared with the preoperative value) was evident in 27 patients (27/97 hemispheres; 28%). Among them, 8 (8 hemispheres) developed CHP syndrome. Multivariate analysis revealed that the hemispheric MRA score (0–6), the summed ACA, MCA, and PCA scores for the affected hemisphere, was significantly associated with the development of CHP syndrome (p = 0.011). The hemispheric MRA score was also significantly correlated with the CHP phenomenon, either symptomatic or asymptomatic (p < 0.001). Conclusion: The signal intensity of the intracranial major arteries, including the ACA, MCA, and PCA, on preoperative 3D-TOF MRA may identify adult MMD patients at higher risk for CHP after direct revascularization surgery.

Significance of Quantitative Cerebral Blood Flow Measurement in the Acute Stage after Revascularization Surgery for Adult Moyamoya Disease: Implication for the Pathological Threshold of Local Cerebral Hyperperfusion

Objective: Superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis is a standard surgical procedure for adult patients with moyamoya disease (MMD) and plays a role in preventing ischemic and/or hemorrhagic stroke. Cerebral hyperperfusion (CHP) syndrome is a potential complication of this procedure that can result in deleterious outcomes, such as delayed intracerebral hemorrhage, but the exact threshold of the pathological increase in postoperative cerebral blood flow (CBF) is unclear. Thus, we analyzed local CBF in the acute stage after revascularization surgery for adult MMD to predict CHP syndrome under modern perioperative management. Materials and Methods: Fifty-nine consecutive adult MMD patients, aged 17–66 years old (mean 43.1), underwent STA-MCA anastomosis with indirect pial synangiosis for 65 affected hemispheres. All patients were perioperatively managed by strict blood pressure control (systolic pressure of 110–130 mm Hg) to prevent CHP syndrome. Local CBF at the site of anastomosis was quantitatively measured using the autoradiographic method by N-isopropyl-p-[¹²³I] iodoamphetamine single-photon emission computed tomography 1 and 7 days after surgery, in addition to the preoperative CBF value at the corresponding area. We defined CHP phenomenon as a local CBF increase over 150% compared to the preoperative value. Then, we investigated the correlation between local hemodynamic change and the development of CHP syndrome. Results: After 65 surgeries, 5 patients developed CHP syndrome, including 2 patients with delayed intracerebral hemorrhage (3.0%), 1 with symptomatic subarachnoid hemorrhage (1.5%), and 2 with focal neurological deterioration without hemorrhage. The CBF increase ratio was significantly higher in patients with CHP syndrome (270.7%) than in patients without CHP syndrome (135.2%, p = 0.003). Based on receiver operating characteristic analysis, the cutoff value for the pathological postoperative CBF increase ratio was 184.5% for CHP syndrome (sensitivity = 83.3%, specificity = 94.2%, area under the curve [AUC] value = 0.825) and 241.3% for hemorrhagic CHP syndrome (sensitivity = 75.0%, specificity = 97.2%, AUC value = 0.742). Conclusion: Quantitative measurement of the local CBF value in the early postoperative period provides essential information to predict CHP syndrome after STA-MCA anastomosis in patients with adult MMD. The pathological threshold of hemorrhagic CHP syndrome was as high as 241.3% by the local CBF increase ratio, but 2 patients (3.0%) developed delayed intracerebral hemorrhage in this series that were managed following the intensive perioperative management protocol. Thus, we recommend routine CBF measurement in the acute stage after direct revascularization surgery for adult MMD and satisfactory blood pressure control to avoid the deleterious effects of CHP.

The A 1 receptor agonist R-Pia reduces the imbalance between cerebral glucose metabolism and blood flow during status epilepticus: Could this mechanism be involved with neuroprotection?

It is well known that the uncoupling between local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF), i.e. decrease in LCBF rates with high LCGU, is frequently associated with seizure-induced neuronal damage. This study was performed to assess if the neuroprotective effect of the adenosinergic A 1 receptor agonist R-N-phenylisopropyladenosine (R-Pia) injected prior to pilocarpine is able to reduce the uncoupling between LCGU and LCBF during status epilepticus (SE). Four groups of rats were studied: Saline, Pilo, R-Pia + Saline and R-Pia + Pilo. For LCGU and LCBF studies, rats were subjected to autoradiography using [ 14C]-2-deoxyglucose and [ 14C]-iodoantypirine, respectively. Radioligands were injected 4 h after SE onset. Neuronal loss was evaluated by Fluorojade-B (FJB) at two time points after SE onset (24 h and 7 days). The results showed a significant increase in LCGU in almost all brain regions studied in the Pilo and R-Pia + Pilo groups compared to controls. However, in R-Pia pretreated rats, the uncoupling between LCGU and LCBF was moderated in a limited number of structures as substantia nigra pars reticulata and hippocampal formation rather in favor of hyperperfusion. Significant increases in LCBF were observed in the entorhinal cortex, thalamic nuclei, mammillary body, red nucleus, zona incerta, pontine nucleus and visual cortex. The neuroprotective effect of R-Pia assessed by FJB showed a lower density of degenerating cells in the hippocampal formation, piriform cortex and basolateral amygdala. In conclusion our data shows that the neuroprotective effect of R-Pia was accompanied by a compensatory metabolic input in brain areas involved with seizures generation.

Targeted increase in cerebral blood flow by transcranial near‐infrared laser irradiation

Brain function is highly dependent on cerebral blood flow (CBF). The precise mechanisms by which blood flow is controlled by NIR laser irradiation on the central nervous system (CNS) have not been elucidated. In this study, we examined the effect of 808 nm laser diode irradiation on CBF in mice. We examined the effect of NIR irradiation on CBF at three different power densities (0.8, 1.6 and 3.2 W/cm(2)) and directly measured nitric oxide (NO) in brain tissue during NIR laser irradiation using an amperometric NO-selective electrode. We also examined the contribution of NO and a neurotransmitter, glutamate, to the regulation of CBF by using a nitric oxide synthase (NOS) inhibitor, N(g)-nitro-L-arginine methyl ester hydrochloride (L-NAME), and an N-methyl-D-aspartate (NMDA) receptor blocker, MK-801, respectively. We examined the change in brain tissue temperature during NIR laser irradiation. We also investigated the protection effect of NIR laser irradiation on transient cerebral ischemia using transient bilateral common carotid artery occlusion (BCCAO) in mice. We showed that NIR laser irradiation (1.6 W/cm(2) for 15-45 minutes) increased local CBF by 30% compared to that in control mice. NIR laser irradiation also induced a significant increase in cerebral NO concentration. In mice that received L-NAME, NIR laser irradiation did not induce any increase in CBF. Mice administered MK-801 showed an immediate increase but did not show a delayed additional increase in local CBF. The increase in brain tissue temperature induced by laser irradiation was estimated to be as low as 0.8 degrees C at 1.6 W/cm(2), indicating that the heating effect is not a main mechanism of the CBF increase in this condition. Pretreatment with NIR laser irradiation improved residual CBF and reduced the numbers of apoptotic cells in the hippocampus. Our data suggest that NIR laser irradiation is a promising experimental and therapeutic tool in the field of cerebral circulation research.

Effect of stage 2 kindling on local cerebral blood flow rates in rats with genetic absence epilepsy

Genetic absence epilepsy rats from Strasbourg (GAERS) are resistant to the progression of kindling seizures. We studied local cerebral blood flow (LCBF) changes in brain regions involved in seizures in both GAERS and nonepileptic rats (NEC) to map the differences that may be related to the resistance to kindling. Electrodes were implanted in the amygdala of adult NEC and GAERS male rats, which were stimulated to reach stage 2. Quantitative autoradiographic measurements of LCBF were performed by the [(14)C]-iodoantipyrine ([(14)C]IAP) autoradiographic technique allowing the precise mapping of regional perfusion changes. LCBF rates were measured bilaterally in 43 brain regions. The tracer infusion lasted for 60 s and started at 15 s before seizure induction. Rates of LCBF increased in stimulated GAERS and NEC groups compared to nonstimulated controls. The LCBF increase in stimulated GAERS was larger and more widespread than that observed in stimulated NEC. The LCBF increase in the somatosensory cortex, ventrobasal and anterior thalamic nuclei, hypothalamus, subthalamic nucleus, piriform, entorhinal and perirhinal cortex, amygdala, CA2 region of hippocampus, and substantia nigra was statistically significantly larger in stimulated GAERS compared to stimulated NEC rats. The results show that more brain regions are activated by kindling stimulation in GAERS. This widespread activation in GAERS involves the somatosensory cortex and thalamus, which are both known to be involved in the expression of absence seizures as well as numerous limbic regions thought not to play a role in the expression of absence seizures, suggesting an interaction between corticothalamocortical and limbic circuitries.

Apparent diffusion time of oxygen from blood to tissue in rat cerebral cortex: implication for tissue oxygen dynamics during brain functions

To investigate the dynamics of tissue oxygen demand and supply during brain functions, we simultaneously recorded Po(2) and local cerebral blood flow (LCBF) with an oxygen microelectrode and laser Doppler flowmetry, respectively, in rat somatosensory cortex. Electrical hindlimb stimuli were applied for 1, 2, and 5 s to vary the duration of evoked cerebral metabolic rate of oxygen (CMR(O(2))). The electrical stimulation induced a robust increase in Po(2) (4-9 Torr at peak) after an increase in LCBF (14-26% at peak). A consistent lag of approximately 1.2 s (0.6-2.3 s for individual animals) in the Po(2) relative to LCBF was found, irrespective of stimulus length. It is argued that the lag in Po(2) was predominantly caused by the time required for oxygen to diffuse through tissue. During brain functions, the supply of fresh oxygen further lagged because of the latency of LCBF onset ( approximately 0.4 s). The results indicate that the tissue oxygen supports excess demand until the arrival of fresh oxygen. However, a large drop in Po(2) was not observed, indicating that the evoked neural activity demands little extra oxygen or that the time course of excess demand is as slow as the increase in supply. Thus the dynamics of Po(2) during brain functions predominantly depend on the time course of LCBF. Possible factors influencing the lag between demand and supply are discussed, including vascular spacing, reactivity of the vessels, and diffusivity of oxygen.

Changes in red blood cell behavior during cerebral blood flow increase in the rat somatosensory cortex: a study of laser-Doppler flowmetry.

The purpose of this study was to investigate red blood cell (RBC) behavior during an increase in local cerebral blood flow (LCBF). We measured changes in RBC behavior by using laser-Doppler flowmetry (LDF) in alpha-chloralose-anesthetized rats. An increase in LCBF was carried out by approximately 2.5 and 4.0% CO(2) inhalation and activation of the somatosensory cortex. The activation of the cortex was induced by electrical stimulation of the hind paw with 1.5-mA pulses (0.1 ms) applied at frequencies of 0.2, 1, 5, and 10 Hz for a 5 s duration. The increases in LCBF and RBC velocity during both CO(2) inhalations were larger than that in RBC concentration (p < 0.05). LCBF and RBC velocity during 4.0% CO(2) inhalation were larger than those during 2.5% CO(2) inhalation (p < 0.05), though there was no significant difference in RBC concentration between the two conditions, suggesting a limitation of capillary volume. During somatosensory stimulation, the evoked LCBF increased with increasing stimulus frequency up to 5 Hz and decreased at 10 Hz. The responses of RBC concentration at 0.2 and 10 Hz were greater than those of RBC velocity (p < 0.05), but no significant differences in response magnitude were found at 1 and 5 Hz between RBC concentration and RBC velocity. These results suggest that the increase in LCBF during neuronal activity is different from that of controlling the LCBF as induced by CO(2), and that the regulation of RBC concentration and RBC velocity is controlled by independent mechanisms.

Effect of stimulation of the dorsal aspect of the cervical spinal cord on ’Iocal cerebral blood flow and EEG in the cat

Currently there is considerable interest in electrical stimulation of the dorsal aspect of the cervical spinal cord as a potentially effective therapy for persistent vegetative patients. The authors assessed change in the local cerebral blood flow (LCBF) and electroencephalogram (EEe) in the cat following spinal cord stimulation (SCS). In 31 adult cats under isoflurane anesthesia, an electrode for SCS was introduced epidurally to the midline of the C2-C3 segment. Stimulation was performed at 25 Hz and 0.7 msec for30 min. These animals were divided into five groups by the voltage: (1) 2V (n = 7), (2) 4V (n = 7), (3) 6V (n = 7), (4) 4V with intravenous injection of muscarinic cholinergic agents - atropine sulfate (n =5), and (5) sham-operated control (n = 5) without stimulation. LCBF was measured by laser Doppler flowmetry through bilateral small burr holes at the parietal area during and 60 min after stimulation. At 2~ LCBF increased only during SCSI then returned to the pre-stimulated level, while the increase continued until the end of the experiment at 4Vand 6V. The increase in LCBF was not affected by atropine sulfate. EEe showed spike and wave or polyspikes after SCS in two animals of the 6V group, but not in the 2V and 4V groups, and moreover a moderate increase ofthe background activity at only 4V. The present data suggested that SCS at 4Vcan provide the appropriate microcirculatory enhancement with less harmful influence which continues to increase 30 min after SCSI although the exact mechanism should be elucidated continuously. Within the limitation of animal experiments, this study could provide the logical basis for determining the condition of SCS. [Neural Res 2000; 22: 386-392]

Modulation of evoked cerebral blood flow under excessive blood supply and hyperoxic conditions.

We measured the field potential and local cerebral blood flow (LCBF) using laser-Doppler flowmetry in alpha-chloralose anesthetized rats during activation of the somatosensory cortex by electrical stimulation of the hind paw under independent administration of additional carbon dioxide and oxygen. The aim of this study was to test the hypothesis that the increase in LCBF during activation of the cortex (evoked LCBF) is not directed toward supplying oxygen for oxidative metabolism. Under the hypercapnic condition (PaCO(2) = 74. 9 +/- 14.3 mmHg), the baseline LCBF was about 46.5% higher than that under the normocapnic condition (PaCO(2) = 35.7 +/- 2.1 mmHg) (p < 0. 001), but after normalization for each baseline (divided by the prestimulus level), there was no significant difference in the peak value and the rise time of normalized evoked LCBF. On the other hand, the baseline level of LCBF under the hyperoxic condition (PaO(2) = 479.4 +/- 77.2 mmHg) was about 5.0% lower than that under the normoxic condition (PaO(2) = 105.5 +/- 7.8 mmHg) (p < 0.01), suggesting mild vasoconstriction under the condition of hyperoxia at rest. The peak value of normalized evoked LCBF under the hyperoxic condition was about 6.5% higher than that under the normoxic condition (p < 0.05). In addition, the rise time of evoked LCBF was earlier under the hyperoxic condition (0.37 +/- 0.16 s) than that under the normoxic condition (0.52 +/- 0.12 s) (p < 0.01). The field potential measured during stimulation under hypercapnic and hyperoxic conditions was not significantly different when compared with that under normal gas conditions. These results support our hypothesis and suggest that the excess oxygen is involved in the mechanism underlying the regulation of LCBF.

Nitric oxide and the cerebral-blood-flow response to somatosensory activation following deafferentation.

The single-vibrissa stimulation model in the rat was utilized to study the microvascular coupling between functional activation and local cerebral blood flow (LCBF) in both normal cortex and in cortex that had been peripherally deafferented. In addition, the role of chronic nitric oxide synthase (NOS) inhibition on the LCBF response to vibrissa stimulation was examined. One-day-old rats underwent deafferentation of all vibrissae on one side of the face, sparing C3, and received daily administration of either saline or N omega-nitro-L-arginine (L-NA). After seven weeks of treatment, LCBF was measured autoradiographically in conscious rats with [14C]N-isopropyl-p-iodoamphetamine while C3 was stimulated bilaterally. Stimulation produced a greater increase in LCBF in the deafferented cortex of both the saline (30.4%) and L-NA treated (25.7%) animals than in the intact cortex (19.9% and 16%, respectively). The area of activation of LCBF (0.176 mm2) was comparable to the area metabolically activated (0.149 mm2), and the increase in area of LCBF activation following deafferentation (169%) was smaller than the increase in area that was metabolically activated (287%). Chronic inhibition of NOS did not alter the spatial extent of the blood-flow response.

Hemodynamics evoked by microelectrical direct stimulation in rat somatosensory cortex

The aim of this study was to estimate the timing (latency) of the increase in red blood cell (RBC) velocity and RBC concentration, and the magnitude of response in local cerebral blood flow (LCBF) for neuronal activation. We measured LCBF change during activation of the somatosensory cortex by direct microelectrical stimulation. Electrical stimuli of 5, 10 and 50 Hz of 1 ms pulse with 10–15 μA, were given for 5 s. LCBF, RBC velocity and RBC concentration were monitored by laser-Doppler flowmetry (LDF) in α-chloralose anesthetized rats ( n=7). LCBF, RBC velocity and RBC concentration increased nearly proportionally to stimulus frequency, i.e. neuronal activity. LCBF rose ≈0.5 s after the onset of stimulation, and there was no significant time lag of the latencies among LCBF, RBC velocity and RBC concentration at the same stimulus frequency. We interpret these results to mean that the onset of LCBF increase on cortical activation is reflected by a rapid change in arteriole (resistance vessel) dilation and capillary volume. The data also elucidate the linear relationship between LCBF increase and cortical activity.

Induced hypertension treatment to improve cerebral ischemic injury after transient forebrain ischemia

The effect of induced hypertension treatment on cerebral ischemia is still controversial. We investigated the preferred blood pressure manipulation level and pressor agent required to reduce cerebral ischemic injury following transient forebrain ischemia induced by bilateral occlusion of the common carotid arteries in anesthetized gerbils. Following 60-min cerebral ischemia, we evaluated the preferred blood pressure manipulation level and pressor agent required to treat cerebral ischemic injury after reperfusion by examining the effects of different levels of mean arterial blood pressure (MABP), increased with phenylephrine or angiotensin II or decreased by blood withdrawal, on cerebral blood flow (CBF), survival ratio, cerebral edema, and brain energy metabolism following transient forebrain ischemia in gerbils. Mild phenylephrine-induced hypertension treatment (21±4 mmHg) during post-cerebral ischemia–reperfusion improved the survival ratio and reduced cerebral edema, which was also associated with an increase in local CBF and a recovery of brain energy metabolism. However, intense phenylephrine-induced hypertension, angiotensin II-induced hypertension, or hypotension worsen the survival rate and produced extra cerebral edema, that were also associated with deterioration of brain energy metabolism. These results demonstrate that a mild induced hypertension with phenylephrine (21±4 mmHg above the baseline level) results in reduction of the cerebral edema and improves the survival ratio and brain energy metabolism. Furthermore, angiotensin II may have neurotoxic effect to use as the pressor agent for induced hypertension after cerebral ischemia.

Vasodilator responses to acetazolamide tested in subtypes of vascular dementia

Thirty seven vascular dementia (VAD) patients were categorized into eight subtypes based on clinical, radiological, and pathogenetic features. Cerebral vasodilator responses to acetazolamide were then compared with age-matched normal controls and stroke patients without dementia. VAD results were compared with 42 normals and 19 cognitively intact stroke patients. Regional cerebral vasodilator responses were quantitated utilizing xenon contrasted computed tomography measures of local cerebral blood flow (LCBF) before and after oral administration of acetazolamide. LCBF changes (DeltaLCBF) before and after acetazolamide were calculated within cortical and subcortical, gray and white matter. Clinical VAD subtypes were: type 1, multi-infarct dementia (MID); type 2, strategically placed infarcts; type 3, subcortical lacunar infarcts; type 4, Binswanger's subcortical arteriosclerotic leukoencephalopathy; type 5, subcortical infarctions due to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), inflammatory angitis, or antiphospholipid antibodies; type 6, admixtures of above types; type 7, cerebral hemorrhagic lesions; and type 8, VAD combined with Alzheimer's disease (DAT). The group with subcortical VAD comprised types 3-5. The group with cortical VAD comprised the remainder (types 1, 2, and 6-8). Cerebral vasodilator responses were also compared between these two main groups. Cerebral vasodilator responses identified differences between the two main groups of VAD patients, those with cortical and those with subcortical dementia. Leukoaraiosis was measurably greater in subcortical VAD compared with cortical VAD. Among subcortical VAD patients, cortical LCBF increases after administration of acetazolamide were greater compared with cortical VAD and with normal controls. Cognitive impairments in subcortical VAD are attributable to cortical disconnection syndromes. This concept is supported by reduced perfusion in deactivated cortex. In patients with subcortical VAD, deactivated cortical LCBF becomes promptly activated by acetazolamide resulting in marked cortical LCBF increases. Leukoaraiosis is greater among VAD patients and leukoaraiosis contributes to cortical disconnections, confirmed by excessive cortical vasodilator responses to acetazolamide.

The effect of high-dose albumin therapy on local cerebral perfusion after transient focal cerebral ischemia in rats

We have shown that high-concentration albumin therapy is markedly neuroprotective in focal cerebral ischemia. The present study was conducted to ascertain the degree to which hemodynamic alterations are responsible for this therapeutic effect. Normothermic, physiologically regulated male Sprague–Dawley rats received a 2-h period of middle cerebral artery occlusion (MCAo) by insertion of an intraluminal suture coated with poly- l-lysine. Albumin (25% human serum albumin solution) or vehicle (0.9% sodium chloride) was administered intravenously at a dose of 1% of body weight immediately after suture withdrawal following 2-h MCAo. Local cerebral blood flow (LCBF) was measured autoradiographically with 14C−iodoantipyrine after 1 h of recirculation. Novel image-processing methods were used to compare average LCBF data sets against previously obtained infarction-frequency data on a pixel-by-pixel basis. Albumin therapy reduced mean hematocrit by 42% but produced no other systemic alterations. Pixel-based histopathological analysis revealed large, consistent cortical and subcortical infarcts in saline-treated rats with MCAo; albumin therapy reduced mean cortical infarct volume by 85%. Within regions showing albumin-associated neuroprotection, numbers of pixels having LCBF in the upper ischemic-core flow range (0.12–0.24 ml g −1 min −1) were reduced by 8.6-fold by albumin therapy when compared to saline-treated rats; and numbers of pixels with LCBF in the lower penumbral flow range (0.24–0.36 ml g −1 min −1) were reduced by 3.1-fold in albumin-treated rats ( p=0.04 by repeated-measures analysis of variance). Analysis of the [albumin–saline] 3-dimensional difference-image data set revealed a circumferential zone of statistically significant albumin-associated LCBF increase within the posterior portion of the ischemic hemisphere, surrounding the core-region of prior ischemia. Thus, high-concentration albumin therapy improves local perfusion to regions of critical LCBF reduction. The spatial extent of this LCBF effect, however, appears too small to account fully for the marked neuroprotective efficacy of this therapy. We suggest that other, non-hemodynamic mechanisms may also be contributory.

Local cerebral blood flow in motor neuron disease: correlation with clinical findings

Local cerebral blood flow (CBF) measured by xenon-enhanced CT was correlated with the clinical findings in 21 patients with motor neuron disease (mean ± SD age, 60 ± 10 years). In 11 patients, CBF was also measured after intravenous injection of 2 mg thyrotropin releasing hormone (TRH). There were no significant differences in CBF of the cerebral cortex, basal ganglia, thalamus, and subcortical white matter with respect to age, duration of illness, or presence (n = 9) or absence (n = 12) of bulbar palsy. In patients with upper motor neuron disturbance (n = 10), however, local CBF in the frontal cortex was significantly lower (p < 0.05) than in those without it (n = 11). Within the frontal cortex, CBF reduction was marked in the upper posterolateral part (p < 0.05) that included the motor and premotor areas. Intravenous administration of TRH did not significantly alter the local CBF in any of the brain regions examined. An additional patient with motor neuron disease and severe dementia showed marked CBF reduction in the frontal lobe, which was in common with but much greater than the reduction in those exhibiting subcortical dementia (e.g., progressive supranuclear palsy). We conclude that in motor neuron disease patients with upper motor neuron involvement, the selective reduction of CBF in brain regions that include primary motor and premotor areas may reflect functional disturbance or neuronal degeneration in these regions. The ameliorating effect of TRH in patients with motor neuron disease, if any, appears not to be related to increases in local CBF or activation of brain function.

Sequential changes in cerebrovascular reserve capacity in three-vessel occlusion rats

To understand the pathophysiology of hemodynamic compromise, we evaluated the cerebrovascular reserve capacity of a cerebral hemisphere in rats with 3-vessel occlusion (3VO). The bilateral vertebral and left common carotid arteries were occluded in Wistar rats. Sequential changes in local cerebral blood flow (LCBF) and local cerebral plasma volume (LCPV) were measured by [14C]iodoantipyrine and [14C]dextran autoradiography, respectively. There was no significant difference in LCBF between 3VO and control rats at rest. After acetazolamide administration, however, an increase of LCBF in the left hemisphere was less significant compared to that in the right side in the 3VO rats. The left and right ratio was 0.67 ± 0.15 (P < 0.05) in the parietal cortex and 0.70 ± 0.10 (P < 0.01) in the caudate nucleus. This asymmetrical response to acetazolamide administration gradually corrected by 7 days after 3VO. A significant increase of the LCPV in the ischemic side was observed between day 0 and the 5th day. The 3VO rat is a useful model for studies on the pathophysiology of a hemodynamically compromised state.