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1.  The effect of vagus nerve stimulation during transient focal cerebral ischemia on chronic outcome in rats 
Journal of Neuroscience Research  2012;90(4):887-894.
The aim of this study was to investigate the effect of vagus nerve stimulation (VNS) on infarct volume and neurological recovery up to three weeks following transient focal cerebral ischemia. Transient ischemia was produced by filament occlusion of the proximal middle cerebral artery (MCA) in rats. The right vagus nerve was stimulated starting 30 minutes after MCA occlusion and consisted of 30 second pulse trains (20 Hz) delivered to the animal’s right vagus nerve every 5 minutes for a total period of 60 minutes (n=10). All the procedures were duplicated but no stimulus was delivered in a control group (n=10). Neurological evaluations were performed in all animals at 24 hours, 48 hours, 1 week, 2 weeks and 3 weeks after MCA occlusion, and animals were euthanized and neuronal damage evaluated in H&E stained sections. The ischemic lesion volume was smaller in the VNS-treated animals in comparison to the non-stimulated group (p<0.02). Although the functional score in both treated and untreated groups improved over the three week observation period (p<0.001), there was still a statistically significant improvement due to VNS treatment compared with control animals (p<0.05). Cerebral blood flow changes in the MCA territory during ischemia did not differ between the VNS-treated animals (31.9±10.4 % of baseline) and control (29.9±9.1 %) animals (p=0.6). Stimulation of the vagus nerve for only a brief period early in ischemia provides neuroprotection in transient ischemia with neuroprotection persisting for at least three weeks.
PMCID: PMC3306061  PMID: 22420043
vagus nerve; cerebral ischemia; neuroprotection; cerebral blood flow
2.  The effect of right vagus nerve stimulation on focal cerebral ischemia: an experimental study in the rat 
Brain Stimulation  2011;5(1):1-10.
Background
The aim of this study was to determine the effect of vagus nerve stimulation (VNS) on infarct size after transient and after permanent focal cerebral ischemia in rats and to test the hypothesis that VNS-induced neuroprotection is due to changes in cerebral blood flow.
Methods
Ischemia was produced by either temporary proximal middle cerebral artery occlusion (TMCAO) or permanent distal middle cerebral artery occlusion (PMCAO). Stimulating electrodes were implanted on the cervical part of the right vagus nerve, and electrical stimulation was initiated 30 minutes after the induction of ischemia and delivered for 30 seconds every 5 minutes for 1 hour. All the procedures were duplicated but no stimulus was delivered in control groups. Cerebral blood flow in the MCA territory was continuously monitored with laser speckle contrast imaging. A neurological evaluation was undertaken after 24 hours of ischemia, and animals were euthanized and neuronal damage evaluated.
Results
Ischemic lesion volume was smaller in VNS-treated animals in both the temporary and permanent ischemic groups (p<0.01). VNS-treated animals in TMCAO had better functional scores at 24 h as compared with control animals (p<0.01), but there were no statistically significant differences in the neurobehavioral scores in PMCAO (p=0.089). CBF changes in the MCA territory during ischemia did not differ between the VNS-treated animals and control animals in either group.
Conclusion
VNS offers neuroprotection against stroke in both temporary and permanent ischemia. Although the precise mechanism of this effect remains to be determined, alterations in cerebral blood flow do not appear to play a role. VNS could readily be translated to clinical practice.
doi:10.1016/j.brs.2011.01.009
PMCID: PMC3264742  PMID: 22037134
vagus nerve stimulation; cerebral ischemia; photothrombosis; neuroprotection
3.  Neurovascular coupling varies with level of global cerebral ischemia in a rat model 
In this study, cerebral blood flow, oxygenation, metabolic, and electrical functional responses to forepaw stimulation were monitored in rats at different levels of global cerebral ischemia from mild to severe. Laser speckle contrast imaging and optical imaging of intrinsic signals were used to measure changes in blood flow and oxygenation, respectively, along with a compartmental model to calculate changes in oxygen metabolism from these measured changes. To characterize the electrical response to functional stimulation, we measured somatosensory evoked potentials (SEPs). Global graded ischemia was induced through unilateral carotid artery occlusion, bilateral carotid artery occlusion, bilateral carotid and right subclavian artery (SCA) occlusion, or carotid and SCA occlusion with negative lower body pressure. We found that the amplitude of the functional metabolic response remained tightly coupled to the amplitude of the SEP at all levels of ischemia observed. However, as the level of ischemia became more severe, the flow response was more strongly attenuated than the electrical response, suggesting that global ischemia was associated with an uncoupling between the functional flow and electrical responses.
doi:10.1038/jcbfm.2012.137
PMCID: PMC3597370  PMID: 23032485
cerebral hemodynamics; evoked potentials; global ischemia; intrinsic optical imaging; neurovascular coupling
4.  Peri-infarct flow transients predict outcome in rat focal brain ischemia 
Neuroscience  2012;226:197-207.
Spreading depolarizations are accompanied by transient changes in cerebral blood flow (CBF). In a post-hoc analysis of previously studied control rats we analysed CBF time courses after middle cerebral artery occlusion in the rat in order to test whether intra-ischemic flow, reperfusion, and different parameters of peri-infarct flow transients (PIFTs) (amplitude, number) can predict outcome. Sprague-Dawley rats anesthetized with either halothane (n=23) or isoflurane (n=32) underwent 90-minute filament occlusion of the middle cerebral artery followed by 72 hours of reperfusion. The infarct size was determined by 2,3,5-triphenyltetrazolium chloride staining. Relative CBF changes were monitored by laser Doppler flowmetry at 4–5 mm lateral, and 1–2 mm posterior to Bregma. An additional filament occlusion study (n=12) was performed to validate that PIFTs were coupled to direct current shifts of spreading depolarization. The PIFT-direct current shift study revealed that every PIFT was associated with a negative direct current shift typical of spreading depolarization. Post-hoc analysis showed that the number of PIFTs, especially with the combination of intra-ischemic level of flow, can predict the development of cortical infarcts. These findings show that PIFTs can serve as an early biomarker in predicting outcome in preclinical animal studies.
doi:10.1016/j.neuroscience.2012.08.049
PMCID: PMC3490006  PMID: 22986160
rat; filament occlusion; spreading depolarization; peri-infarct flow transient; reperfusion
5.  Blood Oxygen Level Dependent Angiography (BOLDangio) and Its Potential Applications in Cancer Research 
NMR in biomedicine  2012;25(10):1125-1132.
Clinically, development of anti-angiogenic drugs for cancer therapy is pivotal. Longitudinal monitoring of tumor angiogenesis can help clinicians determine the effectiveness of anti-angiogenic therapy. Blood Oxygen Level Dependent (BOLD) effect has been widely used for functional imaging and tumor oxygenation assessment. In this study, the BOLD effect is investigated under different levels of oxygen inhalation for the development of a novel angiographic MRI technique, Blood Oxygen Level Dependent angiography (BOLDangio). Under short-term (<10 min) generalized hypoxia, which is induced by the inhalation of 8% oxygen, we measure BOLD contrast as high as 25% from vessels at 9.4T using a simple gradient echo (GRE) pulse sequence. This produces high resolution 2D and 3D maps of normal and tumor brain vasculature in less than 10 minutes. Additionally, this technique reliably detects metastatic tumors and tumor induced intracranial hemorrhage. BOLDangio provides a sensitive research tool for MRI of vasculature under normal and pathological conditions. Thus, it may be applied as a simple monitoring technique for measuring the effectiveness of anti-angiogenic drugs in a preclinical environment.
doi:10.1002/nbm.2780
PMCID: PMC3390450  PMID: 22302557
blood oxygen level dependent angiography; tumor angiogenesis; vasculature; tumor metastasis; intracranial hemorrhage; MRI
6.  Alpha-chloralose is a Suitable Anesthetic for Chronic Focal Cerebral Ischemia Studies in the Rat: A comparative study 
Brain research  2007;1191:157-167.
α–chloralose is widely used as an anesthetic in studies of the cerebrovasculature because it provides robust metabolic and hemodynamic responses to functional stimulation. However, there have been no controlled studies of focal ischemia in the rat under α–chloralose anesthesia. Artificially ventilated rats were prepared using 1.2−1.5 % isoflurane anesthesia for filament occlusion of the right middle cerebral artery (MCA), and anesthesia was either switched to α–chloralose (60 mg/kg bolus, 30 mg/kg/hr; n=10) or was maintained on 1% isoflurane (n=10). Following temporary MCA occlusion EEG was monitored from a screw electrode and changes in cerebral blood flow (rCBF) measured with a laser Doppler probe placed over the ischemic cortex. This study shows that α–chloralose is a safe anesthetic for ischemia studies and provides excellent survival. Compared with isoflurane, the cortical and total infarct volumes are larger in the α–chloralose anesthetized animals, while the functional outcome at 72 hours is similar. The total duration of peri-infarct flow transients (PIFTs) is also significantly longer in α–chloralose anesthetized animals. The average amplitude of the flow transients showed a good correlation with the extent of edema in all animals as did the total duration of non-convulsive seizures (NCS) in the α–chloralose anesthetized animals.
doi:10.1016/j.brainres.2007.11.037
PMCID: PMC2266075  PMID: 18096143
α–chloralose; edema; focal ischemia; isoflurane; non-convulsive seizures; peri-infarct flow transients
7.  Influence of probe pressure on the diffuse correlation spectroscopy blood flow signal: extra-cerebral contributions 
Biomedical Optics Express  2013;4(7):978-994.
A pilot study explores relative contributions of extra-cerebral (scalp/skull) versus brain (cerebral) tissues to the blood flow index determined by diffuse correlation spectroscopy (DCS). Microvascular DCS flow measurements were made on the head during baseline and breath-holding/hyperventilation tasks, both with and without pressure. Baseline (resting) data enabled estimation of extra-cerebral flow signals and their pressure dependencies. A simple two-component model was used to derive baseline and activated cerebral blood flow (CBF) signals, and the DCS flow indices were also cross-correlated with concurrent Transcranial Doppler Ultrasound (TCD) blood velocity measurements. The study suggests new pressure-dependent experimental paradigms for elucidation of blood flow contributions from extra-cerebral and cerebral tissues.
doi:10.1364/BOE.4.000978
PMCID: PMC3704102  PMID: 23847725
(170.3880) Medical and biological imaging; (170.2655) Functional monitoring and imaging; (170.3660) Light propagation in tissues; (170.6480) Spectroscopy, speckle
9.  Magnetic Resonance Imaging of Glutamate 
Nature Medicine  2012;18(2):302-306.
Glutamate (Glu) exhibits a pH and concentration dependent chemical exchange saturation transfer effect (CEST) between its -amine group and bulk water, here termed GluCEST. GluCEST asymmetry is observed at ~3 parts per million downfield from bulk water. Following middle cerebral artery occlusion in the rat brain, an approximately 100% elevation of GluCEST in the ipsilateral side compared to the contralateral side was observed, and is predominantly due to pH changes. In a rat brain tumor model with blood brain barrier disruption, intravenous Glu injection resulted in a clear elevation of GluCEST and a comparable increase in the proton magnetic resonance spectroscopy signal of Glu. GluCEST maps from healthy human brain at 7T were also obtained. These results demonstrate the feasibility and potential of GluCEST for mapping relative changes in Glu concentration as well as pH in vivo. Potential contributions from other brain metabolites to the GluCEST effect are also discussed.
doi:10.1038/nm.2615
PMCID: PMC3274604  PMID: 22270722
10.  3-Monoiodothyronamine: the rationale for its action as an endogenous adrenergic-blocking neuromodulator 
Brain research  2010;1351:130-140.
The investigations reported here were designed to gain insights into the role of 3-monoiodothyronamine (T1AM) in the brain, where the amine was originally identified and characterized. Extensive deiodinase studies indicated that T1AM was derived from the T4 metabolite, reverse triiodothyronine (revT3), while functional studies provided well-confirmed evidence that T1AM has strong adrenergic blocking effects. Because a state of adrenergic overactivity prevails when triiodothyronine (T3) concentrations becomes excessive, the possibility that T3’s metabolic partner, revT3, might give rise to an antagonist of those T3 actions was thought to be reasonable. All T1AM studies thus far have required use of pharmacological doses. Therefore we considered that choosing a physiological site of action was a priority and focused on the locus coeruleus (LC), the major noradrenergic control center in the brain. Site-directed injections of T1AM into the LC elicited a significant, dose-dependent neuronal firing rate change in a subset of adrenergic neurons with an EC50=2.7 μM, a dose well within the physiological range. Further evidence for its physiological actions came from autoradiographic images obtained following intravenous carrier-free 125I-labeled T1AM injection. These showed that the amine bound with high affinity to the LC and to other selected brain nuclei, each of which is both an LC target and a known T3 binding site. This new evidence points to a physiological role for T1AM as an endogenous adrenergic-blocking neuromodulator in the central noradrenergic system.
doi:10.1016/j.brainres.2010.06.067
PMCID: PMC2926234  PMID: 20615397
Thyronamines; thyroid hormone; noradrenergic; locus coeruleus; autoradiography; electrophysiology
11.  Interaction between Nitric Oxide Synthase Inhibitor Induced Oscillations and the Activation Flow Coupling Response 
Brain research  2009;1309:19-28.
The role of nitric oxide (NO) in the activation-flow coupling (AFC) response to periodic electrical forepaw stimulation was investigated using signal averaged laser Doppler (LD) flowmetry. LD measures of calculated cerebral blood flow (CBF) were obtained both prior and after intra-peritoneal administration of the non-selective nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine (L-NNA) (40 mg/kg). Characteristic baseline low frequency vasomotion oscillations (0.17 Hz) were observed after L-NNA administration. These LDCBF oscillations were synchronous within but not between hemispheres. L-NNA reduced the magnitude of the AFC response (p< 0.05) for longer stimuli (1 minute) with longer inter-stimulus intervals (2 minutes). In contrast, the magnitude of the AFC response for short duration stimuli (4 seconds) with short inter-stimulus intervals (20 seconds) was augmented (p < 0.05) after L-NNA. An interaction occurred between L-NNA induced vasomotion oscillations and the AFC response with the greatest increase occurring at the stimulus harmonic closest to the oscillatory frequency. Nitric oxide may therefore modulate the effects of other vasodilators involved in vasomotion oscillations and the AFC response.
doi:10.1016/j.brainres.2009.09.119
PMCID: PMC2789854  PMID: 19900416
nitric oxide; oscillations; laser-Doppler flowmetry; cerebral blood flow
12.  The Biological Effect of Contralateral Forepaw Stimulation in Rat Focal Cerebral Ischemia: A Multispectral Optical Imaging Study 
Our group has already published the possible neuroprotective effect of contralateral forepaw stimulation in temporary focal ischemia in a study. However, the background is still unclear. In the present study we investigated the possible mechanism by monitoring focal ischemia with multispectral [laser speckle, imaging of intrinsic signals (OIS)] imaging. Sprague–Dawley rats were prepared using 1.2% isoflurane anesthesia. The middle cerebral artery was occluded by photothrombosis (4 mW) and the common carotid artery was ligated permanently. Physiological variables were constantly monitored during the experiment. A 6 × 6 mm area centered 3 mm posterior and 4 mm lateral to Bregma was thinned for laser speckle and OIS imaging. Nine circular regions of interests (0.3 mm in diameter) were evenly spaced on the speckle contrast image for the analysis of peri-infarct flow transients, blood flow, and metabolic changes. Both the sham (n = 7) and forepaw-stimulated animals (n = 7) underwent neurological examinations 24 h after ischemia at which point all animals were sacrificed and the infarct size was determined by triphenyltetrazolium chloride. The physiological variables were in normal range and the experimental protocol did not cause significant differences between groups. Both the neurological scores (sham: 3.6 ± 1.7, stimulated: 4.3 ± 1.4) and the infarct volume (sham: 124 ± 39 mm3, stimulated: 147 ± 47 mm3) did not show significant differences between groups. The forepaw stimulation did not increase the intra-ischemic flow neither over the penumbral or the peri-ischemic area. However, the hemoglobin transients related metabolic load (CMRO2) was significantly lower (p < 0.001) while the averaged number of hyperemic flow transients were significantly (p = 0.013) higher in the forepaw (sham: 3.5 ± 2.2, stimulated: 7.0 ± 2.3) stimulated animals.
doi:10.3389/fnene.2010.00019
PMCID: PMC2922941  PMID: 20725601
optical imaging; focal cerebral ischemia; forepaw stimulation; middle cerebral artery occlusion; photothrombosis; speckle contrast; OIS; flow transients
13.  Acute functional recovery of cerebral blood flow after forebrain ischemia in rat 
After complete cerebral ischemia, the postischemic blood flow response to functional activation is severely attenuated for several hours. However, little is known about the spatial and temporal extent of the blood flow response in the acute postischemic period after incomplete cerebral ischemia. To investigate the relative cerebral blood flow (rCBF) response in the somatosensory cortex of rat to controlled vibrissae stimulation after transient incomplete ischemia (15-min bilateral common carotid artery occlusion + hypotension), we employed laser speckle imaging combined with statistical parametric mapping. We found that the ischemic insult had a significant impact on the baseline blood flow (P < 0.005) and the activation area in response to functional stimulation was significantly reduced after ischemia (P < 0.005). The maximum rCBF response in the activation area determined from the statistical analysis did not change significantly up to 3 h after ischemia (P > 0.1). However, the time when rCBF response reached its maximum was significantly delayed (P < 0.0001) from 2.4 ± 0.2 secs before ischemia to 3.6 ± 0.1 secs at 20 mins into reperfusion (P < 0.001); the delay was reduced gradually to 2.9 ± 0.2 secs after 3 h, which was still significantly greater than that observed before the insult (P = 0.04).
doi:10.1038/jcbfm.2008.21
PMCID: PMC2771551  PMID: 18382471
cerebral blood flow; cerebral ischemia; functional activation; functional recovery; laser speckle imaging; statistical parametric map
14.  Transcranial Optical Monitoring of Cerebrovascular Hemodynamics in Acute Stroke Patients 
Optics express  2009;17(5):3884-3902.
“Diffuse correlation spectroscopy” (DCS) is a technology for non-invasive transcranial measurement of cerebral blood flow (CBF) that can be hybridized with “near-infrared spectroscopy” (NIRS). Taken together these methods hold potential for monitoring hemodynamics in stroke patients. We explore the utility of DCS and NIRS to measure effects of head-of-bed (HOB) positioning at 30°, 15°, 0°, −5° and 0° angles in patients with acute ischemic stroke affecting frontal cortex and in controls. HOB positioning significantly altered CBF, oxy-hemoglobin (HbO2) and total-hemoglobin (THC) concentrations. Moreover, the presence of an ipsilateral infarct was a significant effect for all parameters. Results are consistent with the notion of impaired CBF autoregulation in the infarcted hemisphere.
PMCID: PMC2724658  PMID: 19259230
15.  Regional Differences in the Coupling between Resting Cerebral Blood Flow and Metabolism may Indicate Action Preparedness as a Default State 
Cerebral Cortex (New York, NY)  2008;19(2):375-382.
Although most functional neuroimaging studies examine task effects, interest intensifies in the “default” resting brain. Resting conditions show consistent regional activity, yet oxygen extraction fraction constancy across regions. We compared resting cerebral metabolic rates of glucose (CMRgl) measured with 18F-labeled 2-fluoro-2-deoxy-D-glucose to cerebral blood flow (CBF) 15O-H2O measures, using the same positron emission tomography scanner in 2 samples (n = 60 and 30) of healthy right-handed adults. Region to whole-brain ratios were calculated for 35 standard regions of interest, and compared between CBF and CMRgl to determine perfusion relative to metabolism. Primary visual and auditory areas showed coupling between CBF and CMRgl, limbic and subcortical regions—basal ganglia, thalamus and posterior fossa structures—were hyperperfused, whereas association cortices were hypoperfused. Hyperperfusion was higher in left than right hemisphere for most cortical and subcallosal limbic regions, but symmetric in cingulate, basal ganglia and somatomotor regions. Hyperperfused regions are perhaps those where activation is anticipated at short notice, whereas downstream cortical modulatory regions have longer “lead times” for deployment. The novel observation of systematic uncoupling of CBF and CMRgl may help elucidate the potential biological significance of the “default” resting state. Whether greater left hemispheric hyperperfusion reflects lateral dominance needs further examination.
doi:10.1093/cercor/bhn087
PMCID: PMC2638785  PMID: 18534991
functional neuroimaging; metabolic coupling; resting brain
16.  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

Results 1-16 (16)