Rise In Cerebral Blood Flow Research Articles

Changes in cerebral connectivity and brain tissue pulsations with the antidepressant response to an equimolar mixture of oxygen and nitrous oxide: an MRI and ultrasound study.

Nitrous oxide (N2O) has recently emerged as a potential fast-acting antidepressant but the cerebral mechanisms involved in this effect remain speculative. We hypothesized that the antidepressant response to an Equimolar Mixture of Oxygen and Nitrous Oxide (EMONO) would be associated with changes in cerebral connectivity and brain tissue pulsations (BTP). Thirty participants (20 with a major depressive episode resistant to at least one antidepressant and 10 healthy controls-HC, aged 25-50, only females) were exposed to a 1-h single session of EMONO and followed for 1 week. We defined response as a reduction of at least 50% in the MADRS score 1 week after exposure. Cerebral connectivity of the Anterior Cingulate Cortex (ACC), using ROI-based resting state fMRI, and BTP, using ultrasound Tissue Pulsatility Imaging, were compared before and rapidly after exposure (as well as during exposure for BTP) among HC, non-responders and responders. We conducted analyses to compare group × time, group, and time effects. Nine (45%) depressed participants were considered responders and eleven (55%) non-responders. In responders, we observed a significant reduction in the connectivity of the subgenual ACC with the precuneus. Connectivity of the supracallosal ACC with the mid-cingulate also significantly decreased after exposure in HC and in non-responders. BTP significantly increased in the three groups between baseline and gas exposure, but the increase in BTP within the first 10 min was only significant in responders. We found that a single session of EMONO can rapidly modify the functional connectivity in the subgenual ACC-precuneus, nodes within the default mode network, in depressed participants responders to EMONO. In addition, larger increases in BTP, associated with a significant rise in cerebral blood flow, appear to promote the antidepressant response, possibly by facilitating optimal drug delivery to the brain. Our study identified potential cerebral mechanisms related to the antidepressant response of N2O, as well as potential markers for treatment response with this fast-acting antidepressant.

Hypercapnia elicits differential vascular and blood flow responses in the cerebral circulation and active skeletal muscles in exercising humans.

The purpose of this study was to investigate the effects of a rise in arterial carbon dioxide pressure (PaCO2) on vascular and blood flow responses in the cerebral circulation and active skeletal muscles during dynamic exercise in humans. Thirteen healthy young adults (three women) participated in hypercapnia and normocapnia trials. In both trials, participants performed a two‐legged dynamic knee extension exercise at a constant workload that increased heart rate to roughly 100 beats min−1. In the hypercapnia trial, participants performed the exercise with spontaneous breathing while end‐tidal carbon dioxide pressure (PETCO2), an index of PaCO2, was held at 60 mmHg by inhaling hypercapnic gas (O2: 20.3 ± 0.1%; CO2: 6.0 ± 0.5%). In the normocapnia trial, minute ventilation during exercise was matched to the value in the hypercapnia trial by performing voluntary hyperventilation with PETCO2 clamped at baseline level (i.e., 40–45 mmHg) through inhalation of mildly hypercapnic gas (O2: 20.6 ± 0.1%; CO2: 2.7 ± 1.0%). Middle cerebral artery mean blood velocity and the cerebral vascular conductance index were higher in the hypercapnia trial than in the normocapnia trial. By contrast, vascular conductance in the exercising leg was lower in the hypercapnia trial than in the normocapnia trial. Blood flow to the exercising leg did not differ between the two trials. These results demonstrate that hypercapnia‐induced vasomotion in active skeletal muscles is opposite to that in the cerebral circulation. These differential vascular responses may cause a preferential rise in cerebral blood flow.

To Study Acute Changes in Brain Oxygenation on MRI in Healthcare Workers Using N95 Mask and PPE Kits for Six Hours a Day.

Background Due to long working hours wearing an N95 mask and PPE kit during the COVID-19 pandemic, the healthcare workers (HCWs) complained of headaches, confusion, and exhaustion. This study was therefore performed to study the changes in brain oxygenation. Aim To compare brain oxygenation in health care workers wearing an N95 mask with a PPE kit versus a three-ply mask during an intensive care setting for 6 hours. Materials and Methods Thirty clinicians and 30 paramedical staff participated in the study. The control (three-ply mask) and subject (N95 mask with PPE) groups included 15 clinicians and 15 paramedical staff. A comparative analysis of brain oxygenation using a 3T magnetic resonance imaging (MRI) machine was performed in these two groups at the beginning and the end of their work shift. Results The mean age of the individuals in the control and subject groups was 30.8 and 30.13 years, respectively. The median value of brain oxygenation in the control and subject groups in the pre-shift was between 33 and 31 and post-shift was 30 and 24. The drop in brain oxygenation in subjects was more than the controls ( p = 0.004) in the post-shift assessments. The cerebral blood flow (CBF) in the bilateral middle cerebral artery (MCA) using arterial spin labeling (ASL) showed a rise in CBF in both groups post-shift as compared with the pre-shift values. The median values of the right and left MCA in the control and subject groups pre-shift were 82.75/83.45 and 89.75/106.65. The post-shift median values of both MCAs of the control and subject groups were 115.65/115.55 and 109.60/119.49. Conclusion MRI-BOLD imaging revealed a significant drop in brain oxygenation in the subject group as compared with the control group. Multiphasic-ASL showed a compensatory rise in CBF in both groups.

Cerebral Hyperperfusion Syndrome after Carotid Revascularization: A Brief Review

AbstractCerebral hyperperfusion (CHS) syndrome is a relatively rare but potentially devastating event that can complicate carotid endarterectomy and carotid stenting. It is associated with increased cerebral perfusion usually more than 100% from the baseline along with ipsilateral headache, seizures, focal neurological deficits, encephalopathy, intracranial hemorrhage, or subarachnoid hemorrhage. Various risk factors have been identified but most important risk factor is preprocedure evidence of reduced cerebral vasoreactivity with or without contralateral severe carotid stenosis or occlusion. Although diagnosis is suspected in patients with clinical suspicion, it can be radiologically demonstrated with computed tomography (CT), magnetic resonance imaging (MRI), and by dynamic imaging of cerebral perfusion such as transcranial Doppler (TCD), CT, and MR perfusion, and single-photon emission computed tomography (SPECT). Management is usually centered around prompt recognition and active regulation of blood pressure in perioperative and postoperative periods to limit the rise of cerebral blood flow. Prognosis depends on the early detection and prompt management of CHS. If detected early, coupled with intensive blood pressure management, almost all patients will recover over a period of time. For those patients who are diagnosed late and those progressing to intracranial hemorrhage (ICH), the prognosis is not nearly as good.

Abstract 196: Sanguinate (PEGylated-carboxyhemoglobin-bovine) Improves Cerebral Blood Flow and Oxygen Extraction to Vulnerable Brain Regions in Patients at Risk for Delayed Cerebral Ischemia After Subarachnoid Hemorrhage

Introduction: Sanguinate is a dual-action oxygen transfer and carbon monoxide-releasing agent with efficacy in animal models of focal brain ischemia and established safety in health volunteers. We performed a dose-escalation study in subarachnoid hemorrhage (SAH) patients at risk for delayed cerebral ischemia (DCI) to evaluate tolerability and explore efficacy in improving cerebral blood flow (CBF) and flow-metabolism balance to vulnerable brain regions. Methods: 12 subjects were studied over three dose tiers: 160mg/kg, 240 mg/kg, and 320 mg/kg, with close safety evaluation prior to proceeding to higher doses. After baseline 15 O-PET measurement of global and regional CBF and oxygen extraction fraction (OEF), Sanguinate was infused over two hours; PET was repeated immediately after and again at 24-hours. Vulnerable brain regions were defined as those with baseline OEF ≥ 0.5. Results: Sanguinate infusion resulted in a significant but transient rise in mean arterial pressure (115±15 to 127±13 mm Hg) that was not dose-dependent. No adverse physiologic or clinical effects were observed with infusion at any dose. Global CBF did not rise significantly after Sanguinate (42.6±7 to 45.9±9 ml/100g/min, p=0.18). However, in the 28% of regions classified as vulnerable, Sanguinate resulted in a significant rise in CBF (42.2±11 to 51.2±18) and reduction in OEF (0.6±0.1 to 0.5±0.11, both p<0.001). The increase in regional CBF was only seen with the two higher doses but OEF improved in all tiers. However, response was attenuated at 24-hours. Conclusions: We safely administered a novel oxygen transport and vasodilating agent to a cohort of patients with SAH. Sanguinate infusion appeared to improve CBF and flow-metabolism balance in vulnerable brain regions and warrants further study in those at-risk for DCI. Higher or repeat dosing may be required for sustained efficacy.

Electroencephalographic Periodic Discharges and Frequency-Dependent Brain Tissue Hypoxia in Acute Brain Injury

Periodic discharges (PDs) that do not meet seizure criteria, also termed the ictal interictal continuum, are pervasive on electroencephalographic (EEG) recordings after acute brain injury. However, their association with brain homeostasis and the need for clinical intervention remain unknown. To determine whether distinct PD patterns can be identified that, similar to electrographic seizures, cause brain tissue hypoxia, a measure of ongoing brain injury. This prospective cohort study included 90 comatose patients with high-grade spontaneous subarachnoid hemorrhage who underwent continuous surface (scalp) EEG (sEEG) recording and multimodality monitoring, including invasive measurements of intracortical (depth) EEG (dEEG), partial pressure of oxygen in interstitial brain tissue (Pbto2), and regional cerebral blood flow (CBF). Patient data were collected from June 1, 2006, to September 1, 2014, at a single tertiary care center. The retrospective analysis was performed from September 1, 2014, to May 1, 2016, with a hypothesis that the effect on brain tissue oxygenation was primarily dependent on the discharge frequency. Electroencephalographic recordings were visually classified based on PD frequency and spatial distribution of discharges. Correlations between mean multimodality monitoring data and change-point analyses were performed to characterize electrophysiological changes by applying bootstrapping. Of the 90 patients included in the study (26 men and 64 women; mean [SD] age, 55 [15] years), 32 (36%) had PDs on sEEG and dEEG recordings and 21 (23%) on dEEG recordings only. Frequencies of PDs ranged from 0.5 to 2.5 Hz. Median Pbto2 was 23 mm Hg without PDs compared with 16 mm Hg at 2.0 Hz and 14 mm Hg at 2.5 Hz (differences were significant for 0 vs 2.5 Hz based on bootstrapping). Change-point analysis confirmed a temporal association of high-frequency PD onset (≥2.0 Hz) and Pbto2 reduction (median normalized Pbto2 decreased by 25% 5-10 minutes after onset). Increased regional CBF of 21.0 mL/100 g/min for 0 Hz, 25.9 mL/100 g/min for 1.0 Hz, 27.5 mL/100 g/min for 1.5 Hz, and 34.7 mL/100 g/min for 2.0 Hz and increased global cerebral perfusion pressure of 91 mm Hg for 0 Hz, 100.5 mm Hg for 0.5 Hz, 95.5 mm Hg for 1.0 Hz, 97.0 mm Hg for 2.0 Hz, 98.0 mm Hg for 2.5 Hz, 95.0 mm Hg for 2.5 Hz, and 67.8 mm Hg for 3.0 Hz were seen for higher PD frequencies. These data give some support to consider redefining the continuum between seizures and PDs, suggesting that additional damage after acute brain injury may be reflected by frequency changes in electrocerebral recordings. Similar to seizures, cerebral blood flow increases in patients with PDs to compensate for the increased metabolic demand but higher-frequency PDs (>2 per second) may be inadequately compensated without an additional rise in CBF and associated with brain tissue hypoxia, or higher-frequency PDs may reflect inadequacies in brain compensatory mechanisms.

Effects of striatal nitric oxide production on regional cerebral blood flow and seizure development in rats exposed to extreme hyperoxia.

The endogenous vasodilator and signaling molecule nitric oxide has been implicated in cerebral hyperemia, sympathoexcitation, and seizures induced by hyperbaric oxygen (HBO2) at or above 3 atmospheres absolute (ATA). It is unknown whether these events in the onset of central nervous system oxygen toxicity originate within specific brain structures and whether blood flow is diverted to the brain from peripheral organs with high basal flow, such as the kidney. To explore these questions, total and regional cerebral blood flow (CBF) were measured in brain structures of the central autonomic network in anesthetized rats in HBO2 at 6 ATA. Electroencephalogram (EEG) recordings, cardiovascular hemodynamics, and renal blood flow (RBF) were also monitored. As expected, mean arterial blood pressure and total and regional CBF increased preceding EEG spikes while RBF was unaltered. Of the brain structures examined, the earliest rise in CBF occurred in the striatum, suggesting increased neuronal activation. Continuous unilateral or bilateral striatal infusion of the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester attenuated CBF responses in that structure, but global EEG discharges persisted and did not differ from controls. Our novel findings indicate that: 1) cerebral hyperemia in extreme HBO2 in rats does not occur at the expense of renal perfusion, highlighting the remarkable autoregulatory capability of the kidney, and 2) in spite of a sentinel increase in striatal blood flow, additional brain structure(s) likely govern the pathogenesis of HBO2-induced seizures because EEG discharge latency was unchanged by local blockade of striatal nitric oxide production and concomitant hyperemia.

Effect of an Inhibitor of Neuronal Nitric Oxide Synthase 7-Nitroindazole on Cerebral Hemodynamic Response and Brain Excitability in Urethane-Anesthetized Rats

The role of neuronal nitric oxide synthase (nNOS) in the pathophysiology of epilepsy and seizures remains disputable. One of the reasons why results from the acute in vivo studies display controversies might be the effect on the regulation of cerebral blood flow (CBF) during pharmacologically induced alterations of NO system. We examined neurovascular coupling in the rat sensorimotor cortex in response to transcallosal stimulation under nNOS inhibition by 7-nitroindazole (7-NI). Adult Wistar rats were anesthetized with urethane and epidural silver EEG electrodes were implanted over sensorimotor cortices. Regional CBF was measured by Laser Doppler Flowmetry (LDF). We catheterized a common carotid artery to measure arterial blood pressure (BP). 7-NI did not significantly affect blood pressure and heart rate. Electrophysiological recordings of evoked potentials (EPs) revealed no effect on their amplitude, rhythmic potentiation or depression of EPs. Transcallosal stimulation of the contralateral cortex induced a frequency dependent rise in CBF. Although 7-NI did not significantly affect basal CBF and cortical excitability, hemodynamic responses to the transcallosal stimulation were diminished implicating a role of nNOS in neurovascular coupling. Urethane anesthesia is suitable for future epileptological experiments. Our findings demonstrate that NO contributes to the hemodynamic response during brain activation.

Transcranial ultrasound analysis of cerebral blood flow during induced hypertension in acute ischemic stroke - a case series

BackgroundCurrent recommendations of stroke treatment favour a moderately elevated blood pressure in the acute phase, based on the concept of an improved cerebral perfusion. Here, cerebral blood flow was assessed in a case series of patients with acute hemodynamic stroke by means of transcranial colour-coded sonography (TCCS) to study the effects of pharmacologically induced hypertension.FindingsWe investigated six patients with acute hemodynamic stroke and blood pressure-dependent clinical fluctuation of neurological symptoms. TCCS was performed during the initiation phase of catecholamine-induced controlled hypertension. A blood pressure-dependent increase of flow velocity in the ipsilesional middle and the posterior cerebral artery was found in all patients (mean increase 0.80% and 0.65% per mmHg, respectively).ConclusionsCatecholamine-induced hypertension in severe hemodynamic stroke leads to an ultrasound-detectable rise of cerebral blood flow. This finding gives ‘proof-of-principle’ evidence, supporting active blood pressure management in this selected group of stroke patients. Outcome-related questions of target blood pressure, treatment duration or applicability to other forms of stroke, however, remain to be studied. In this, transcranial ultrasound may be a valuable tool for patient selection and subsequent bedside monitoring.

Inhalation versus endovenous sedation in subarachnoid hemorrhage patients

Isoflurane is a volatile anesthetic that has a vasodilating effect on cerebral vessels producing a cerebral blood flow increase. Furthermore, it has been shown in animal studies that isoflurane, when used as a preconditioning agent, has neuroprotective properties, inducing tolerance to ischemia. However, it is not routinely used in neurointensive care because of the potential increase in intracranial pressure caused by the rise in cerebral blood flow. Nevertheless, subarachnoid hemorrhage patients who are at risk for vasospasm may benefit from an increase in cerebral blood flow. We measured regional cerebral blood flow during intravenous sedation with propofol and during sedation with isoflurane in patients with severe subarachnoid hemorrhage not having intracranial hypertension. The study is a crossover, open clinical trial (NCT00830843). Neurointensive care unit of an academic hospital. Thirteen patients with severe subarachnoid hemorrhage, (median Fisher scale 4), monitored on clinical indication with intracranial pressure device and a thermal diffusion probe for the assessment of regional cerebral blood flow. An intracranial pressure>18 mm Hg was an exclusion criterion. Cerebral and hemodynamic variables were assessed at three steps. Step 1: sedation with propofol 3-4 mg/kg/hr; step 2: after 1 hr of propofol discontinuation and isoflurane 0.8%; step 3: after 1 hr of propofol at the same previous infusion rate. Cerebral perfusion pressure and arterial PCO2 were maintained constant. Mean cerebral artery flow velocity and jugular vein oxygen saturation were measured at the end of each step. Regional cerebral blood flow increased significantly during step 2 (39.3±29 mL/100 hg/min) compared to step 1 (20.8±10.7) and step 3 (24.7±8). There was no difference in regional cerebral blood flow comparing step 1 vs. step 3. No significant difference in intracranial pressure, mean cerebral artery transcranial Doppler velocity, PaCO2, cerebral perfusion pressure between the different steps. Isoflurane increases regional cerebral blood flow in comparison to propofol. Intracranial pressure did not change significantly in the population not affected by intracranial hypertension.

Response to the reply of J. Duffin to our letter entitled ‘Acetazolamide and cerebrovascular function at high altitude’

Response to the reply of J. Duffin to our letter entitled ‘Acetazolamide and cerebrovascular function at high altitude’

Free radical signaling in the subfornical organ (SFO) is required for the neurometabolic flow coupling dysfunction induced by angiotensin‐II (AngII) hypertension (HTN)

HTN disrupts cerebral blood vessels and causes stroke and dementia. In particular, HTN alters the coupling of cerebral blood flow (CBF) with brain metabolism. In AngII “slow pressor” HTN, reactive oxygen species (ROS) in the SFO mediate the blood pressure (BP) elevation. We studied whether ROS in the SFO are also required for the cerebrovascular dysfunction. Neocortical CBF was monitored by a laser‐Doppler probe through a cranial window in anesthetized mice (n=5/group). The CBF rise induced by neural activity (whisker stimulation; WS) was tested after infusion of AngII (600ng/kg/min) or vehicle (V) for 14dd. Ang II elevated mean BP from 70±2 to 92±2 mmHg, increased ROS in the SFO (2.3±0.3 folds; p<0.05), and attenuated the CBF response to WS (V: 23±2; AngII: 12±1±%)(p<0.05). Comparable HTN by phenylephrine (PE) did not alter the CBF response (V: 22±1; PE:23±1%). Adenoviral gene transfer of the ROS scavenger CuZn‐superoxide dismutase to the SFO attenuated the AngII‐induced ROS increase in the SFO (1.1±0.5 folds; p>0.05), prevented the HTN (V: 73±4; AngII: 74±2mmHg) and blocked the CBF dysfunction (V: 21±3; AngII:22±1%). We conclude that the dysfunction in flow‐metabolism coupling induced by slow pressor AngII HTN cannot be attributed to the BP elevation, but requires ROS signaling in the SFO. The effect is likely to involve neurohumoral mechanisms linking the SFO to neurovascular coupling (Supported by HL96571).

Cyclosporine A, FK506, and NIM811 ameliorate prolonged CBF reduction and impaired neurovascular coupling after cortical spreading depression.

Cortical spreading depression (CSD) is associated with mitochondrial depolarization, increasing intracellular Ca(2+), and the release of free fatty acids, which favor opening of the mitochondrial permeability transition pore (mPTP) and activation of calcineurin (CaN). Here, we test the hypothesis that cyclosporine A (CsA), which blocks both mPTP and CaN, ameliorates the persistent reduction of cerebral blood flow (CBF), impaired vascular reactivity, and a persistent rise in the cerebral metabolic rate of oxygen (CMRO(2)) following CSD. In addition to CsA, we used the specific mPTP blocker NIM811 and the specific CaN blocker FK506. Cortical spreading depression was induced in rat frontal cortex. Electrocortical activity was recorded by glass microelectrodes, CBF by laser Doppler flowmetry, and tissue oxygen tension with polarographic microelectrodes. Electrocortical activity, basal CBF, CMRO(2), and neurovascular and neurometabolic coupling were unaffected by all three drugs under control conditions. NIM811 augmented the rise in CBF observed during CSD. Cyclosporine A and FK506 ameliorated the persistent decrease in CBF after CSD. All three drugs prevented disruption of neurovascular coupling after CSD; the rise in CMRO(2) was unchanged. Our data suggest that blockade of mPTP formation and CaN activation may prevent persistent CBF reduction and vascular dysfunction after CSD.

Regulation of cerebral blood flow in mammals during chronic hypoxia: a matter of balance

Respiratory-induced changes in the partial pressures of arterial carbon dioxide (PaCO2) and oxygen (PaO2) play a major role in cerebral blood flow (CBF) regulation. Elevations in PaCO2 (hypercapnia) lead to vasodilatation and increases in CBF, whereas reductions in PaCO2 (hypocapnia) lead to vasoconstriction and decreases in CBF. A fall in PaO2 (hypoxia) below a certain threshold (<40-45 mmHg) also produces cerebral vasodilatation. Upon initial exposure to hypoxia, CBF is elevated via a greater relative degree of hypoxia compared with hypocapnia. At this point, hypoxia-induced elevations in blood pressure and loss of cerebral autoregulation, stimulation of neuronal pathways, angiogenesis, release of adenosine, endothelium-derived NO and a variety of autocoids and cytokines are additional factors acting to increase CBF. Following 2-3 days, however, the process of ventilatory acclimatization results in a progressive rise in ventilation, which increases PaO2 and reduces PaCO2, collectively acting to attenuate the initial rise in CBF. Other factors acting to lower CBF include elevations in haematocrit, sympathetic nerve activity and local and endothelium-derived vasoconstrictors. Hypoxia-induced alterations of cerebrovascular reactivity, autoregulation and pulmonary vascular tone may also affect CBF. Thus, the extent of change in CBF during exposure to hypoxia is dependent on the balance between the myriad of vasodilators and constrictors derived from the endothelium, neuronal innervations and perfusion pressure. This review examines the extent and mechanisms by which hypoxia regulates CBF. Particular focus will be given to the marked influence of hypoxia associated with exposure to high altitude and chronic lung disease. The associated implications of these hypoxia-induced integrative alterations for the regulation of CBF are discussed, and future avenues for research are proposed.

Cerebral blood flow and cerebral edema in rats with diabetic ketoacidosis.

OBJECTIVE— Cerebral edema (CE) is a potentially life-threatening complication of diabetic ketoacidosis (DKA) in children. Osmotic fluctuations during DKA treatment have been considered responsible, but recent data instead suggest that cerebral hypoperfusion may be involved and that activation of cerebral ion transporters may occur. Diminished cerebral blood flow (CBF) during DKA, however, has not been previously demonstrated. We investigated CBF and edema formation in a rat model of DKA and determined the effects of bumetanide, an inhibitor of Na-K-Cl cotransport.RESEARCH DESIGN AND METHODS— Juvenile rats with streptozotocin-induced DKA were treated with intravenous saline and insulin, similar to human treatment protocols. CBF was determined by magnetic resonance (MR) perfusion–weighted imaging before and during treatment, and CE was assessed by determining apparent diffusion coefficients (ADCs) using MR diffusion–weighted imaging.RESULTS— CBF was significantly reduced in DKA and was responsive to alterations in pCO2. ADC values were reduced, consistent with cell swelling. The reduction in ADCs correlated with dehydration, as reflected in blood urea nitrogen concentrations. Bumetanide caused a rapid rise in ADCs of DKA rats without significantly changing CBF, while saline/insulin caused a rapid rise in CBF and a gradual rise in ADCs. DKA rats treated with bumetanide plus saline/insulin showed a trend toward more rapid rise in cortical ADCs and a larger rise in striatal CBF than those observed with saline/insulin alone.CONCLUSIONS— These data demonstrate that CE in DKA is accompanied by cerebral hypoperfusion before treatment and suggest that blocking Na-K-Cl cotransport may reduce cerebral cell swelling.

Activity-induced tissue oxygenation changes in rat cerebellar cortex: interplay of postsynaptic activation and blood flow.

Functional neuroimaging relies on the robust coupling between neuronal activity, metabolism and cerebral blood flow (CBF), but the physiological basis of the neuroimaging signals is still poorly understood. We examined the mechanisms of activity-dependent changes in tissue oxygenation in relation to variations in CBF responses and postsynaptic activity in rat cerebellar cortex. To increase synaptic activity we stimulated the monosynaptic, glutamatergic climbing fibres that excite Purkinje cells via AMPA receptors. We used local field potentials to indicate synaptic activity, and recorded tissue oxygen partial pressure (P(tiss,O2)) by polarographic microelectrodes, and CBF using laser-Doppler flowmetry. The disappearance rate of oxygen in the tissue increased linearly with synaptic activity. This indicated that, without a threshold, oxygen consumption increased as a linear function of synaptic activity. The reduction in P(tiss,O2) preceded the rise in CBF. The time integral (area) of the negative P(tiss,O2) response increased non-linearly showing saturation at high levels of synaptic activity, concomitant with a steep rise in CBF. This was accompanied by a positive change in P(tiss,O2). Neuronal nitric oxide synthase inhibition enhanced the initial negative P(tiss,O2) response ('dip'), while attenuating the evoked CBF increase and positive P(tiss,O2) response equally. This indicates that increases in CBF counteract activity-induced reductions in P(tiss,O2), and suggests the presence of a tissue oxygen reserve. The changes in P(tiss,O2) and CBF were strongly attenuated by AMPA receptor blockade. Our findings suggest an inverse relationship between negative P(tiss,O2) and CBF responses, and provide direct in vivo evidence for a tight coupling between activity in postsynaptic AMPA receptors and cerebellar oxygen consumption.

Cerebral Blood Flow in Acute Liver Failure: A Finding in Search of a Mechanism

In the last few years, several abnormalities of cerebral blood flow (CBF), namely loss of cerebral autoregulation, altered reactivity to carbon dioxide, and development of cerebral hyperemia, have been described in patients as well as experimental models of acute liver failure (ALF) and/or hyperammonemia. The development of cerebral hyperemia seems particularly relevant to the pathogenesis of brain edema in ALF. In addition to the potential increase of brain blood volume causing a rise in intracranial pressure, an increase of CBF could facilitate the movement of water across the blood brain barrier in an osmotically altered brain. Because maneuvers that abrogate the rise of CBF have been shown to prevent or ameliorate brain edema in ALF/hyperammonemia, elucidation of the mechanism by which the rise of CBF occurs is important. In the rat after portacaval anastomosis receiving an ammonia infusion, the signal resulting in cerebral hyperemia arises within the brain once maximal glutamine accumulation has occurred in astrocytes. Several mediators potentially involved in the development of cerebral hyperemia in ALF are examined in this review, but further work is needed to assess the role, if any, of each of them.

Vasopressin accelerates experimental ammonia-induced brain edema in rats after portacaval anastomosis

Background/Aims: Cerebral hyperemia is an important contributor to the development of brain edema in fulminant hepatic failure. Rats receiving an ammonia infusion after portacaval anastomosis (PCA) demonstrate a rise in cerebral blood flow (CBF) with brain edema at 180 min. Vasopressin (VP), a systemic vasoconstrictor which in the rat dilates cerebral vessels through V 2 receptors, was used to ascertain the effects of increasing CBF. Methods: Changes in CBF were measured with Laser Doppler flowmetry (LDF). Absolute CBF was measured with radioactive microspheres to calculate oxygen and ammonia uptake. Results: Compared to the NH 3+Vehicle group, VP+NH 3 infusion accelerated the rise in CBF (117±21 vs. −6±12%, P<0.01), and the development of brain edema (81.09±0.17 vs. 80.29±0.06%, P<0.01). Radioactive microspheres confirmed these results (254±44 vs. 106±9.5 ml/min/100 g, P<0.01). Oxygen uptake was similar. Ammonia uptake was more than twofold higher in the VP+NH 3 group. A V 1 antagonist negated the higher mean arterial pressure (MAP) that occurs with VP but cerebral hyperemia still occurred. A V 2 antagonist resulted in similar systemic pressures, CBF and brain water compared to the VP+NH 3 group. Conclusions: In this model, an increase in CBF with VP hastens the development of brain edema while increasing ammonia delivery to the brain.

Coupling and uncoupling of activity-dependent increases of neuronal activity and blood flow in rat somatosensory cortex.

1. Electrical stimulation of the infraorbital nerve was used to examine the coupling between neuronal activity and cerebral blood flow (CBF) in rat somatosensory cortex by laser Doppler flowmetry and extracellular recordings of field potentials. 2. The relationship between field potential (FP) and CBF amplitudes was examined as a function of the stimulus intensity (0--2.0 mA) at fixed frequency (3 Hz). FP amplitudes up to 2.0-2.5 mV were unaccompanied by increases of CBF. Above this threshold, CBF and FP amplitudes increased proportionally. 3. At fixed stimulus intensity of 1.5 mA, CBF increases were highly correlated to FP amplitudes at low frequencies of stimulation (< 2 Hz), but uncoupling was observed at stimulation frequencies of 2--5 Hz. The evoked responses were independent of stimulus duration (8--32 s). 4. The first rise in CBF occurred within the first 0.2 s after onset of stimulation in the upper 0--250 microm of the cortex. Latencies were longer (1.0--1.2 s) in lower cortical layers in which CBF and FP amplitudes were larger. 5. Local AMPA receptor blockade attenuated CBF and FP amplitudes proportionally. 6. This study showed that activity-dependent increases in neuronal activity and CBF were linearly coupled under defined conditions, but neuronal activity was well developed before CBF started to increase. Consequently, the absence of a rise in CBF does not exclude the presence of significant neuronal activity. The CBF increase in upper cortical layers preceded the rise in lower layers suggesting that vessels close to or at the brain surface are the first to react to neuronal activity. The activity-dependent rise in CBF was explained by postsynaptic activity in glutamatergic neurons.

Cerebral hyperemia and nitric oxide synthase in rats with ammonia-induced brain edema

Background/Aim : Brain edema is a common fatal complication in acute liver failure. It is related to an acute change in brain osmolarity secondary to the glial accumulation of glutamine. Since high cerebral blood flow (CBF) precedes cerebral herniation in fulminant hepatic failure we first determined if an increase in brain water and glutamine are prerequisite to a rise in CBF in a model of ammonia-induced brain edema. Secondly, we determined if such a cerebral hyperperfusion is mediated by nitric oxide synthase (NOS). Methods : Male rats received an end-to-side portacaval anastomosis (PCA). At 24 h, they were anesthetized with ketamine and infused with ammonium acetate (55 μM/kg per min). Studies were performed at 60, 90, 120, 150 and 180 min after starting the ammonia infusion and once the intracranial pressure had risen three-fold (mean 210′). Brain water (BW) was measured using the gravimetry method and CBF with the radioactive microsphere technique. Glutamine (GLN) in the CSF was sampled via a cisterna magna catheter. The neuronal NOS was specifically inhibited by 1-2-trifluoromethylphenyl imidazole (TRIM, 50 mg/kg intraperitoneally) and in separate studies nonspecifically by N -omega-nitro- l -arginine ( l -NNA, 2 μg/kg per min intravenously) Results : At 90′, brain water was significantly increased ( P <0.015) as compared to the 60′ group while CBF was significantly different at 150′. A significant correlation was observed between values of CBF and brain water ( r =0.88, n =36, P <0.001). Administration of either TRIM or l -NNA did not prevent the development of cerebral hyperperfusion and edema. Conclusion : We observed that cerebral hyperemia follows an initial rise in brain water content, rather than in the cerebrospinal fluid concentration of glutamine. The rise in CBF further correlated with brain water accumulation and was of critical importance for the development of intracranial hypertension. The unique mechanism for the rise in CBF in hyperammonemia was not prevented by NOS inhibition indicating that NO is not the mediator of high CBF and intracranial hypertension.