Effects of cerebrovascular autoregulation and CO2 reactivity in experimental localized brainstem infarction

Abstract

Using the previously reported method of experimental localized brainstem infarct in dogs, we designed this study to elucidate sequential changes of regional cerebral blood flow (rCBF) in three separate regions of the central nervous system: the cerebral cortex, thalamus, and midbrain. The data obtained were referred to in subsequent investigations of cerebrovascular autoregulation and vasomotor reactivity to C0₂. Localized brainstem infarct was produced by permanently occluding the perforators of the posterior cerebral arteries between the bilateral origins of the posterior communicating arteries. The hydrogen clearance method was applied to measure rCBF. Cerebrovascular autoregulation and CO₂ reactivity were assessed in three regions 1, 3, and 5 h after vascular occlusion, respectively. Vascular occlusion resulted in a decrease of rCBF that was 65% in the midbrain and close to 30%–40% in the thalamus. However, no significant change was seen in the cerebral cortex even 5 h after vascular occlusion. Induced hypertension impaired autoregulation in the thalamus, while it was preserved in the cerebral cortex. Induced hypotension did not alter autoregulation in any of the three regions. A marked loss of CO₂ reactivity was observed in the ischemic brainstem, although it was well preserved in the cerebral cortex. The results suggest that noradrenergic fibers originating from the cervical sympathetic ganglia play a main role in the cerebrovascular autoregulation in the cerebral cortex, while noradrenergic fibers possibly originating from the autonomic centers in the brainstem are responsible in the thalamus; that the noradrenergic neuron probably is not involved in the maintenance of cerebral blood flow during hypotension; and that the effect of CO₂ is mediated by its direct effect on the arteriolar wall in the central nervous system. [Neurol Res 2000; 22: 197–203]     

Delayed recovery of CO2 reactivity after one hour's complete ischaemia of cat brain

Summary The cerebrovascular CO₂ reactivity was examined after 6h, 1, 2, and 3 days and 1 year following 1h complete brain ischaemia in the cat. After 6h recirculation, the CO₂ reactivity was completely suppressed although major EEG activity had recovered. After 2 days, CO₂ reactivity began to reappear, but even after 1 year restitution was not complete. The prolonged (though partly reversible) attenuation of CO₂ responsiveness suggests that ischaemia is followed by a long-lasting state of haemodynamic imbalance, which may be responsible for the slow progress of post-ischaemic recovery processes.     

Hypercapnia stimulates prostaglandin E(2) but not prostaglandin I(2) release in endothelial cells cultured from microvessels of human fetal brain

Hypercapnia-induced cerebral vasodilation involves prostanoids, in newborns. The source of these prostanoids, however, is not yet determined. In the present study we address the hypothesis that microvascular endothelial cells of human fetal cerebrum increase the synthesis of dilator prostanoids in response to high pCO(2). Cells were isolated from a 22-week-old human fetus. Indication of induced abortion was 46 XY-t(3,10) 3q-25 chromosome abnormality. Normocapnia or hypercapnia was performed during normoxic and normothermic conditions in the medium of the cell culture. After normocapnic or hypercapnic stimuli, the amounts of released prostaglandin E(2) and 6-keto-prostaglandin F(1alpha) (the stable metabolite of prostaglandin I(2)) were measured by radioimmunoassay. Endothelial cells cultured from human fetal brain microvessels express PGE(2) and 6-keto-PGF(1alpha) in different degrees. Hypercapnic stimulus induced a significant increase of PGE(2), while expression of 6-keto-PGF(1alpha) was not augmented by the same stimulus. PGE(2) of endothelial origin, therefore, could be a factor in the mediation of the hypercapnia-induced vasodilation in human fetuses.     

CO2 has no therapeutic effect on early microvasospasm after experimental subarachnoid hemorrhage

In addition to delayed vasospasm also early brain injury, which occurs during the first few days after subarachnoid hemorrhage (SAH) when large cerebral arteries are still fully functional, plays an important role for the outcome after SAH. In the current study, we investigated the hypothesis that carbon dioxide (CO₂), a strong cerebral vasodilator, has a therapeutic potential against early posthemorrhagic microvasospasm. C57BL/6 mice (n=36) and Sprague-Dawley rats (n=23) were subjected to sham surgery or SAH by filament perforation. The pial microcirculation in the mice was visualized 3 and 24 hours after SAH using intravital fluorescence microscopy. Partial pressure of CO₂ (PaCO₂) was modulated by hyper- or hypoventilation or by inhalation of 10% CO₂. In rats, CO₂-mediated changes in cerebral blood flow (CBF) were measured at the same time points using laser Doppler fluxmetry. Increased PaCO₂ caused vasodilatation in sham-operated animals. Following SAH, however, cerebral arterioles were nonreactive to CO₂. This lack of microvascular CO₂ reactivity was accompanied by a complete loss of CO₂-induced hyperemia. Our data show that CO₂ is not able to dilate spastic microvessels and to increase CBF early after SAH. Future therapeutic approaches will therefore need to address mechanisms beyond CO₂.     

Bi-hemispheric CBF and Its CO2 Reactivity of TIAs and Completed Strokes in ICA Occlusions

\

Bi-hemispheric cerebral blood flow (CBF) measurements during rest and hyperventilation, with intra-arteria1 ¹³³Xe injection method, were investigated in 19 cases, angiographically diagnosed as unilateral internal carotid artery (ICA) occlusion, including 8 cases with TIAs and 11 cases with completed strokes as the onset. Indices of cerebral vascular resistance and CO₂ reactivity with decreasing arterial\PCO₂ were also investigated.

A significant decrease (P < 0.05) of hemispheric mean CBF was noted in the ischemic hemisphere, but normal flow values in the unaffected hemisphere and preserved CO₂ responsiveness during hyperventilation were observed in both the affected and unaffected hemispheres in patients with TIAs. Moreover, a direct relationship between CBF and blood pressure, observed in 11 cases with completed strokes, was not recognized in 8 cases with TIAs.

A degree of the abnormalities of the affected hemisphere in cerebral circulation was suggested to be somewhat different between TIAs and completed strokes in ICA occlusions, and bi-hemispheric CBF measurements would be an useful method for evaluating the various indices of the CBF in ICA occlusions.     

The effect of basal vasodilation on hypercapnic and hypocapnic reactivity measured using magnetic resonance imaging

Cerebrovascular reactivity to vasodilatory hypercapnic and vasoconstrictive hypocapnic challenges is known to be altered in several hemodynamic disorders, which is often attributable to changes in smooth muscle-mediated vascular compliance. Recently, attenuated reactivity to hypercapnia but enhanced reactivity to hypocapnia was observed in patients with chronic stroke. We hypothesize that the latter observation could be explained by a change in the basal vascular tone. In particular, reduced cerebral perfusion pressure, as is prevalent in these patients, may cause vasodilation through autoregulatory mechanisms, and this compensatory baseline condition may alter reactivity to vasoconstrictive hypocapnic challenges. To test this hypothesis, a predilated vascular condition was created in young, healthy subjects (n=11; age=23 to 36 years) using inhalation of 4% CO₂. Using blood oxygenation level-dependent functional magnetic resonance imaging at 3 T, breath holding and cued deep breathing respiratory challenges were administered to assess hypercapnia and hypocapnia reactivity, respectively. During the predilated condition, vasoconstrictive reactivity to hypocapnia was significantly (21.1%, P=0.016) enhanced throughout the gray matter, whereas there was no significant change (6.4%, P=0.459) in hypercapnic vasodilatory reactivity. This suggests that baseline vasodilation may explain the enhanced hypocapnia reactivity observed in some stroke patients, and that hypocapnia challenges may help identify the level of vascular compliance in patients with reduced cerebral perfusion pressure.     

Cerebrovascular reactivity in the brain white matter: magnitude,temporal characteristics,and age effects

White matter (WM) comprises about half of the brain and its dysfunction is implicated in many brain disorders. While structural properties in healthy and diseased WM have been extensively studied, relatively little is known about the physiology underlying these structural characteristics. Recent advances in magnetic resonance (MR) technologies provided new opportunities to better understand perfusion and microvasculature in the WM. Here, we aim to evaluate vasodilatory capacity of the WM vasculature, which is thought to be important in tissue ischemia and autoregulation. Fifteen younger and fifteen older subjects performed a CO₂ inhalation task while blood-oxygenation-level-dependent (BOLD) magnetic resonance imaging (MRI) images were continuously collected. The cerebrovascular reactivity (CVR) index showed that the value of CVR in the WM (0.03±0.002%/mm Hg) was positive, but was significantly lower than that in the gray matter (GM) (0.22±0.01%/mm Hg). More strikingly, the WM response showed a temporal delay of 19±3 seconds compared with GM, which was attributed to the longer time it takes for extravascular CO₂ to change. With age, WM CVR response becomes greater and faster, which is opposite to the changes seen in the GM. These data suggest that characteristics of WM CVR are different from that of GM and caution should be used when interpreting pathologic WM CVR results.     

Assessment of cerebrovascular reserve in unilateral middle cerebral artery stenosis using perfusion CT and CO2 inhalation tests

Purpose/Aim of the study: Cerebrovascular reactivity (CVR) is an important marker for assessing cerebrovascular disease. This study assessed the CVR by perfusion computed tomography (CT) and CO₂ inhalation tests in patients with unilateral middle cerebral artery (MCA) stenosis disease. Materials and Methods: Thirty-one patients with unilateral MCA stenosis disease diagnosed by digital subtraction angiography were studied. Patients were divided into two groups according to the degree of stenosis: severe and moderate. The regional cerebral blood flow (CBF) before and after CO₂ inhalation was determined by perfusion CT. Regional CVR values were obtained by the following formula: increase (%) = (post-CBF) ? (pre-CBF)/(pre-CBF) × 100%. Results: No significant differences in the mean CBF in the MCA stenosis region were found between the affected and contralateral sides before the CO₂ inhalation test; after the test, CBF was more significantly decreased on the affected side than on the contralateral side. The changes in CBF on the affected side were categorized into three types: increased CBF (17 cases), decreased CBF (12 cases) and no change in CBF (2 cases). The rate of CVR impairment among severe stenosis patients (13/19) was higher than that among moderate stenosis patients (3/12). CVR was significantly correlated with the degree of stenosis (r = 0.423, P = 0.018). Conclusion: CVR impairment was found in approximately half of patients with unilateral MCA stenosis. Along with an increase in the degree of stenosis, patients with unilateral MCA stenosis were more likely to exhibit CVR impairment. It is important to assess the CVR in patients with unilateral MCA stenosis, especially those with severe stenosis.     

Experiential,autonomic, and respiratory correlates of CO2 reactivity in individuals with high and low anxiety sensitivity

Psychometric studies indicate that anxiety sensitivity (AS) is a risk factor for anxiety disorders such as panic disorder (PD). To better understand the psychophysiological basis of AS and its relation to clinical anxiety, we examined whether high-AS individuals show similarly elevated reactivity to inhalations of carbon dioxide (CO₂) as previously reported for PD and social phobia in this task. Healthy individuals with high and low AS were exposed to eight standardized inhalations of 20% CO₂-enriched air, preceded and followed by inhalations of room air. Anxiety and dyspnea, in addition to autonomic and respiratory responses were measured every 15 s. Throughout the task, high AS participants showed a respiratory pattern of faster, shallower breathing and reduced inhalation of CO₂ indicative of anticipatory or contextual anxiety. In addition, they showed elevated dyspnea responses to the second set of air inhalations accompanied by elevated heart rate, which could be due to sensitization or conditioning. Respiratory abnormalities seem to be common to high AS individuals and PD patients when considering previous findings with this task. Similarly, sensitization or conditioning of anxious and dyspneic symptoms might be common to high AS and clinical anxiety. Respiratory conditionability deserves greater attention in anxiety disorder research.     

Persistence of phencyclidine in fetal brain

Phencyclidine residues were found in the brains of rat pups of mothers dosed with this drug during pregnancy. These levels were significant at times after dosing when maternal levels of phencyclidine in serum or brain were low or undetectable. The persistence of this compound in fetal serum was also not prolonged. Maternal ingestion of PCP for a relatively brief time may result in an extended exposure of the developing nervous system.     

Evaluation of cerebral autoregulation following diffuse brain injury in rats

Abstract

The normal cerebral circulation has the ability to maintain a stable cerebral blood flow over a wide range of cerebral perfusion p(essures and this is known as cerebral autoregulation. This autoregulation may be impaired in the injured brain. Closed head injury was induced in 28 Sprague-Dawley rats weighing 400-450 g. Four groups were studied: control group, head injured rat from meter height using 350 g, 400 g and 450 g respectively. CBF, volume velocity was monitored using laser-Doppler flowmetry together with monitoring of ICP and arterial blood pressure. Correlation to assess the relationship between CBF and CPP was done in each animal every hour. If correlation coefficient was> 0.85 and CPP was within normal range, loss of autoregulation was hypothesized. Chi square test, ANOVA test and unpaired Studen(s t-test were done and significant level of p < 0.05 was established. Mean CBF in injured rats was significantly lower than controls (p = 0.028) at the fifth hour. CBV was lower in the group of 450 g 1 m impact than in controls at 3 h (p = 0.04). Velocity in the group ofall injured rats, was significantly lower than in controls at 3 h (p = 0.032) and at 4 h (p = 0.027). Loss ofautoregulation was seen during first four hours after trauma in all groups of rats who sustained injury. Statistical significant difference (p = 0.041) in loss of autoregulation between injured and control animals was seen. No loss of autoregulation was observed in the control group. In conclusion CBF and CPP provide information about loss of autoregulation in diffuse brain injury. Decrease in CBF and increase of ICP is observed as a result ofloss of cerebral autoregulation. Knowledge of loss of autoregulation could give important information and help in the management of head injured patients. [Neural Res 1997; 19: 393-402]     

Cerebral Blood Flow and CO2 Reactivity in Transient Ischemic Attacks: Comparison between TIAs due to the ICA Occlusion and ICA Mild Stenosis

Hemispheric mean cerebral blood flow (CBF), together with its CO₂ reactivity in response to hyperventilation, was investigated in 18 patients with transient ischemic attacks (TIAs) by intraarterial ₁₃₃Xe injection method in a subacute-chronic stage of the clinical course. In 8 patients, the lesion responsible for symptoms was regarded as unilateral internal carotid artery (ICA) occlusion, and in 10 patients, it was regarded as unilateral ICA mild stenosis <50% stenosis in diameter). Resting flow values were significantly (P < 0.05) decreased in the affected hemisphere of TIA due to the ICA occlusion as compared with the unaffected hemisphere of the same patient, regarded as the relative control. It was not decreased in the affected hemisphere of TIA due to the ICA mild stenosis as compared with the control. With respect to the responsiveness of CBF to changes in Pa_CO2, it was preserved in both TIAs, due to the ICA occlusion and ICA mild stenosis. Vasoparalysis was not observed in either types of TIAs in the subacute-chronic stage. However, in the relationship of blood pressure and CO₂ reactivity, expressed as ΔCBF(%)/ΔPa_CO2, pressure-dependent CO₂ reactivity as a group was observed with significance (P < 0.05) in 8 cases of TIA due to the ICA occlusion, while no such relationship was noted in 10 cases of TIA due to the ICA mild stenosis. Moreover, clinical features were different between TIAs due to the ICA occlusion and ICA mild stenosis, i.e., more typical, repeatable TIA (6.3 ± 3.7 times) with shorter duration (<30 minutes) was observed in TIAs due to the ICA mild stenosis, while more prolonged, less repeatable TIA (2.4 ± 1.4 times) was observed in TIAs due to fixed obstruction of the ICA. From these observations, two different possible mechanisms as to the pathogenesis of TIA might be expected, e.g., TIA of microembolic origin due to the ICA mild stenosis, and TIA of hemodynamic origin due to fixed obstruction of the ICA, for whom the bypass surgery might be beneficial, i.e., all TIAs are not based on the same mechanism.     

Body fluids after CO2 inhalation: Insight into panic mechanisms?

Summary Blood gases and electrolyte fluctuations were studied in arterial blood, after a single 35% CO₂–65% O₂ inhalation, which is known to trigger panic attacks in patients with panic disorder. The immediate effect of this maneuver was a brief hypercapnic acidosis followed by a slight alkalotic rebound, with shifts in Ca²⁺ and K⁺. The possible effect of these changes on neuronal membrane excitability is discussed, referring to recent experimental findings in panic provocation.     

Modified flow- and oxygen-related autoregulation indices for continuous monitoring of cerebral autoregulation

Continuous monitoring of brain tissue partial pressure of oxygen (ptiO₂), thermal-diffusion regional cerebral blood flow (TD-rCBF) and cerebral perfusion pressure (CPP) allows the calculation of flow- and oxygen-related autoregulation indices ORx and FRx. The influence of temporal phase shifts on ORx and FRx due to a delay in the response time of ptiO₂ and TD-rCBF has received little attention. We investigated the impact of phase shifts between changes in CPP and the corresponding ptiO₂ and TD-rCBF responses on the degree of correlation of ORx and FRx. In five patients with aneurysmal subarachnoid hemorrhage continuous multimodal neuromonitoring was performed for 7-10 days. In each patient the phase shift of the ptiO₂- and TD-rCBF-response after spontaneous positive or negative CPP fluctuations during two 1-h time periods of disturbed cerebral autoregulation was determined. For these periods, ORx and FRx were calculated as Pearson correlation coefficients before (ORx and FRx) and after (ORx_sync and FRx_sync) temporal synchronization of ptiO₂, TD-rCBF and CPP. The mean temporal phase shift after CPP fluctuations was 65 ± 11 s for ptiO₂ and 12 ± 4 s for TD-rCBF. Before synchronization, ORx and FRx were determined at 0.52 ± 0.3 and 0.59 ± 0.3, respectively. After synchronization, ORx_sync and FRx_sync correlated significantly stronger than unsynchronized indices (ORx_sync: 0.66 ± 0.3; FRx_sync: 0.62 ± 0.3; p < 0.01 vs. ORx and FRx, respectively). These findings suggest that ORx and FRx are subject to temporal latency shifts of ptiO₂ and TD-rCBF in regard to spontaneous CPP fluctuations. Temporal synchronization for the calculation of both ORx and FRx may permit continuous monitoring of these indices with higher sensitivity.     

The four-dimensional stress test: psychological, sympathetic-adrenal-medullary, parasympathetic and hypothalamic-pituitary-adrenal responses following inhalation of 35% CO2

BACKGROUND: Hypercapnia is a threat to homeostasis and results in neuroendocrine, autonomic and anxiogenic responses. The inhalation of carbon dioxide (CO2) may, therefore, provide a good paradigm for exploring the pathways by which stress can lead to increased susceptibility to ill-health through physiological and psychological stress reactivity. The current study was designed, therefore, to assess the psychological and physiological responses to the inhalation of CO2. METHODS: Healthy participants (N = 24) inhaled a single vital capacity breath of a mixture of CO2 (35%) and oxygen (65%). Blood pressure and heart rate were recorded for 5 min before and after the test and blood and saliva samples were taken immediately before and 2, 10, 20 and 30 min post-inhalation for the measurement of noradrenaline, salivary and serum cortisol and salivary alpha amylase. In addition, psychosomatic symptoms were recorded immediately before and after the test. The same protocol was repeated 4-6 weeks later at the same time of day. RESULTS: A single inhalation of CO2 increased blood pressure, noradrenaline, salivary alpha amylase and psychosomatic symptoms, but decreased heart rate at both testing sessions. Analyses of salivary cortisol data revealed that 70% of the sample could be reliably classified as either responders (i.e. demonstrated a post-CO2 cortisol increase) or non-responders (i.e. responded with a decrease or no change in cortisol following CO2) at both test sessions. Responders also perceived the test to be more aversive than non-responders. CONCLUSIONS: Inhalation of 35% CO2 reliably stimulated the key mechanisms involved in the human stress response. The inter-individual differences in the reactivity of the hypothalamic-pituitary-adrenal axis were also related to differences in the perception of the test.     

Interleukin-2 promotes survival and neurite extension of cultured neurons from fetal rat brain

We investigated the effects of interleukin-2 (IL-2) on the survival and morphology of primary cultured neurons from fetal rat brain. Addition of recombinant human IL-2 significantly supported the survival of brain neurons in high cell density culture, but did not show any effect on the neuronal survival in low cell density culture. In addition, IL-2 significantly promoted the neurite elongation and branching of hippocampal neurons in low cell density culture. These results suggest that IL-2 supports neuronal survival indirectly and promotes neuritogenesis by directly acting on brain neurons.     

Behavioral abnormalities of fetal growth retardation model rats with reduced amounts of brain proteoglycans

Fetal growth retardation (FGR) is a critical problem in the neonatal period, because a substantial population of infants born with FGR go on to develop various developmental disorders. In the present study, we produced FGR model rats by continuous administration of a synthetic thromboxane A₂ analogue (STA₂) to pregnant rats. The FGR pups exhibited a significant delay in postnatal neurological development. Moreover, behavioral analyses revealed the presence of a learning disability in juvenile FGR male rats. To investigate the mechanism underlying the neurological disorders, histological and biochemical analyses of the brain of FGR rats were performed. The density of neurons in the cortical plate of an FGR brain was low compared with the brains of a similarly aged, healthy rat. Consistent with this finding, the density of TUNEL-positive cells was higher in the cortical plate of FGR brains. Western blot analyses showed that the levels of three brain-specific chondroitin sulfate proteoglycans (CSPGs), neurocan, phosphacan, and neuroglycan C, were all significantly reduced in the brain of neonatal FGR rats compared with those of the control. The reduction of CSPG-levels and morphological changes in the brain may be relevant to neurological dysfunction in FGR.     

Total excision of spinal lipomas using CO2 laser at low power. Experimental and clinical observations

Total excision of spinal lipomas (SL) is difficult because of the intimate adhesion between the fibro-adipose tissue and the neural structures. Radical surgery in SL can provoke nervous lesions; therefore many authors recommend only partial excision as a means of decompression. Nevertheless the role of traction or tethering of the spinal cord in all spinal disraphism, including SL, is known to be very important in determining the clinical picture. So partial removal of SL cannot be effective in releasing the tethered cord. The use of a CO₂ laser at low power (3-5 W) permitted radical surgery without any neural damage and complications in 2 adult patients with large, not well capsulated SL. These patients were previously operated on by the same surgeon with conventional microsurgical techniques for partial excision. After CO₂ laser surgery there was significant improvement of the clinical pictures, the follow-up being respectively 24 and 36 months. This clinical experience was performed after a CO₂ laser had successfully been used in an experimental model in rats simulating a condition of SL. Using power of 3-5 W was not sufficient to attain an immediate vaporization, but the adipose tissue first changed into a transparent liquidacross which it was possible to recognize the interfaces between the neural structures and the adipose tissue.     

Correlation between fetal brain activity patterns and behavioral states: an exploratory fetal magnetoencephalography study

The fetal brain remains inaccessible to neurophysiological studies. Magnetoencephalography (MEG) is being assessed to fill this gap. We performed 40 fetal MEG (fMEG) recordings with gestational ages (GA) ranging from 30 to 37 weeks. The data from each recording were divided into 15 second epochs which in turn were classified as continuous (CO), discontinuous (DC), or artifact. The fetal behavioral state, quiet or active sleep, was determined using previously defined criteria based on fetal movements and heart rate variability. We studied the correlation between the fetal state, the GA and the percentage of CO and DC epochs. We also analyzed the spectral edge frequency (SEF) and studied its relation with state and GA. We found that the odds of a DC epoch decreased by 6% per week as the GA increased (P = 0.0036). This decrease was mainly generated by changes during quiet sleep, which showed 52% DC epochs before a 35 week GA versus 38% after 35 weeks (P = 0.0006). Active sleep did not show a significant change in DC epochs with GA. When both states were compared for MEG patterns within each GA group (before and after 35 weeks), the early group was found to have more DC epochs in quiet sleep (54%) compared to active sleep (42%) (P = 0.036). No significant difference in DC epochs between the two states was noted in the late GA group. Analysis of SEF showed a significant difference (P = 0.0014) before and after a 35 week GA, with higher SEF noted at late GA. However, when both quiet and active sleep states were compared within each GA group, the SEF did not show a significant difference. We conclude that fMEG shows reproducible variations in gross features and frequency content, depending on GA and behavioral state. Fetal MEG is a promising tool to investigate fetal brain physiology and maturation.