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1.  Dynamic Tracking of Acute Ischemic Tissue Fates Using Improved Unsupervised ISODATA Analysis of High-Resolution Quantitative Perfusion and Diffusion Data 
Summary
High-resolution (200 × 200 × 1,500 (μm3) imaging was performed to derive quantitative cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) maps in stroke rats (permanent occlusion) every 30 minutes up to 3 hours after occlusion onset, followed by histology at 24 hours. An improved automated iterative-self-organizing-data-analysis-algorithm (ISODATA) was developed to dynamically track ischemic tissue fate on a pixel-by-pixel basis during the acute phase. ISODATA-resolved clusters were overlaid on the CBF-ADC scatterplots and image spaces. Tissue volume ADC, and CBF of each ISODATA cluster were derived. In contrast to the single-cluster normal left hemisphere (ADC = 0.74 ± 0.02 × 10−3 mm2/s, CBF = 1.36 ± 0.22 mL g−1min−1, mean ± SD, n = 8), the right ischemic hemisphere exhibited three ISODATA clusters, namely: “normal” (normal ADC and CBF), “ischemic core” (low CBF and ADC), and at-risk “perfusion-diffusion mismatch” (low CBF but normal ADC). At 180 minutes, the mismatch disappeared in five rats (Group I, 180-minute “core” lesion volume = 255 ± 62 mm3 and 24-hour infarct volume = 253 ± 55 mm3, P > 0.05), while a substantial mismatch persisted in three rats (Group II, 180-minute CBF-abnormal volume = 198 ± 7 mm3 and 24-hour infarct volume 148 ± 18 mm3, P < 0.05). The CBF (0.3 ± 0.09 mL g−1min−1) of the “persistent mismatch” (Group II, 0.3 ± 0.09 mL g−1 min−1) was above the CBF viability threshold (0.2 to 0.3 mL g−1min−1) throughout and its ADC (0.70 ± 0.03 × 10−3 mm2/s) did not decrease as ischemia progressed. In contrast, the CBF (0.08 ± 0.03 mL g−1min−1) of the analogous brain region in Group I was below the CBF viability threshold, and its ADC gradually decreased from 0.63 ± 0.05 to 0.43 ± 0.03 × 10−3 mm2/s (ADC viability threshold = 0.53 ± 0.02 × 10−3 mm2/s). The modified ISODATA analysis of the ADC and CBF tissue characteristics during the acute phase could provide a useful and unbiased means to characterize and predict tissue fates in ischemic brain injury and to monitor therapeutic intervention.
PMCID: PMC2962944  PMID: 15362719
Viability thresholds; Penumbra; Perfusion-diffusion mismatch; Diffusion-weighted imaging; Perfusion-weighted imaging; Multispectral analysis
2.  Noninvasive Optical Measurement of Cerebral Blood Flow in Mice Using Molecular Dynamics Analysis of Indocyanine Green 
PLoS ONE  2012;7(10):e48383.
In preclinical studies of ischemic brain disorders, it is crucial to measure cerebral blood flow (CBF); however, this requires radiological techniques with heavy instrumentation or invasive procedures. Here, we propose a noninvasive and easy-to-use optical imaging technique for measuring CBF in experimental small animals. Mice were injected with indocyanine green (ICG) via tail-vein catheterization. Time-series near-infrared fluorescence signals excited by 760 nm light-emitting diodes were imaged overhead by a charge-coupled device coupled with an 830 nm bandpass-filter. We calculated four CBF parameters including arrival time, rising time and mean transit time of a bolus and blood flow index based on time and intensity information of ICG fluorescence dynamics. CBF maps were generated using the parameters to estimate the status of CBF, and they dominantly represented intracerebral blood flows in mice even in the presence of an intact skull and scalp. We demonstrated that this noninvasive optical imaging technique successfully detected reduced local CBF during middle cerebral artery occlusion. We further showed that the proposed method is sufficiently sensitive to detect the differences between CBF status in mice anesthetized with either isoflurane or ketamine–xylazine, and monitor the dynamic changes in CBF after reperfusion during transient middle cerebral artery occlusion. The near-infrared optical imaging of ICG fluorescence combined with a time-series analysis of the molecular dynamics can be a useful noninvasive tool for preclinical studies of brain ischemia.
doi:10.1371/journal.pone.0048383
PMCID: PMC3485229  PMID: 23119000
3.  Phenylephrine-Induced Hypertension during Transient Middle Cerebral Artery Occlusion Alleviates Ischemic Brain Injury in Spontaneously Hypertensive Rats 
Brain research  2012;1477:83-91.
Arterial hypertension is a major risk factor for ischemic stroke. However, the management of preexisting hypertension is still controversial in the treatment of acute stroke in hypertensive patients. The present study evaluates the influence of preserving hypertension during focal cerebral ischemia on stroke outcome in a rat model of chronic hypertension, the spontaneously hypertensive rats (SHR). Focal cerebral ischemia was induced by transient (1-hour) occlusion of the middle cerebral artery, during which mean arterial blood pressure was maintained at normotension (110-120 mmHg, group 1, n=6) or hypertension (160-170 mmHg, group 2, n=6) using phenylephrine. T2-, diffusion- and perfusion-weighted MRI were performed serially at five different time points: before and during ischemia, and at 1, 4 and 7 days after ischemia. Lesion volume and brain edema were estimated from apparent diffusion coefficient maps and T2-weighted images. Regional cerebral blood flow (rCBF) was measured within and outside the perfusion deficient lesion and in the corresponding regions of the contralesional hemisphere. Neurological deficits were evaluated after reperfusion. Infarct volume, edema, and neurological deficits were significantly reduced in group 2 versus group 1. In addition, higher values and rapid restoration of rCBF were observed in group 2, while rCBF in both hemispheres was significantly decreased in group 1. Maintaining preexisting hypertension alleviates ischemic brain injury in SHR by increasing collateral circulation to the ischemic region and allowing rapid restoration of rCBF. The data suggest that maintaining preexisting hypertension is a valuable approach to managing hypertensive patients suffering from acute ischemic stroke.
doi:10.1016/j.brainres.2012.08.024
PMCID: PMC3456967  PMID: 22954904
arterial spin labeling; cerebral blood flow; hypertension; ischemic stroke; magnetic resonance imaging; spontaneously hypertensive rats
4.  Comparison of oxygen-15 PET and transcranial Doppler CO2-reactivity measurements in identifying haemodynamic compromise in patients with symptomatic occlusion of the internal carotid artery 
EJNMMI Research  2012;2:30.
Background
Transcranial Doppler (TCD) CO2-reactivity and oxygen-15 positron emission tomography (PET) have both been used to measure the cerebral haemodynamic state in patients who may have a compromised blood flow. Our purpose was to investigate whether PET and TCD identify the same patients with an impaired flow state of the brain in patients with internal carotid artery (ICA) occlusion.
Methods
Patients with recent transient ischaemic attack or minor ischaemic stroke associated with ICA occlusion underwent TCD with measurement of CO2-reactivity and oxygen-15 PET within a median time interval of 6 days.
Results
We included 24 patients (mean age 64 ± 10 years). Seventeen (71%) patients had impaired CO2-reactivity (≤20%), of whom six had absent reactivity (0%) or steal (<0%) in the hemisphere ipsilateral to the ICA occlusion. PET of the perfusion state of the hemisphere ipsilateral to the ICA occlusion demonstrated stage 1 haemodynamic compromise (decreased cerebral blood flow (CBF) or increased cerebral blood volume (CBV) without increased oxygen extraction fraction (OEF)) in 13 patients and stage 2 (increased OEF) in 2 patients. In 12 patients (50%), there was agreement between TCD and PET, indicating haemodynamic compromise in 10 and a normal flow state of the brain in 2 patients. There was no significant correlation between CO2-reactivity and CBF ipsilateral/contralateral hemispheric ratio (r = 0.168, p value = 0.432), OEF ratio (r = −0.242, p value = 0.255), or CBV/CBF ratio (r = −0.368, p value = 0.077).
Conclusions
In patients with symptomatic ICA occlusion, identification of an impaired flow state of the brain by PET and TCD CO2-reactivity shows concordance in only half of the patients.
doi:10.1186/2191-219X-2-30
PMCID: PMC3444322  PMID: 22682265
carotid artery disease; haemodynamic; PET; transcranial Doppler; stroke
5.  Fenofibrate improves cerebral blood flow after middle cerebral artery occlusion in mice 
Fibrates, one group of peroxisome proliferator-activated receptor (PPAR) activators, are lipid lowering drugs. Fibrates have been shown to attenuate brain tissue injury after focal cerebral ischemia. In this study, we investigated the impact of fenofibrate on cerebral blood flow (CBF) in male wild-type and PPARα-null mice. Animals were treated for 7 days with fenofibrate and subjected to 2 h of filamentous middle cerebral artery occlusion (MCAO) and reperfusion under isoflurane anesthesia. Cortical surface CBF was measured by laser speckle imaging. Regional CBF (rCBF) in non-ischemic animals was measured by 14C-iodoantipyrine autoradiography. Fenofibrate did not affect rCBF and mean arterial blood pressure in non-ischemic animals. In ischemic animals, laser speckle imaging showed delayed expansions of ischemic area, which was attenuated by fenofibrate. Fenofibrate also enhanced CBF recovery after reperfusion. However, such effects of fenofibrate on CBF in the ischemic brain were not observed in PPARα-null mice. These findings show that fenofibrate improves CBF in the ischemic hemisphere. Moreover, fenofibrate requires PPARα expression for the cerebrovascular protective effects in the ischemic brain.
doi:10.1038/jcbfm.2009.185
PMCID: PMC2801771  PMID: 19724288
neuroprotection; nuclear receptors; fibrate; PPAR; eNOS; autoradiography; cerebral ischemia
6.  Fenofibrate improves cerebral blood flow after middle cerebral artery occlusion in mice 
Fibrates, one group of peroxisome proliferator-activated receptor (PPAR) activators, are lipid lowering drugs. Fibrates have been shown to attenuate brain tissue injury after focal cerebral ischemia. In this study, we investigated the impact of fenofibrate on cerebral blood flow (CBF) in male wild type and PPARα-null mice. Animals were treated for 7 days with fenofibrate and subjected to 2 h of filamentous middle cerebral artery occlusion and reperfusion under isoflurane anesthesia. Cortical surface CBF was measured by laser speckle imaging. Regional CBF (rCBF) in nonischemic animals was measured by 14C-iodoantipyrine autoradiography. Fenofibrate did not affect rCBF and mean arterial blood pressure in nonischemic animals. In ischemic animals, laser speckle imaging showed delayed expansions of ischemic area, which was attenuated by fenofibrate. Fenofibrate also enhanced CBF recovery after reperfusion. However, such effects of fenofibrate on CBF in the ischemic brain were not observed in PPARα-null mice. These findings show that fenofibrate improves CBF in the ischemic hemisphere. Moreover, fenofibrate requires PPARα expression for the cerebrovascular protective effects in the ischemic brain.
doi:10.1038/jcbfm.2009.185
PMCID: PMC2801771  PMID: 19724288
autoradiography; cerebral ischemia; eNOS; fibrate; nuclear receptors; neuroprotection
7.  Sustained Reperfusion after Blockade of Glycoprotein-Receptor-Ib in Focal Cerebral Ischemia: An MRI Study at 17.6 Tesla 
PLoS ONE  2011;6(4):e18386.
Background
Inhibition of early platelet adhesion by blockade of glycoprotein-IB (GPIb) protects mice from ischemic stroke. To elucidate underlying mechanisms in-vivo, infarct development was followed by ultra-high field MRI at 17.6 Tesla.
Methods
Cerebral infarction was induced by transient-middle-cerebral-artery-occlusion (tMCAO) for 1 hour in C57/BL6 control mice (N = 10) and mice treated with 100 µg Fab-fragments of the GPIb blocking antibody p0p/B 1 h after tMCAO (N = 10). To control for the effect of reperfusion, additional mice underwent permanent occlusion and received anti-GPIb treatment (N = 6; pMCAO) or remained without treatment (N = 3; pMCAO). MRI 2 h and 24 h after MCAO measured cerebral-blood-flow (CBF) by continuous arterial-spin labelling, the apparent-diffusion-coefficient (ADC), quantitative-T2 and T2-weighted imaging. All images were registered to a standard mouse brain MRI atlas and statistically analysed voxel-wise, and by cortico-subcortical ROI analysis.
Results
Anti-GPIb treatment led to a relative increase of postischemic CBF vs. controls in the cortical territory of the MCA (2 h: 44.2±6.9 ml/100 g/min versus 24 h: 60.5±8.4; p = 0.0012, F(1,18) = 14.63) after tMCAO. Subcortical CBF 2 h after tMCAO was higher in anti-GPIb treated animals (45.3±5.9 vs. controls: 33.6±4.3; p = 0.04). In both regions, CBF findings were clearly related to a lower probability of infarction (Cortex/Subcortex of treated group: 35%/65% vs. controls: 95%/100%) and improved quantitative-T2 and ADC. After pMCAO, anti-GPIb treated mice developed similar infarcts preceded by severe irreversible hypoperfusion as controls after tMCAO indicating dependency of stroke protection on reperfusion.
Conclusion
Blockade of platelet adhesion by anti-GPIb-Fab-fragments results in substantially improved CBF early during reperfusion. This finding was in exact spatial correspondence with the prevention of cerebral infarction and indicates in-vivo an increased patency of the microcirculation. Thus, progression of infarction during early ischemia and reperfusion can be mitigated by anti-platelet treatment.
doi:10.1371/journal.pone.0018386
PMCID: PMC3069968  PMID: 21483769
8.  Intracerebral Hemorrhage after Carotid Artery Stenting without Evidence of Hyperperfusion in Positron Emission Tomography 
Interventional Neuroradiology  2007;13(2):191-199.
Summary
A 75-year-old man with a recent history of transient left hemiparesis and dysarthria was referred to our hospital. Angiography showed right internal carotid artery (ICA) occlusion and left ICA 89% stenosis. Positron emission tomography (PET) showed decreased cerebral blood flow (CBF), and increased oxygen extraction fraction (OEF) and cerebral blood volume (CBV) in the right hemisphere.
In the left hemisphere, CBV was increased, but CBF and OEF remained normal. One month after the transient ischemic attack, left carotid artery stenting (CAS) was performed without complications. Diffusion-weighted magnetic resonance imaging (MRI) on the day after CAS showed no fresh ischemic lesion. PET on the second day after CAS showed increased CBF and decreased OEF and CBV in the right hemisphere as compared with those before CAS. In the left hemisphere, decreased CBV was observed and CBF was slightly increased as compared with those before CAS.
The postoperative course was uneventful, but on the fifth day after CAS, the patient suddenly showed a focal seizure and right motor weakness. Emergency computed tomography scanning showed massive intracranial hemorrhage with severe brain edema in the left hemisphere. Although CBF study is useful to predict the hyperperfusion syndrome, we cannot disregard the possibility of intracerebral hemorrhage after CAS for carotid artery stenosis when there is no evidence of hyperperfusion on postoperative CBF study.
PMCID: PMC3345483  PMID: 20566149
hyperperfusion, carotid artery stenting, positron emission tomography
9.  Dehydration affects cerebral blood flow but not its metabolic rate for oxygen during maximal exercise in trained humans 
The Journal of Physiology  2014;592(Pt 14):3143-3160.
Intense exercise is associated with a reduction in cerebral blood flow (CBF), but regulation of CBF during strenuous exercise in the heat with dehydration is unclear. We assessed internal (ICA) and common carotid artery (CCA) haemodynamics (indicative of CBF and extra-cranial blood flow), middle cerebral artery velocity (MCA Vmean), arterial–venous differences and blood temperature in 10 trained males during incremental cycling to exhaustion in the heat (35°C) in control, dehydrated and rehydrated states. Dehydration reduced body mass (75.8 ± 3 vs. 78.2 ± 3 kg), increased internal temperature (38.3 ± 0.1 vs. 36.8 ± 0.1°C), impaired exercise capacity (269 ± 11 vs. 336 ± 14 W), and lowered ICA and MCA Vmean by 12–23% without compromising CCA blood flow. During euhydrated incremental exercise on a separate day, however, exercise capacity and ICA, MCA Vmean and CCA dynamics were preserved. The fast decline in cerebral perfusion with dehydration was accompanied by increased O2 extraction (P < 0.05), resulting in a maintained cerebral metabolic rate for oxygen (CMRO2). In all conditions, reductions in ICA and MCA Vmean were associated with declining cerebral vascular conductance, increasing jugular venous noradrenaline, and falling arterial carbon dioxide tension () (R2 ≥ 0.41, P ≤ 0.01) whereas CCA flow and conductance were related to elevated blood temperature. In conclusion, dehydration accelerated the decline in CBF by decreasing and enhancing vasoconstrictor activity. However, the circulatory strain on the human brain during maximal exercise does not compromise CMRO2 because of compensatory increases in O2 extraction.
doi:10.1113/jphysiol.2014.272104
PMCID: PMC4214665  PMID: 24835170
10.  Dehydration affects cerebral blood flow but not its metabolic rate for oxygen during maximal exercise in trained humans 
The Journal of Physiology  2014;592(14):3143-3160.
Intense exercise is associated with a reduction in cerebral blood flow (CBF), but regulation of CBF during strenuous exercise in the heat with dehydration is unclear. We assessed internal (ICA) and common carotid artery (CCA) haemodynamics (indicative of CBF and extra-cranial blood flow), middle cerebral artery velocity (MCA Vmean), arterial–venous differences and blood temperature in 10 trained males during incremental cycling to exhaustion in the heat (35°C) in control, dehydrated and rehydrated states. Dehydration reduced body mass (75.8 ± 3 vs. 78.2 ± 3 kg), increased internal temperature (38.3 ± 0.1 vs. 36.8 ± 0.1°C), impaired exercise capacity (269 ± 11 vs. 336 ± 14 W), and lowered ICA and MCA Vmean by 12–23% without compromising CCA blood flow. During euhydrated incremental exercise on a separate day, however, exercise capacity and ICA, MCA Vmean and CCA dynamics were preserved. The fast decline in cerebral perfusion with dehydration was accompanied by increased O2 extraction (P < 0.05), resulting in a maintained cerebral metabolic rate for oxygen (CMRO2). In all conditions, reductions in ICA and MCA Vmean were associated with declining cerebral vascular conductance, increasing jugular venous noradrenaline, and falling arterial carbon dioxide tension () (R2 ≥ 0.41, P ≤ 0.01) whereas CCA flow and conductance were related to elevated blood temperature. In conclusion, dehydration accelerated the decline in CBF by decreasing and enhancing vasoconstrictor activity. However, the circulatory strain on the human brain during maximal exercise does not compromise CMRO2 because of compensatory increases in O2 extraction.
doi:10.1113/jphysiol.2014.272104
PMCID: PMC4214665  PMID: 24835170
11.  Acute treatment with rosuvastatin protects insulin resistant (C57BL/6J ob/ob) mice against transient cerebral ischemia 
The purpose of this study was to investigate the short-term effects of rosuvastatin (RSV), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on transient, focal cerebral ischemia in C57BL/6J ob/ob mice with insulin resistance (IR). Male ob/ob, lean, or wild-type (WT) mice were treated with RSV (10 mg/kg per day, i.p.) or vehicle for 3 days. Ischemia was induced by 60 mins of middle cerebral artery occlusion (MCAO) and cortical blood flow (CBF) was monitored by laser-Doppler flowmetry. Infarct volumes were measured 24 h after reperfusion. IR mice exhibited a higher infarct volume compared with Lean or WT mice, and RSV reduced infarct volume only in obese mice (40%±3% versus 32%±3%, P < 0.05). Blood cholesterol and insulin levels were elevated in ob/ob mice but were unaffected by RSV. The CBF reductions during MCAO were similar in all groups and were not affected by RSV. Although RSV did not increase cortical endothelial NO synthase (eNOS) levels in the ob/ob mice, it attenuated the increased cortical expression of intracellular adhesion molecule-1 (ICAM-1) after MCAO from ob/ob mice. Thus, RSV protects against stroke in IR mice by a mechanism independent of effects on the lipid profile, CBF, or eNOS but dependent on suppression of post-MCAO ICAM-1 expression.
doi:10.1038/jcbfm.2008.81
PMCID: PMC2632795  PMID: 18665182
middle cerebral artery occlusion; cerebral circulation; endothelial nitric oxide synthase; ICAM-1; statins; strokes
12.  Statistical prediction of tissue fate in acute ischemic brain injury 
An algorithm was developed to statistically predict ischemic tissue fate on a pixel-by-pixel basis. Quantitative high-resolution (200 × 200 µm) cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) were measured on acute stroke rats subjected to permanent middle cerebral artery occlusion and an automated clustering (ISODATA) technique was used to classify ischemic tissue types. Probability and probability density profiles were derived from a training data set (n = 6) and probability maps of risk of subsequent infarction were computed in another group of animals (n = 6) as ischemia progressed. Predictions were applied to overall tissue fate. Performance measures (sensitivity, specificity, and receiver operating characteristic) showed that prediction made based on combined ADC + CBF data outperformed those based on ADC or CBF data alone. At the optimal operating points, combined ADC + CBF predicted tissue infarction with 86%±4% sensitivity and 89%±6% specificity. More importantly, probability of infarct (PI) for different ISODATA-derived ischemic tissue types were also computed: (1) For the ‘normal’ cluster in the ischemic right hemisphere, PI based on combined ADC + CBF data (PI[ADC + CBF]) accurately reflected tissue fate, whereas PI[ADC] and PI[CBF] overestimated infarct probability. (2) For the ‘perfusion–diffusion mismatch’ cluster, PI[ADC + CBF] accurately predicted tissue fate, whereas PI[ADC] underestimated and PI[CBF] overestimated infarct probability. (3) For the core cluster, PI[ADC + CBF], PI[ADC], and PI[CBF] prediction were high and similar (~90%). This study shows an algorithm to statistically predict overall, normal, ischemic core, and ‘penumbral’ tissue fate using early quantitative perfusion and diffusion information. It is suggested that this approach can be applied to stroke patients in a computationally inexpensive manner.
doi:10.1038/sj.jcbfm.9600126
PMCID: PMC2949953  PMID: 15829912
DWI; multispectral analysis; penumbra; perfusion–diffusion mismatch; PWI; viability thresholds
13.  Effects of Reperfusion on ADC and CBF Pixel-by-Pixel Dynamics in Stroke: Characterizing Tissue Fates using Quantitative Diffusion and Perfusion Imaging 
Summary
The effects of reperfusion on the spatiotemporal dynamics of transient (60 minutes) focal ischemic brain injury in rats were evaluated on a pixel-by-pixel basis using quantitative cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) measurements every 30 minutes for 3 hours and compared to post-mortem histology at 24 hours. Four biologically relevant clusters were classified based on ADC (0.53 ± 0.02 × 10−3mm2/s, SD) and CBF (0.30 ± 0.09ml/g/min) viability thresholds, namely: (1) the “normal” cluster with ADC and CBF > thresholds; (2) the “mismatch” cluster with ADC > threshold but CBF < threshold; (3) the “core” cluster with ADC and CBF < thresholds; and (4) “non-nourishing reperfusion zone” where ADC < threshold but CBF > threshold. The spatio-temporal progression of tissue volumes, ADC and CBF of each cluster were evaluated. Pixels of each cluster on the CBF-ADC space were mapped onto the image space. Following reperfusion, 28% of the “core” pixels and 90% of the “mismatch” (defined at 60 minutes) pixels were salvaged at 180 minutes, which correlated with histology. The ADC and CBF of subsequently salvaged tissues were significantly higher than those became infarcted. Salvaging “core” pixels indicated that reduced ADC was not synonymous with irreversible injury; duration of exposure and severity of reduced ADC and CBF were likely critical. Projection profiles showed a bimodal ADC, but uni-modal CBF, distributions. The ADC bimodal minima, obtained without histological correlation, were similar to the histology-derived ADC and CBF viability thresholds, and could have potential clinical applications. This study demonstrated a simple but powerful approach to evaluate, on a pixel-by-pixel basis, the spatio-temporal evolution of ischemic brain injury, and a potential for statistical prediction of tissue fate.
PMCID: PMC2962955  PMID: 15091108
Penumbra; Oligemia; Viability thresholds; Hyperemia; Perfusion-diffusion mismatch; Stroke; DWI; PWI
14.  A Novel Mouse Model of Ischemic Carotid Artery Disease 
PLoS ONE  2014;9(6):e100257.
Background
Carotid artery occlusive disease gradually develops over time, eventually leading to cerebral infarction and high mortality rate. Animal models replicating cerebral infarction resulting from carotid artery occlusive disease have thus been developed to test potential novel treatments, which could be subsequently administered clinically.
Methods
Adult C57BL/6J male mice were subjected to ameroid constrictor (AC) placement to gradually narrow the bilateral common carotid arteries. Cerebral blood flow (CBF) was measured at several time points. At 7 and 28 days post-operation, post-mortem brain samples were analyzed for ischemic changes.
Results
The mortality rate was 58.8% at 28 days post-operation. Surviving mice with AC showed continuous reduction of CBF by up to 70% of the baseline level at 28 days. Most of the mice (75%) showed multiple cerebral infarctions in the gray and white matter. Non-surviving mice showed critical CBF reduction below 20–30% of the baseline level before death.
Conclusion
The application of the AC on the bilateral common carotid arteries in mice could offer a reliable model of severe cerebrovascular insufficiency due to carotid artery occlusive disease and may thus be useful in exploring pharmacological intervention in stroke through monitoring survival rate, infarct formation, and CBF profile.
doi:10.1371/journal.pone.0100257
PMCID: PMC4062537  PMID: 24940742
15.  Interindividual variations of cerebral blood flow, oxygen delivery, and metabolism in relation to hemoglobin concentration measured by positron emission tomography in humans 
Regional cerebral blood flow (CBF) and oxygen metabolism can be measured by positron emission tomography (PET) with 15O-labeled compounds. Hemoglobin (Hb) concentration of blood, a primary determinant of arterial oxygen content (CaO2), influences cerebral circulation. We investigated interindividual variations of CBF, cerebral blood volume (CBV), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) in relation to Hb concentration in healthy human volunteers (n=17) and in patients with unilateral steno-occlusive disease (n=44). For the patients, data obtained only from the contralateral hemisphere (normal side) were analyzed. The CBF and OEF were inversely correlated with Hb concentration, but CMRO2 was independent of Hb concentration. Oxygen delivery defined as a product of CaO2 and CBF (CaO2 CBF) increased with a rise of Hb concentration. The analysis with a simple oxygen model showed that oxygen diffusion parameter (L) was constant over the range of Hb concentration, indicating that a homeostatic mechanism controlling CBF is necessary to maintain CMRO2. The current findings provide important knowledge to understand the control mechanism of cerebral circulation and to interpret the 15O PET data in clinical practice.
doi:10.1038/jcbfm.2010.13
PMCID: PMC2949226  PMID: 20160738
15O PET; CBF; CMRO2; hemoglobin; OEF
16.  Cerebral Hemodynamic Changes Induced by a Lumbar Puncture in Good-Grade Subarachnoid Hemorrhage 
Background
Patients with good-grade subarachnoid hemorrhage (SAH) are those without initial neurological deficit. However, they can die or present severe deficit due to secondary insult leading to brain ischemia. After SAH, in a known context of energy crisis, vasospasm, hydrocephalus and intracranial hypertension contribute to unfavorable outcome. Lumbar puncture (LP) is sometimes performed in an attempt to reduce intracranial pressure (ICP) and release headaches. We hypothesize that in good-grade SAH patients, a 20-ml LP releases headaches, reduces ICP and improves cerebral blood flow (CBF) as measured with O15 PET scan.
Methods
Six good-grade (WFNS grade 1or 2) SAH patients (mean age 48 years, 2 women, 4 men) were prospectively included. All aneurysms (4 anterior communicating artery and 2 right middle cerebral artery) were coiled at day 1. Patients were managed according to our local protocol. LP was performed for severe headache (VAS >7) despite maximal painkiller treatment. Patients were included when the LP was clinically needed. The 20-ml LP was done in the PET scan (mean delay between SAH and LP: 3.5 days). LP allows hydrostatic measurement of ICP. Arterial blood pressure (ABP) was noninvasively gauged with photoplethysmography. Every signal was monitored and analyzed off-line. Regional CBF (rCBF) was measured semiquantitatively with O15 PET before and after LP. Then we calculated the difference between baseline and post-LP condition for each area: positive value means augmentation of rCBF after the LP, negative value means reduction of rCBF. Individual descriptive analysis of CBF was first performed for each patient; then a statistical group analysis was done with SPM for all voxels using t statistics converted to Z scores (p < 0.01, Z score >3.2).
Results
A 20-ml LP yielded a reduction in pain (–4), a drop in ICP (24.3 ± 12.5 to 6.9 ± 4.7 mm Hg), but no change in ABP. Descriptive and statistical image analysis showed a heterogeneous and biphasic change in cerebral hemodynamics: rCBF was not kept constant and either augmented or decreased after the drop in ICP. Hence, cerebrovascular reactivity was spatially heterogeneous within the brain. rCBF seems to augment in the brain region roughly close to the bleed and to be reduced in the rest of the brain, with a rough plane of symmetry.
Conclusions
In good-grade SAH, LP releases headaches and lowers ICP. LP and the drop in ICP have a heterogeneous and biphasic effect on rCBF, suggesting that cerebrovascular reactivity is not spatially homogeneous within the brain.
doi:10.1159/000339580
PMCID: PMC3493014  PMID: 23139682
Subarachnoid hemorrhage; Cerebral blood flow; Lumbar puncture; Intracranial pressure; PET scanner
17.  The Time of Maximum Post-Ischemic Hyperperfusion Indicates Infarct Growth Following Transient Experimental Ischemia 
PLoS ONE  2013;8(5):e65322.
After recanalization, cerebral blood flow (CBF) can increase above baseline in cerebral ischemia. However, the significance of post-ischemic hyperperfusion for tissue recovery remains unclear. To analyze the course of post-ischemic hyperperfusion and its impact on vascular function, we used magnetic resonance imaging (MRI) with pulsed arterial spin labeling (pASL) and measured CBF quantitatively during and after a 60 minute transient middle cerebral artery occlusion (MCAO) in adult rats. We added a 5% CO2 - challenge to analyze vasoreactivity in the same animals. Results from MRI were compared to histological correlates of angiogenesis. We found that CBF in the ischemic area recovered within one day and reached values significantly above contralateral thereafter. The extent of hyperperfusion changed over time, which was related to final infarct size: early (day 1) maximal hyperperfusion was associated with smaller lesions, whereas a later (day 4) maximum indicated large lesions. Furthermore, after initial vasoparalysis within the ischemic area, vasoreactivity on day 14 was above baseline in a fraction of animals, along with a higher density of blood vessels in the ischemic border zone. These data provide further evidence that late post-ischemic hyperperfusion is a sequel of ischemic damage in regions that are likely to undergo infarction. However, it is transient and its resolution coincides with re-gaining of vascular structure and function.
doi:10.1371/journal.pone.0065322
PMCID: PMC3669346  PMID: 23741488
18.  Correlation of Early Reduction in the Apparent Diffusion Coefficient of Water with Blood Flow Reduction During Middle Cerebral Artery Occlusion in Rats 
To determine the relationship between reductions in the apparent diffusion coefficient of water (ADC) and in cerebral blood flow (CBF) during focal ischemia, we used diffusion-weighted magnetic resonance (D-MR) imaging and autoradiographic CBF analysis to examine rats subjected to 30 or 90 min of permanent middle cerebral artery (MCA) occlusion. In the 30-min occlusion group (n = l0), the area with substantially reduced ADC (15% or more below the contralateral level [ADCJ15]) corresponded best to the area with CBF below 25 ml/lOO g/min and was significantly smaller than the area with CBF below 50 m1/100 g/min (CBF50), a level associated with reduced protein synthesis and delayed necrosis (40 ± 13% versus 74 ± 8% of the ischemic hemisphere; P < 0.OOOl). In the 90-min occlusion group (n = 6), the ADC15 area corresponded best to the CBF30 to CBF35 area and was again significantly smaller than the CBF50 area (54 ± 13% versus 73 ± 20%, P < 0.05). Thus, the area of substantially reduced ADC at 30 and 90 min represents only 53% and 74%, respectively, of the tissue at risk for infarction. These findings indicate a potential limitation in using early D-MR imaging to predict stroke outcome.
PMCID: PMC2733355  PMID: 7500876
diffusion-weighted MRI; focal cerebral ischemia; rat; cerebral blood flow
19.  Perfusion-CT compared to H215O/O15O PET in Patients with Chronic Cervical Carotid Artery Occlusion 
Neuroradiology  2008;50(9):745-751.
Background and Purpose
As part of the Carotid Occlusion Surgery Study (COSS), patients with chronic cervical carotid artery occlusive disease are selected for extracranial-intracranial bypass surgery based on the results of 15O2/H215O PET imaging. The purpose of this study was to compare the results of Perfusion-CT (PCT) with those of 15O2/H215O PET in a subset of COSS patients.
Materials & Methods
Six patients enrolled in COSS underwent a standard-of-care PCT in addition to the 15O2/H215O PET study used for determining study eligibility. PCT and PET studies were coregistered and then processed separately by different radiologists. Relative measurement of cerebral blood flow (CBF) and oxygen extraction fraction (OEF) without arterial sampling were calculated from two PET scans, one for O15O inhalation and one for H215O injection. PCT datasets were processed using different arterial input functions (AIF), on the side of the carotid occlusion (“ischemic” inputs) and on the contralateral side (“nonischemic” inputs). The same sets of symmetric regions of interests (anterior, middle and posterior cerebral artery distribution) were drawn on both hemispheres on matching slices from both imaging modalities (PCT and PET). Relative PCT and PET CBF values (“ischemic” side divided by “nonischemic” side) were compared using linear regression model, in order to determine the most appropriate arterial input function for PCT. As a secondary analysis, PCT values of relative CBF, cerebral blood volume (CBV) and mean transit time (MTT) using the most accurate arterial input function were evaluated for linear regression with respect to relative PET OEF values, which are used for determining study eligibility in COSS.
Results
The most accurate PCT relative CBF maps with respect to the gold standard PET CBF, were obtained when CBF values for each arterial territory are calculated using a dedicated AIF for each territory (ACA AIF for ACA territory, right MCA AIF for right MCA territory, left MCA AIF for left MCA territory) (R2 = 0.796, p < 0.001). PCT MTT is the parameter that showed the best correlation with the count-based PET OEF ratios (slope = 0.124, intercept = 0.676, R2 = 0.590, p < 0.001).
Conclusion
PCT relative CBF compares favorably to PET relative CBF in patients with chronic carotid occlusion when processed using a dedicated AIF for each territory. The PCT MTT parameter correlated best with PET relative OEF. Prospective investigations are needed to assess whether PCT can be used as an alternative to PET OEF to identify patients with recently symptomatic carotid artery occlusion who are at high risk for subsequent stroke.
doi:10.1007/s00234-008-0403-9
PMCID: PMC2586154  PMID: 18509627
chronic carotid occlusion; PET; perfusion-CT; processing; arterial input function
20.  Stroke penumbra defined by an MRI-based oxygen challenge technique: 2. Validation based on the consequences of reperfusion 
Magnetic resonance imaging (MRI) with oxygen challenge (T2∗ OC) uses oxygen as a metabolic biotracer to define penumbral tissue based on CMRO2 and oxygen extraction fraction. Penumbra displays a greater T2∗ signal change during OC than surrounding tissue. Since timely restoration of cerebral blood flow (CBF) should salvage penumbra, T2∗ OC was tested by examining the consequences of reperfusion on T2∗ OC-defined penumbra. Transient ischemia (109±20 minutes) was induced in male Sprague-Dawley rats (n = 8). Penumbra was identified on T2∗-weighted MRI during OC. Ischemia and ischemic injury were identified on CBF and apparent diffusion coefficient maps, respectively. Reperfusion was induced and scans repeated. T2 for final infarct and T2∗ OC were run on day 7. T2∗ signal increase to OC was 3.4% in contralateral cortex and caudate nucleus and was unaffected by reperfusion. In OC-defined penumbra, T2∗ signal increased by 8.4%±4.1% during ischemia and returned to 3.25%±0.8% following reperfusion. Ischemic core T2∗ signal increase was 0.39%±0.47% during ischemia and 0.84%±1.8% on reperfusion. Penumbral CBF increased from 41.94±13 to 116.5±25 mL per 100 g per minute on reperfusion. On day 7, OC-defined penumbra gave a normal OC response and was located outside the infarct. T2∗ OC-defined penumbra recovered when CBF was restored, providing further validation of the utility of T2∗ OC for acute stroke management.
doi:10.1038/jcbfm.2011.67
PMCID: PMC3160486  PMID: 21559030
ADC; CBF; imaging; MCAO; T2*
21.  Stroke penumbra defined by an MRI-based oxygen challenge technique: 2. Validation based on the consequences of reperfusion 
Magnetic resonance imaging (MRI) with oxygen challenge (T2* OC) uses oxygen as a metabolic biotracer to define penumbral tissue based on CMRO2 and oxygen extraction fraction. Penumbra displays a greater T2* signal change during OC than surrounding tissue. Since timely restoration of cerebral blood flow (CBF) should salvage penumbra, T2* OC was tested by examining the consequences of reperfusion on T2* OC-defined penumbra. Transient ischemia (109±20 minutes) was induced in male Sprague-Dawley rats (n=8). Penumbra was identified on T2*-weighted MRI during OC. Ischemia and ischemic injury were identified on CBF and apparent diffusion coefficient maps, respectively. Reperfusion was induced and scans repeated. T2 for final infarct and T2* OC were run on day 7. T2* signal increase to OC was 3.4% in contralateral cortex and caudate nucleus and was unaffected by reperfusion. In OC-defined penumbra, T2* signal increased by 8.4%±4.1% during ischemia and returned to 3.25%±0.8% following reperfusion. Ischemic core T2* signal increase was 0.39%±0.47% during ischemia and 0.84%±1.8% on reperfusion. Penumbral CBF increased from 41.94±13 to 116.5±25 mL per 100 g per minute on reperfusion. On day 7, OC-defined penumbra gave a normal OC response and was located outside the infarct. T2* OC-defined penumbra recovered when CBF was restored, providing further validation of the utility of T2* OC for acute stroke management.
doi:10.1038/jcbfm.2011.67
PMCID: PMC3160486  PMID: 21559030
ADC; CBF; imaging; MCAO; T2*
22.  Higher cerebral function and hemispheric blood flow during awake carotid artery balloon test occlusions 
OBJECTIVES—Measures capable of detecting early alterations of brain function during acute cerebral ischaemia have not been adequately defined. Internal carotid artery (ICA) test occlusions provide a well controlled environment to investigate the effects of reversible acute hemispheric hypoperfusion on brain function. A continuous time estimation task was developed that reliably demonstrated alterations in higher cerebral function before development of any deficits in elementary neurological function during ICA balloon catheter test occlusions. In the present study, we hypothesised that alterations in our behavioural task would correlate significantly with absolute level of ipsilateral CBF.
METHODS—Twenty five patients underwent awake ICA test occlusions during which sustained attention and ipsilateral CBF were measured simultaneously using our time estimation task and the intracarotid 133Xe washout method. Alteration in sustained attention was correlated with CBF after occlusion using Fisher's exact test.
RESULTS—Deterioration in sustained attention was significantly associated with ipsilateral CBF below 30 ml/g/min (Fisher's exact test, p=0.047). Changes in individual patients' performance on the behavioural task correlated in real time with changes occurring either at the point of occlusion or at a specific threshold of induced hypotension. Sensitivity for our behavioural test in predicting CBF was 75%; specificity 70%.
CONCLUSIONS—Monitoring sustained attention during carotid balloon test occlusions seems to be a sensitive means to detect decreases in CBF as measured by 133Xe washout. Correlation between higher cerebral function and CBF can allow more detailed investigations of physiological relations between cerebral haemodynamics and brain function in human conditions of cerebral ischaemia.


PMCID: PMC1736397  PMID: 10329746
23.  Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning 
Neuroscience  2007;151(4):1099-1103.
Remote ischemic preconditioning is an emerging concept for stroke treatment, but its protection against focal stroke has not been established. We tested whether remote preconditioning, performed in the ipsilateral hind limb, protects against focal stroke and explored its protective parameters. Stroke was generated by a permanent occlusion of the left distal middle cerebral artery (MCA) combined with a 30 minute occlusion of the bilateral common carotid arteries (CCA) in male rats. Limb preconditioning was generated by 5 or 15 minute occlusion followed with the same period of reperfusion of the left hind femoral artery, and repeated for 2 or 3 cycles. Infarct was measured 2 days later. The results showed that rapid preconditioning with 3 cycles of 15 minutes performed immediately before stroke reduced infarct size from 47.7±7.6% of control ischemia to 9.8±8.6%; at 2 cycles of 15 minutes, infarct was reduced to 24.7±7.3%; at 2 cycles of 5 minutes, infarct was not reduced. Delayed preconditioning with 3 cycles of 15 minutes conducted 2 days before stroke also reduced infarct to 23.0 ±10.9%, but with 2 cycles of 15 minutes it offered no protection. The protective effects at these two therapeutic time windows of remote preconditioning are consistent with those of conventional preconditioning, in which the preconditioning ischemia is induced in the brain itself. Unexpectedly, intermediate preconditioning with 3 cycles of 15 minutes performed 12 hours before stroke also reduced infarct to 24.7±4.7%, which contradicts the current dogma for therapeutic time windows for the conventional preconditioning that has no protection at this time point. In conclusion, remote preconditioning performed in one limb protected against ischemic damage after focal cerebral ischemia.
doi:10.1016/j.neuroscience.2007.11.056
PMCID: PMC2696348  PMID: 18201834
preconditioning; remote preconditioning; limb preconditioning; cerebral ischemia; focal ischemia
24.  Autoregulation after ischaemic stroke 
Journal of hypertension  2009;27(11):2218-2222.
Objectives
Absent outcome data from randomized clinical trials, management of hypertension in acute ischaemic stroke remains controversial. Data from human participants have failed to resolve the question whether cerebral blood flow (CBF) in the peri-infarct region will decrease due to impaired autoregulation when systemic mean arterial pressure (MAP) is rapidly reduced.
Methods
Nine participants, 1–11 days after hemispheric ischaemic stroke, with systolic blood pressure more than 145 mmHg, underwent baseline PET measurements of regional CBF. Intravenous nicardipine infusion was then used to rapidly reduce mean arterial pressure 16 ± 7 mmHg and CBF measurement was repeated.
Results
Compared with the contralateral hemisphere, there were no significant differences in the percent change in CBF in the infarct (P = 0.43), peri-infarct region (P = 1.00) or remainder of the ipsilateral hemisphere (P = 0.50). Two participants showed CBF reductions of greater than 19% in both hemispheres.
Conclusion
In this study, selective regional impairment of CBF autoregulation in the infarcted hemisohere to reduced systemic blood pressure was not a characteristic of acute cerebral infarction. Reductions in CBF did occur in some individuals, but it was bihemispheric phenomenon that likely was due to an upward shift of the autoregulatory curve as a consequence of chronic hypertension. These results indicate individual monitoring of changes in global CBF, such as with bedside transcranial Doppler, may be useful to determine individual safe limits when MAP is lowered in the setting of acute ischaemic stroke. The benefit of such an approach can only be demonstrated by clinical trials demonstrating improved patient outcome.
doi:10.1097/HJH.0b013e328330a9a7
PMCID: PMC2888663  PMID: 19644387
autoregulation; blood pressure; cerebral infarction; cerebrovascular circulation
25.  Noninvasive Measurement of Cerebral Blood Flow and Blood Oxygenation Using Near-Infrared and Diffuse Correlation Spectroscopies in Critically Brain-Injured Adults 
Neurocritical care  2010;12(2):173-180.
Background
This study assesses the utility of a hybrid optical instrument for noninvasive transcranial monitoring in the neurointensive care unit. The instrument is based on diffuse correlation spectroscopy (DCS) for measurement of cerebral blood flow (CBF), and near-infrared spectroscopy (NIRS) for measurement of oxy- and deoxy-hemoglobin concentration. DCS/NIRS measurements of CBF and oxygenation from frontal lobes are compared with concurrent xenon-enhanced computed tomography (XeCT) in patients during induced blood pressure changes and carbon dioxide arterial partial pressure variation.
Methods
Seven neurocritical care patients were included in the study. Relative CBF measured by DCS (rCBFDCS), and changes in oxy-hemoglobin (ΔHbO2), deoxy-hemoglobin (ΔHb), and total hemoglobin concentration (ΔTHC), measured by NIRS, were continuously monitored throughout XeCT during a baseline scan and a scan after intervention. CBF from XeCT regions-of-interest (ROIs) under the optical probes were used to calculate relative XeCT CBF (rCBFXeCT) and were then compared to rCBFDCS. Spearman’s rank coefficients were employed to test for associations between rCBFDCS and rCBFXeCT, as well as between rCBF from both modalities and NIRS parameters.
Results
rCBFDCS and rCBFXeCT showed good correlation (rs = 0.73, P = 0.010) across the patient cohort. Moderate correlations between rCBFDCS and ΔHbO2/ΔTHC were also observed. Both NIRS and DCS distinguished the effects of xenon inhalation on CBF, which varied among the patients.
Conclusions
DCS measurements of CBF and NIRS measurements of tissue blood oxygenation were successfully obtained in neurocritical care patients. The potential for DCS to provide continuous, noninvasive bedside monitoring for the purpose of CBF management and individualized care is demonstrated.
doi:10.1007/s12028-009-9305-x
PMCID: PMC2844468  PMID: 19908166
Near-infrared spectroscopy; Diffuse correlation spectroscopy; Cerebral blood flow; Xenon CT; Neurocritical care

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