HIV enters the brain soon after infection causing neuronal damage and microglial/astrocyte dysfunction leading to neuropsychological impairment. We examined the impact of HIV on resting cerebral blood flow (rCBF) within the lenticular nuclei (LN) and visual cortex (VC).
This cross-sectional study used arterial spin labeling MRI (ASL-MRI) to measure rCBF within 33 HIV+ and 26 HIV− subjects. Nonparametric Wilcoxon rank sum test assessed rCBF differences due to HIV serostatus. Classification and regression tree (CART) analysis determined optimal rCBF cutoffs for differentiating HIV serostatus. The effects of neuropsychological impairment and infection duration on rCBF were evaluated.
rCBF within the LN and VC were significantly reduced for HIV+ compared to HIV− subjects. A 2-tiered CART approach using either LN rCBF ≤50.09 mL/100 mL/min or LN rCBF >50.09 mL/100 mL/min but VC rCBF ≤37.05 mL/100 mL/min yielded an 88% (29/33) sensitivity and an 88% (23/26) specificity for differentiating by HIV serostatus. HIV+ subjects, including neuropsychologically unimpaired, had reduced rCBF within the LN (p = 0.02) and VC (p = 0.001) compared to HIV− controls. A temporal progression of brain involvement occurred with LN rCBF significantly reduced for both acute/early (<1 year of seroconversion) and chronic HIV-infected subjects, whereas rCBF in the VC was diminished for only chronic HIV-infected subjects.
Resting cerebral blood flow (rCBF) using arterial spin labeling MRI has the potential to be a noninvasive neuroimaging biomarker for assessing HIV in the brain. rCBF reductions that occur soon after seroconversion possibly reflect neuronal or vascular injury among HIV+ individuals not yet expressing neuropsychological impairment.
= acute/early HIV infection;
= analysis of variance;
= arterial spin labeling MRI;
= classification and regression tree;
= cerebral blood flow;
= chronic HIV infection;
= field of view;
= global deficit score;
= highly active antiretroviral therapy;
= HIV-associated neurocognitive disorders;
= lenticular nuclei;
= resting cerebral blood flow;
= echo time;
= inversion time;
= repetition time;
= visual cortex.
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.
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).
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.
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.
Subarachnoid hemorrhage; Cerebral blood flow; Lumbar puncture; Intracranial pressure; PET scanner
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.
arterial spin labeling; cerebral blood flow; hypertension; ischemic stroke; magnetic resonance imaging; spontaneously hypertensive rats
Chronic alcohol consumption impairs cerebral vasoreactivity, and thus may result in an increase in ischemic brain damage. The goal of this study is to examine the influence of chronic alcohol consumption on transient focal ischemia-induced brain damage. Sprague-Dawley rats were divided into two groups, a control group and an alcohol group. Eight weeks after being fed a liquid diet with or without alcohol, responses of parietal pial arterioles to systemic hypoxia and hypercapnia were measured using a cranial window technique. In separate experiments, rats were subjected to right middle cerebral artery occlusion (MCAO) for 2 hours under ketamine/xylazine or isoflurane anesthesia. Regional cerebral blood flow (rCBF) was monitored through a Laser-Doppler flow probe attached to the lateral aspect of the skull. Neurological evaluation and ischemic lesion were assessed 24-hour after reperfusion. Dilation of pial arterioles in response to hypoxia and hypercapnia was significantly reduced in alcohol-fed rats. Alcohol-fed rats had significantly larger infarct volumes and worse neurological outcomes than nonalcoholfed rats under ketamine/xylazine or isoflurane anesthesia. In addition, rCBF measurement indicated that alcohol-fed rats had less regulatory rebound increase in rCBF after the initial drop in rCBF at the onset of MCAO. Our findings suggest that chronic alcohol consumption exacerbates transient focal ischemia-induced brain damage. Increased ischemic brain damage during alcohol consumption may be related to an impaired cerebral vasoreactivity.
Deep brain stimulation of the subthalamic nucleus (STN DBS) improves motor symptoms in idiopathic Parkinson's disease, yet the mechanism of action remains unclear. Previous studies indicate that STN DBS increases regional cerebral blood flow (rCBF) in immediate downstream targets but does not reveal which brain regions may have functional changes associated with improved motor manifestations. We studied 48 patients with STN DBS who withheld medication overnight and underwent PET scans to measure rCBF responses to bilateral STN DBS. PET scans were performed with bilateral DBS OFF and ON in a counterbalanced order followed by clinical ratings of motor manifestations using Unified Parkinson Disease Rating Scale 3 (UPDRS 3). We investigated whether improvement in UPDRS 3 scores in rigidity, bradykinesia, postural stability and gait correlate with rCBF responses in a priori determined regions. These regions were selected based on a previous study showing significant STN DBS-induced rCBF change in the thalamus, midbrain and supplementary motor area (SMA). We also chose the pedunculopontine nucleus region (PPN) due to mounting evidence of its involvement in locomotion. In the current study, bilateral STN DBS improved rigidity (62%), bradykinesia (44%), gait (49%) and postural stability (56%) (paired t-tests: P < 0.001). As expected, bilateral STN DBS also increased rCBF in the bilateral thalami, right midbrain, and decreased rCBF in the right premotor cortex (P < 0.05, corrected). There were significant correlations between improvement of rigidity and decreased rCBF in the SMA (rs = –0.4, P < 0.02) and between improvement in bradykinesia and increased rCBF in the thalamus (rs = 0.31, P < 0.05). In addition, improved postural reflexes correlated with decreased rCBF in the PPN (rs = –0.38, P < 0.03). These modest correlations between selective motor manifestations and rCBF in specific regions suggest possible regional selectivity for improvement of different motor signs of Parkinson's disease.
Parkinson's disease; deep brain stimulation; subthalamic nucleus; pedunculopontine nucleus; positron emission tomography
Existing neuroimaging studies of vagus nerve stimulation (VNS) in treatment resistant major depression (TRMD) suggest that many brain regions (e.g., prefrontal cortex, thalamus, cingulate cortex, insular cortex) associated with mood disorders undergo alterations in blood flow/metabolism.
Positron emission tomography (PET oxygen-15 labeled water or PET [15O] H2O) was used to identify changes in regional cerebral blood flow (rCBF) in response to immediate VNS in 13 subjects with TRMD. We hypothesized rCBF changes along the afferent pathway of the vagus and in regions associated with depression (e.g., orbitofrontal cortex, amygdala, insular cortex).
Six 90-second PET [15O] H2O scans were performed on 13 subjects in a VNS off-on sequence. Following normalization for global uptake and realignment to standard atlas space, statistical t-images (p < 0.005) were used to evaluate rCBF change.
VNS induced significant rCBF decreases in the left and right lateral orbitofrontal cortex and left inferior temporal lobe. Significant increases were found in the right dorsal anterior cingulate, left posterior limb of the internal capsule/medial putamen, the right superior temporal gyrus, and the left cerebellar body. Post-hoc analysis found small to moderate correlations between baseline acute change in rCBF and antidepressant response following 12 months of VNS.
Regions undergoing rCBF change in response to acute VNS are consistent with the known afferent pathway of the vagus nerve and models of brain network in depression. Larger studies assessing the correlation between acute stimulation patterns and antidepressant outcomes with VNS are needed.
Vagus nerve stimulation; Depression; Positron emission tomography; Regional blood flow; Treatment-resistant depression
Background: Nitric oxide synthase (NOS) activity is increased during hypertension and cerebral ischemia. NOS inactivation reduces stroke-induced cerebral injuries, but little is known about its role in blood-brain barrier (BBB) disruption and cerebral edema formation during stroke in acute hypertension. Here, we investigated the role of NOS inhibition in progression of edema formation and BBB disruptions provoked by ischemia/reperfusion injuries in acute hypertensive rats. Methods: Rats were made acutely hypertensive by aortic coarctation. After 7 days, the rats were randomly selected for the recording of carotid artery pressure, or regional cerebral blood flow (rCBF) using laser Doppler. Ishcemia induced by 60-min middle cerebral artery occlusion (MCAO), followed by 12-h reperfusion. A single i.p. dose of L-NAME (1 mg/kg) was injected before MCAO. After evaluation of neurological disabilities, rats were slaughtered under deep anesthesia to assess cerebral infarction volume, edema, or BBB disruption. Results: A 75-85% reduction in rCBF was occurred during MCAO which returned to pre-occluded levels during reperfusion. Profound neurological disabilities were evidenced after MCAO alongside with severe cerebral infarctions (628 ± 98 mm3), considerable edema (4.05 ± 0.52%) and extensive BBB disruptions (Evans blue extravasation, 8.46 ± 2.03 µg/g). L-NAME drastically improved neurological disabilities, diminished cerebral infarction (264 ± 46 mm3), reduced edema (1.49 ± 0.47%) and BBB disruption (2.93 ± 0.66 µg/g). Conclusion: The harmful actions of NOS activity on cerebral microvascular integrity are intensified by ischemia/reperfusion injuries during acute hypertension. NOS inactivation by L-NAME preserved this integrity and diminished cerebral edema.
Acute hypertension; Ischemia/reperfusion injury; Nitric oxide synthase (NOX); L-NAME; Blood-brain barrier (BBB)
Regional cerebral blood flow (rCBF) is spatially and temporally adjusted to local energy needs. This coupling involves dilation of vessels both at the site of metabolite exchange and upstream of the activated region. Deficits in upstream blood supply limit the ‘capacity to raise rCBF' in response to functional activation and therefore compromise brain function. We here demonstrate in rats that the ‘capacity to raise rCBF' can be determined from real-time measurements of rCBF using laser speckle imaging during an energy challenge induced by cortical spreading depolarizations (CSDs). Cortical spreading depolarizations (CSDs) occur with high incidence in stroke and various other brain injuries and cause large metabolic changes. Various conditions of cerebral perfusion were induced, either by modifying microvascular tone, or by altering upstream blood supply independently. The increase in rCBF per unit of time in response to CSD was linearly correlated to the upstream blood supply. In an experimental model of stroke, we found that this marker of the capacity to raise rCBF which, in pathologic tissue may be additionally limited by impaired vasoactive signaling, was a better indicator of the functional status of cerebral tissue than local rCBF levels.
cortical spreading depolarization; focal cerebral ischemia; upstream blood supply
Cerebral blood flow (CBF) is auto-regulated to meet the brain's metabolic requirements. Oxycyte® is a perfluorocarbon emulsion that acts as a highly effective oxygen carrier compared to blood. The aim of this study is to determine the effects of Oxycyte® on regional CBF (rCBF), by evaluating the effects of stepwise isovolemic hemodilution with Oxycyte® on CBF.
Male rats were intubated and ventilated with 100% O2 under isoflurane anesthesia. The regional (striatum) CBF (rCBF) was measured with a laser doppler flowmeter (LDF). Stepwise isovolemic hemodilution was performed by withdrawing 4ml of blood and substituting the same volume of 5% albumin or 2 ml Oxycyte® plus 2 ml albumin at 20-minute intervals until the hematocrit (Hct) values reached 5%.
In the albumin-treated group, rCBF progressively increased to approximately twice its baseline level (208±30%) when Hct levels were less than 10%. In the Oxycyte®-treated group on the other hand, rCBF increased by significantly smaller increments, and this group's mean rCBF was only slightly higher than baseline (118±18%) when Hct levels were less than 10%. Similarly, in the albumin-treated group, rCBF started to increase when hemodilution with albumin caused the CaO2 to decrease below 17.5 ml/dl. Thereafter, the increase in rCBF was accompanied by a nearly proportional decrease in the CaO2 level. In the Oxycyte®-treated group, the increase in rCBF was significantly smaller than in the albumin-treated group when the CaO2 level dropped below 10 ml/dl (142±20% vs. 186±26%), and rCBF returned to almost baseline levels (106±15) when the CaO2 level was below 7 ml/dl.
Hemodilution with Oxycyte® was accompanied with higher CaO2 and PO2 than control group treated with albumin alone. This effect may be partially responsible for maintaining relatively constant CBF and not allowing the elevated blood flow that was observed with albumin.
Previously, we demonstrated that enhancing cholinergic activity during a working memory (WM) task improves performance and reduces blood flow in the right anterior middle/superior frontal cortex, an area known to be important for WM. The purpose of this study was to evaluate the interaction between WM task demands and cholinergic enhancement on neural responses in the prefrontal cortex. Regional cerebral blood flow (rCBF) was measured using H2 15O and positron emission tomography, as 10 young healthy volunteers performed a parametrically varied match-to-sample WM for faces task. For each item, a picture of a face was presented, followed by a delay (1, 6, 11, or 16 sec), then by the presentation of two faces. Subjects were instructed to identify which face they previously had seen. For control items, nonsense pictures were presented in the same spatial and temporal manner. All conditions were performed during an intravenous infusion of saline and physostigmine (1 mg/hr). Subjects were blind to the substance being infused. Reaction time increased significantly with WM delay, and physostigmine decreased reaction time across delay conditions. Significant task-related rCBF increases during saline infusion were seen in superior frontal, middle frontal, and inferior frontal regions, and the response magnitudes in the regions increased systematically with task difficulty. In all of these prefrontal regions, physostigmine administration significantly reduced rCBF during task, particularly at longer task delays, so that no correlation between task delay and rCBF was observed. In the ventral visual cortex, physostigmine increased rCBF at longer task delays in medial regions, and decreased rCBF over delay conditions in lateral cortical areas. These results indicate that, during cholinergic potentiation, brain activity in prefrontal regions is not modulated by increases in WM task demands, and lends further support to the hypothesis that cholinergic modulation enhances visual processing, making the task easier to perform, and thus, compensate for the need to recruit prefrontal cortical regions as task demands increase.
Regional cerebral blood flow [rCBF] measurements are valuable for identifying angiogenically active tumours, and perfusion computed tomography [CT] has been suggested for that purpose. This study aimed to validate rCBF measurements by perfusion CT with positron-emission tomography [PET] and15O-labelled water [15O-H2O] in healthy subjects.
RCBF was measured twice in 12 healthy subjects with15O-H2O PET and once with perfusion CT performed over the basal ganglia. Matching rCBF values in regions of interest were compared.
Measured with perfusion CT, rCBF was significantly and systematically overestimated. White matter rCBF values were 17.4 ± 2.0 (mean ± SD) mL min-1 100 g-1 for PET and 21.8 ± 3.4 mL min-1 100 g-1 for perfusion CT. Grey matter rCBF values were 48.7 ± 5.0 mL min-1 100 g-1 for PET and 71.8 ± 8.0 mL min-1 100 g-1 for perfusion CT. The overestimation of grey matter rCBF could be reduced from 47% to 20% after normalization to white matter rCBF, but the difference was still significant.
RCBF measured with perfusion CT does contain perfusion information, but neither quantitative nor relative values can substitute rCBF measured by15O-H2O PET yet. This, however, does not necessarily preclude a useful role in patient management.
brain perfusion imaging; PET; oxygen radioisotopes; perfusion CT; healthy human subjects
Background: Stimulant drugs are the most commonly used treatments for attention-deficit/hyperactivity disorder (ADHD), although the mechanism of action of these drugs is still not entirely understood.
Objective: The aim of this study was to investigate the effects of the psychostimulant drug methylphenidate (MPH) on regional cerebral blood flow (rCBF), electrical activity of the brain, and clinical symptoms in children with ADHD using single-photon emission computed tomography (SPECT), electroencephalography (EEG), and neuropsychological tests.
Methods: In this prospective cohort study, pediatric outpatients received MPH for 3 months at a mean dose of 1 mg/kg · d (range, 0.5–1.5 mg/kg · d). They were then administered the Wechsler Intelligence Scale for Children-Revised, the Bender Visual-Motor Gestalt Test (BGT), EEG, and SPECT of the brain. The parents and/or teacher of each child were asked to complete the Conners' Parent Rating Scale (CPRS), the Conners' Teacher Rating Scale (CTRS), and the Turgay Diagnostic and Statistical Manual of Mental Disorders Fourth Edition-based Child and Adolescent Behavior Disorders Screening and Rating Scale (T-DSM-IV-S). All of the evaluations were performed at baseline and after 3 months of MPH treatment. Each child underwent a Stroop test as an activation method 15 minutes before the SPECT procedure.
Results: Sixty patients were assessed for inclusion. Twenty-one children (18 boys [85.7%], 3 girls [14.3%]; mean [SD] age, 9.7 [1.7] years; range, 8–13 years) with a diagnosis of ADHD were included in and completed the study. Mean (SD) BGT scores before MPH treatment compared with after MPH treatment were significantly decreased (9.8 [4.2] vs 6.3 [3.4]; Z = -3.27; P = 0.001). After treatment with MPH, the visual SPECT results suggested that low rCBF was normalized in the right frontotemporal areas in 10 children with ADHD. After treatment, 12 patients (57.1%) had no change in EEG activity, 5 (23.8%) had improvement, and 4 (19.0%) had worsening activity. Patients who had improvement or no worsening on EEG after MPH treatment were associated with significant improvement after MPH treatment compared with before treatment in mean (SD) CTRS scores (25.9 [14.3] vs 35.0 [14.4]; P = 0.003), teachers' T-DSM-IV-S total score (25.1 [14.2] vs 38.4 [18.7]; P = 0.005), and CPRS scores (mothers scores: 29.7 [16.6] vs 42.6 [17.2], P = 0.002; fathers' scores: 29.4 [16.8] vs 41.9 [23.7], P = 0.004). No significant difference was found in these scores in the patients whose EEG findings showed deterioration after MPH treatment. The quantitative values for SPECT observed before treatment compared with those observed after 3 months of MPH treatment were not found to be significantly different in any areas of the brain.
Conclusions: MPH use over 3 months was associated with improvement from baseline in visual-motor function and behavioral disorders in these children and adolescents with ADHD. However, no significant difference in rCBF or electrical activity in the brain was observed in this small study.
attention-deficit/hyperactivity disorder; single-photon emission computed tomography; electroencephalography; methylphenidate
Although cerebral amyloid deposition may precede cognitive impairment by decades, the relationship between amyloid deposition and longitudinal change in neuronal function has not been studied. The aim of this paper is to determine whether nondemented individuals with high and low amyloid burden show different patterns of longitudinal regional cerebral blood flow (rCBF) changes in the years preceding measurement of amyloid deposition.
Twenty-eight nondemented participants (mean (SD) age at [11C] PIB 82.5(4.8) yrs; 6 mildly impaired) from the Baltimore Longitudinal Study of Aging underwent yearly resting-state [15O]H2O PET scans for up to 8 years. [11C]PIB images of amyloid deposition were acquired on average 10.8(0.8) years after the first CBF scan. [11C]PIB distribution volume ratios (DVR) of regions of interest were estimated by fitting a reference tissue model to the measured time activity curves. Based on mean cortical DVR, participants were divided into high and low [11C]PIB retention groups. Differences in longitudinal rCBF changes between high and low [11C]PIB groups were investigated by voxel-based analysis.
Longitudinal rCBF changes differed significantly between high (n=10) and low (n=18) [11C]PIB groups (p<=0.001). Greater longitudinal decreases in rCBF in the high [11C]PIB group were seen in right anterior/mid cingulate, right supramarginal gyrus, left thalamus and midbrain bilaterally relative to the low group. Greater increases in rCBF over time in the high [11C]PIB group were found in left medial and inferior frontal gyri, right precuneus, left inferior parietal lobule, and the left postcentral gyrus.
In this group of nondemented older adults, those with high [11C]PIB show greater longitudinal declines in rCBF in certain areas, representing regions with greater decrements in neuronal function. Greater longitudinal increases in rCBF are also observed in those with higher amyloid load and may represent an attempt to preserve neuronal function in these regions.
PIB; CBF; Longitudinal; Positron Emission Tomography; Aging
Glutamate is a key excitatory neurotransmitter in the brain, and its excessive release plays a key role in the development of neuronal injury. In order to define the effect of nimodipine on glutamate release, we monitored extracellular glutamate release in real-time in a global ischemia rat model with eleven vessel occlusion.
Twelve rats were randomly divided into two groups: the ischemia group and the nimodipine treatment group. The changes of extracellular glutamate level were measured using microdialysis amperometric biosensor, in coincident with cerebral blood flow (CBF) and electroencephalogram. Nimodipine (0.025 µg/100 gm/min) was infused into lateral to the CBF probe, during the ischemic period. Also, we performed Nissl staining method to assess the neuroprotective effect of nimodipine.
During the ischemic period, the mean maximum change in glutamate concentration was 133.22±2.57 µM in the ischemia group and 75.42±4.22 µM (p<0.001) in the group treated with nimodipine. The total amount of glutamate released was significantly different (p<0.001) between groups during the ischemic period. The %cell viability in hippocampus was 47.50±5.64 (p<0.005) in ischemia group, compared with sham group. But, the %cell viability in nimodipine treatment group was 95.46±6.60 in hippocampus (p<0.005).
From the real-time monitoring and Nissl staining results, we suggest that the nimodipine treatment is responsible for the protection of the neuronal cell death through the suppression of extracellular glutamate release in the 11-VO global ischemia model of rat.
Nimodipine; Glutamate; Eleven vessel occlusion ischemia model; Real-time monitoring; Nissl staining
Global cerebral ischemia following cardiac arrest is associated with increased cerebral vasoconstriction and decreased cerebral blood flow, contributing to delayed neuronal cell death and neurological detriments in affected patients. We hypothesize that upregulation of contractile ETB and 5-HT1B receptors, previously demonstrated in cerebral arteries after experimental global ischemia, are a key mechanism behind insufficient perfusion of the post-ischemic brain, proposing blockade of this receptor upregulation as a novel target for prevention of cerebral hypoperfusion and delayed neuronal cell death after global cerebral ischemia. The aim was to characterize the time-course of receptor upregulation and associated neuronal damage after global ischemia and investigate whether treatment with the MEK1/2 inhibitor U0126 can prevent cerebrovascular receptor upregulation and thereby improve functional outcome after global cerebral ischemia. Incomplete global cerebral ischemia was induced in Wistar rats and the time-course of enhanced contractile responses and the effect of U0126 in cerebral arteries were studied by wire myography and the neuronal cell death by TUNEL. The expression of ETB and 5-HT1B receptors was determined by immunofluorescence.
Enhanced vasoconstriction peaked in fore- and midbrain arteries 3 days after ischemia. Neuronal cell death appeared initially in the hippocampus 3 days after ischemia and gradually increased until 7 days post-ischemia. Treatment with U0126 normalised cerebrovascular ETB and 5-HT1B receptor expression and contractile function, reduced hippocampal cell death and improved survival rate compared to vehicle treated animals.
Excessive cerebrovascular expression of contractile ETB and 5-HT1B receptors is a delayed response to global cerebral ischemia peaking 3 days after the insult, which likely contributes to the development of delayed neuronal damage. The enhanced cerebrovascular contractility can be prevented by treatment with the MEK1/2 inhibitor U0126, diminishes neuronal damage and improves survival rate, suggesting MEK1/2 inhibition as a novel strategy for early treatment of neurological consequences following global cerebral ischemia.
The pre-clinical global ischemia model transient bilateral common carotid artery occlusion addresses the unique cascade of events leading to delayed neuronal cell death. However, the inconsistent occurrence of posterior communicating arteries (PcomA) in mice might cause high outcome variability. To determine a means for reducing variability, CD1 mice were subjected to bilateral common carotid artery occlusion for 12 to 40 min. Occlusion duration ≥18 min was applied to mice with bilateral regional cerebral blood flow (rCBF) ≥10% of baseline at 2.5 min of ischemia. However, only groups with ischemic duration ≤18 min were used for statistical analysis because of the high mortality in the other groups. After 7 days, patency of PcomA and hippocampal neuronal loss in the CA1 subfield were evaluated. Outcome variability was reduced when hemispheres containing PcomA were excluded from analysis; ischemic outcome was not affected by the presence of a contralateral PcomA. Extending ischemic duration based on rCBF did not reduce outcome variability because the initial rCBF could not reliably predict PcomA. Therefore, after an optimal ischemic duration, evaluating hippocampal injury in each hemisphere independently according to the existence of PcomA is an effective and reliable method to obtain consistent results in this pre-clinical mouse model.
Cerebral blood flow; Global ischemia; Hippocampus; Posterior communicating artery
OBJECTIVE—The aim of
the present study was to evaluate the regional cerebral blood flow
(rCBF) in patients with postinfectious acute cerebellar ataxia using
single photon emission computed tomography (SPECT).
with postinfectious acute cerebellar ataxia and five control subjects
were examined. The distribution of rCBF was measured by SPECT imaging
after intravenous administration of 123I-IMP (111 MBq). The
rCBF ratio—defined as the ratio of rCBF in the region of interest
(ROI) to that in the occipital cortex—was calculated for each cortical
and subcortical ROI. The mean rCBF ratio of each region was then
compared between the ataxic and control subjects. These patients and
all control subjects were also evaluated using MRI.
RESULTS—The rCBF ratio
was significantly lower in the cerebellum of the ataxic patients than
in the cerebellum of the control subjects (p<0.05). No abnormal
cerebellar morphology and no abnormal signal intensities were found on MRI.
SPECT clearly demonstrated the decreased rCBF in the cerebellum of all
patients with postinfectious acute cerebellar ataxia.
The different clinical trajectories of cocaine-dependent men and women may be a consequence of distinct neurobiological substrates. Hypoperfusion of the orbitofrontal cortex (OFC) has previously been reported in individuals addicted to cocaine and has been posited as a biological mediator of relapse due to impulsivity or impaired decision making.
This study assessed regional cerebral blood flow (rCBF) between abstinent cocaine-dependent men and women and sex-matched healthy controls.
Cocaine-dependent subjects were abstinent from cocaine for 11 to 28 days and had no other major mental health or substance use disorders. rCBF was assessed with single photon emission computed tomography after administration of a placebo saline infusion. A resting scan was also obtained in a subset of cocaine-dependent and control men.
In the 35 cocaine-dependent and 37 healthy control subjects examined, a sex-by-group effect was observed for the left lateral (P = 0.001), right lateral (P = 0.002), and medial (P < 0.02) OFC. Cocaine-dependent men demonstrated significantly lower right and left lateral, but not medial, OFC rCBF compared with sex-matched healthy controls after placebo infusion (P ≤ 0.001). Similar bilateral OFC decreases were observed in male cocaine-dependent subjects at rest. In contrast, cocaine-dependent women showed lower rCBF in the medial, but not lateral, OFC relative to sex-matched healthy controls after placebo infusion (P < 0.01). Male cocaine-dependent subjects also showed decreased rCBF (P < 0.01) in the bilateral anterolateral temporal cortex and anterior cingulate, whereas decreased rCBF was observed in female cocaine-dependent subjects in the bilateral superior frontal gyri. Large and diffuse areas of increased rCBF were observed after placebo infusion in cocaine-dependent men, but not in women, relative to sex-matched healthy controls.
rCBF appears to be reduced in the bilateral OFC in cocaine-dependent men and in the medial OFC in cocaine-dependent women. Sex differences in the medial and lateral OFC rCBF may be relevant to understanding relapse characteristics differentiating men and women addicted to cocaine.
cocaine-related disorders; female; gender; orbitofrontal cortex; single-photon emission-computed tomography
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.
neuroprotection; nuclear receptors; fibrate; PPAR; eNOS; autoradiography; cerebral ischemia
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.
autoradiography; cerebral ischemia; eNOS; fibrate; nuclear receptors; neuroprotection
Acute neutrophil (PMN) recruitment to postischemic cardiac or pulmonary tissue has deleterious effects in the early reperfusion period, but the mechanisms and effects of neutrophil influx in the pathogenesis of evolving stroke remain controversial. To investigate whether PMNs contribute to adverse neurologic sequelae and mortality after stroke, and to study the potential role of the leukocyte adhesion molecule intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of stroke, we used a murine model of transient focal cerebral ischemia consisting of intraluminal middle cerebral artery occlusion for 45 min followed by 22 h of reperfusion. PMN accumulation, monitored by deposition of 111In-labeled PMNs in postischemic cerebral tissue, was increased 2.5-fold in the ipsilateral (infarcted) hemisphere compared with the contralateral (noninfarcted) hemisphere (P < 0.01). Mice immunodepleted of neutrophils before surgery demonstrated a 3.0-fold reduction in infarct volumes (P < 0.001), based on triphenyltetrazolium chloride staining of serial cerebral sections, improved ipsilateral cortical cerebral blood flow (measured by laser Doppler), and reduced neurological deficit compared with controls. In wild-type mice subjected to 45 min of ischemia followed by 22 h of reperfusion, ICAM-1 mRNA was increased in the ipsilateral hemisphere, with immunohistochemistry localizing increased ICAM-1 expression on cerebral microvascular endothelium. The role of ICAM-1 expression in stroke was investigated in homozygous null ICAM-1 mice (ICAM-1 -/-) in comparison with wild-type controls (ICAM-1 +/+). ICAM-1 -/- mice demonstrated a 3.7-fold reduction in infarct volume (P < 0.005), a 35% increase in survival (P < 0.05), and reduced neurologic deficit compared with ICAM-1 +/+ controls. Cerebral blood flow to the infarcted hemisphere was 3.1-fold greater in ICAM-1 -/- mice compared with ICAM-1 +/+ controls (P < 0.01), suggesting an important role for ICAM-1 in the genesis of postischemic cerebral no-reflow. Because PMN-depleted and ICAM-1-deficient mice are relatively resistant to cerebral ischemia-reperfusion injury, these studies suggest an important role for ICAM-1-mediated PMN adhesion in the pathophysiology of evolving stroke.
Background and Purpose
Enhanced angiogenesis facilitates neurovascular remodeling processes and promotes brain functional recovery after stroke. Previous studies from our laboratory demonstrated that valproate (VPA), a histone deacetylase (HDAC) inhibitor, protects against experimental brain ischemia. The present study investigated whether VPA could enhance angiogenesis and promote long-term functional recovery after ischemic stroke.
Male rats underwent middle cerebral artery occlusion (MCAO) for 60 minutes followed by reperfusion for up to 14 days. Assessed parameters were: locomotor function via rotarod test; infarct volume via T2-weighted magnetic resonance imaging; microvessel density via immunohistochemistry; relative cerebral blood flow (rCBF) via perfusion-weighted imaging; protein levels of pro-angiogenic factors via Western blotting; and matrix metalloproteinase (MMP)-2/9 activities via gelatin zymography.
Post-ischemic VPA treatment robustly improved the rotarod performance of MCAO rats on days 7 and 14 after ischemia, and significantly reduced brain infarction on day 14. Concurrently, VPA markedly enhanced microvessel density, facilitated endothelial cell proliferation, and increased rCBF in the ipsilateral cortex. The transcription factor hypoxia-inducible factor (HIF)-1α and its downstream pro-angiogenic factors, vascular endothelial growth factor (VEGF) and MMP-2/9, were upregulated after MCAO and significantly potentiated by VPA in the ipsilateral cortex. Acetylation of histone-H3 and H4 was robustly increased by chronic VPA treatment. The beneficial effects of VPA on rotarod performance and microvessel density were abolished by HIF-1α inhibition.
Chronic VPA treatment enhances angiogenesis and promotes functional recovery after brain ischemia. These effects may involve HDAC inhibition and upregulation of HIF-1α and its downstream pro-angiogenic factors VEGF and MMP-2/9.
angiogenesis; cerebral ischemia; hypoxia-inducible factor-1; matrix metalloproteinase; MRI; valproate; vascular endothelial growth factor
Pulsed arterial spin labeling magnetic resonance imaging (MRI) was performed to investigate the local coupling between resting regional cerebral blood flow (rCBF) and BOLD (blood oxygen level dependent) signal changes in 22 normal human subjects during the administration of 0.25 MAC (minimum alveolar concentration) sevoflurane. Two states were compared with subjects at rest: anesthesia and no-anesthesia. Regions of both significantly increased and decreased resting-state rCBF were observed. Increases were limited primarily to subcortical structures and insula, whereas, decreases were observed primarily in neocortical regions. No significant change was found in global CBF (gCBF). By simultaneously measuring rCBF and BOLD, region-specific anesthetic effects on the coupling between rCBF and BOLD were identified. Multiple comparisons of the agent-induced rCBF and BOLD changes demonstrated significant (P < 0.05) spatial variability in rCBF–BOLD coupling. The slope of the linear regression line for AC, where rCBF was increased by sevoflurane, was markedly smaller than the slope for those ROIs where rCBF was decreased by sevoflurane, indicating a bigger change in BOLD per unit change in rCBF in regions where rCBF was increased by sevoflurane. These results suggest that it would be inaccurate to use a global quantitative model to describe coupling across all brain regions and in all anesthesia conditions. The observed spatial nonuniformity of rCBF and BOLD signal changes suggests that any interpretation of BOLD fMRI data in the presence of an anesthetic requires consideration of these insights.
spatial nonuniformity; pulsed arterial spin labeling; cerebral blood flow; BOLD; coupling; vascular effect; anesthesia; sevoflurane
To characterize the spatial pattern of cerebral ischemic vulnerability to hypoperfusion in stroke patients.
We included 90 patients who underwent admission CT perfusion (CTP) and MRI within 12 hours of ischemic stroke onset. Infarcted brain lesions (“core”) were segmented from admission diffusion-weighted-imaging (DWI), and - along with the CTP parameter maps - coregistered onto MNI-152 brain space, which was parcellated into 125 mirror cortical and subcortical regions per hemisphere. We tested the hypothesis that the percent infarction increment per unit relative cerebral blood flow (rCBF) reduction differs statistically between regions using regression analysis to assess the interaction between regional rCBF and region variables. Next, for each patient, a “vulnerability index” (VI) map was constructed with voxel values equaling the product of that voxel’s rCBF and infarction probability (derived from the MNI-152-transformed, binary, segmented DWI lesions). Voxel-based rCBF threshold for core was determined within the upper 20th percentile of VI map voxel values.
Different regions had different percent infarction increase per unit rCBF reduction (p=0.001). The caudate body, putamen, insular ribbon, paracentral lobule, precentral, middle and inferior frontal gyri had the highest ischemic vulnerability to hypoperfusion. A voxel-based rCBF threshold of <0.42 optimally distinguished infarct core in the highly-vulnerable regions, whereas rCBF <0.16 distinguished core in the remainder of the brain.
We demonstrated regional ischemic vulnerability of the brain to hypoperfusion in acute stroke patients. Location specific - rather than whole-brain - rCBF thresholds may provide a more accurate metric for estimating infarct core using CTP maps.
Stroke; Compute tomography; Magnetic resonance imaging
To analyze the correlation between the pharmacotherapy response and the characteristics of the pre-treatment regional cerebral blood flow (rCBF) in patients with obsessive-compulsive disorder (OCD).
Single-photon emission-computed tomography (SPECT) was used to determine the pre-treatment rCBF in 30 OCD patients and 30 normal controls. Based on their clinical remission response, the subjects were divided into two groups: selective serotonin reuptake inhibitors (SSRIs) and SSRIs plus quetiapine. The subjects with clinical remission response were identified after treatment for a period of 24 weeks, and the rCBF imaging data were processed using statistical parametric mapping (SPM) software with two-sample Z-tests.
Nineteen OCD patients who achieved clinical remission were included in the study. Increased rCBF in forebrain regions, including the frontal lobe, cingulate gyrus, hypothalamus, and basal ganglia, was found in 11 responders to SSRIs compared to normal control patients. The eight SSRI plus quetiapine responders exhibited a decrease in rCBF within posterior brain regions, including the parietal lobe, cerebellar vermis, and occipital lobe, and an increase in rCBF in the frontal lobe, thalamus, basal ganglia, and cerebellum tonsil compared to normal control patients.
The characteristics of increased rCBF in forebrain regions and decreased rCBF in posterior brain regions before treatment of OCD patients was a potentially predictor of treatment response to guide treatment options.
Obsessive-compulsive disorder; Regional cerebral blood flow; SSRI; Quetiapine; Therapy response