Publications by authors named "Ulrich Lindberg"

32 Publications

Assessment of Artificial Intelligence Automatic Multiple Sclerosis Lesion Delineation Tool for Clinical Use.

Clin Neuroradiol 2021 Sep 20. Epub 2021 Sep 20.

Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen east, Denmark.

Purpose: To implement and validate an existing algorithm for automatic delineation of white matter lesions on magnetic resonance imaging (MRI) in patients with multiple sclerosis (MS) on a local single-center dataset.

Methods: We implemented a white matter hyperintensity segmentation model, based on a 2D convolutional neural network, using the conventional T2-weighted fluid attenuated inversion recovery (FLAIR) MRI sequence as input. The model was adapted for delineation of MS lesions by further training on a local dataset of 93 MS patients with a total of 3040 lesions. A quantitative evaluation was performed on ten test patients, in which model-generated masks were compared to manually delineated masks from two expert delineators. A subsequent qualitative evaluation of the implemented model was performed by two expert delineators, in which generated delineation masks on a clinical dataset of 53 patients were rated acceptable (< 10% errors) or unacceptable (> 10% errors) based on the total number of true lesions.

Results: The quantitative evaluation resulted in an average accuracy score (F1) of 0.71, recall of 0.77 and dice similarity coefficient of 0.62. Our implemented model obtained the highest scores in all three metrics, when compared to three out of the box lesion segmentation models. In the clinical evaluation an average of 94% of our 53 model-generated masks were rated acceptable.

Conclusion: After adaptation to our local dataset, the implemented segmentation model was able to delineate MS lesions with a high clinical value as rated by delineation experts while outperforming popular out of the box applications. This serves as a promising step towards implementation of automatic lesion delineation in our MS clinic.
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http://dx.doi.org/10.1007/s00062-021-01089-zDOI Listing
September 2021

Human Cerebral Perfusion, Oxygen Consumption, and Lactate Production in Response to Hypoxic Exposure.

Cereb Cortex 2021 Aug 27. Epub 2021 Aug 27.

Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine, and PET, Copenhagen University Hospital Rigshospitalet, Glostrup 2600, Denmark.

Exposure to moderate hypoxia in humans leads to cerebral lactate production, which occurs even when the cerebral metabolic rate of oxygen (CMRO2) is unaffected. We searched for the mechanism of this lactate production by testing the hypothesis of upregulation of cerebral glycolysis mediated by hypoxic sensing. Describing the pathways counteracting brain hypoxia could help us understand brain diseases associated with hypoxia. A total of 65 subjects participated in this study: 30 subjects were exposed to poikilocapnic hypoxia, 14 were exposed to isocapnic hypoxia, and 21 were exposed to carbon monoxide (CO). Using this setup, we examined whether lactate production reacts to an overall reduction in arterial oxygen concentration or solely to reduced arterial oxygen partial pressure. We measured cerebral blood flow (CBF), CMRO2, and lactate concentrations by magnetic resonance imaging and spectroscopy. CBF increased (P < 10-4), whereas the CMRO2 remained unaffected (P > 0.076) in all groups, as expected. Lactate increased in groups inhaling hypoxic air (poikilocapnic hypoxia: $0.0136\ \frac{\mathrm{mmol}/\mathrm{L}}{\Delta{\mathrm{S}}_{\mathrm{a}}{\mathrm{O}}_2}$, P < 10-6; isocapnic hypoxia: $0.0142\ \frac{\mathrm{mmol}/\mathrm{L}}{\Delta{\mathrm{S}}_{\mathrm{a}}{\mathrm{O}}_2}$, P = 0.003) but was unaffected by CO (P = 0.36). Lactate production was not associated with reduced CMRO2. These results point toward a mechanism of lactate production by upregulation of glycolysis mediated by sensing a reduced arterial oxygen pressure. The released lactate may act as a signaling molecule engaged in vasodilation.
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http://dx.doi.org/10.1093/cercor/bhab294DOI Listing
August 2021

Deep-learning-based attenuation correction in dynamic [O]HO studies using PET/MRI in healthy volunteers.

J Cereb Blood Flow Metab 2021 Jul 11:271678X211029178. Epub 2021 Jul 11.

Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Quantitative [O]HO positron emission tomography (PET) is the accepted reference method for regional cerebral blood flow (rCBF) quantification. To perform reliable quantitative [O]HO-PET studies in PET/MRI scanners, MRI-based attenuation-correction (MRAC) is required. Our aim was to compare two MRAC methods (RESOLUTE and DeepUTE) based on ultrashort echo-time with computed tomography-based reference standard AC (CTAC) in dynamic and static [O]HO-PET. We compared rCBF from quantitative perfusion maps and activity concentration distribution from static images between AC methods in 25 resting [O]HO-PET scans from 14 healthy men at whole-brain, regions of interest and voxel-wise levels. Average whole-brain CBF was 39.9 ± 6.0, 39.0 ± 5.8 and 40.0 ± 5.6 ml/100 g/min for CTAC, RESOLUTE and DeepUTE corrected studies respectively. RESOLUTE underestimated whole-brain CBF by 2.1 ± 1.50% and rCBF in all regions of interest (range -2.4%- -1%) compared to CTAC. DeepUTE showed significant rCBF overestimation only in the occipital lobe (0.6 ± 1.1%). Both MRAC methods showed excellent correlation on rCBF and activity concentration with CTAC, with slopes of linear regression lines between 0.97 and 1.01 and R over 0.99. In conclusion, RESOLUTE and DeepUTE provide AC information comparable to CTAC in dynamic [O]HO-PET but RESOLUTE is associated with a small but systematic underestimation.
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http://dx.doi.org/10.1177/0271678X211029178DOI Listing
July 2021

Exercise-induced fluid shifts are distinct to exercise mode and intensity: a comparison of blood flow-restricted and free-flow resistance exercise.

J Appl Physiol (1985) 2021 06 29;130(6):1822-1835. Epub 2021 Apr 29.

Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

MRI can provide fundamental tools in decoding physiological stressors stimulated by training paradigms. Acute physiological changes induced by three diverse exercise protocols known to elicit similar levels of muscle hypertrophy were evaluated using muscle functional magnetic resonance imaging (mfMRI). The study was a cross-over study with participants ( = 10) performing three acute unilateral knee extensor exercise protocols to failure and a work matched control exercise protocol. Participants were scanned after each exercise protocol; 70% 1 repetition maximum (RM) (FF70); 20% 1RM (FF20); 20% 1RM with blood flow restriction (BFR20); free-flow (FF) control work matched to BFR20 (FF20). Post exercise mfMRI scans were used to obtain interleaved measures of muscle R2 (indicator of edema), R2' (indicator of deoxyhemoglobin), muscle cross sectional area (CSA) blood flow, and diffusion. Both BFR20 and FF20 exercise resulted in a larger acute decrease in R2, decrease in R2', and expansion of the extracellular compartment with slower rates of recovery. BFR20 caused greater acute increases in muscle CSA than FF20 and FF70. Only BFR20 caused acute increases in intracellular volume. Postexercise muscle blood flow was higher after FF70 and FF20 exercise than BFR20. Acute changes in mean diffusivity were similar across all exercise protocols. This study was able to differentiate the acute physiological responses between anabolic exercise protocols. Low-load exercise protocols, known to have relatively higher energy contributions from glycolysis at task failure, elicited a higher mfMRI response. Noninvasive mfMRI represents a promising tool for decoding mechanisms of anabolic adaptation in muscle. Using muscle functional MRI (mfMRI), this study was able to differentiate the acute physiological responses following three established hypertrophic resistance exercise strategies. Low-load exercise protocols performed to failure, with or without blood flow restriction, resulted in larger changes in R (i.e. greater T-shifts) with a slow rate of return to baseline indicative of myocellular fluid shifts. These data were cross evaluated with interleaved measures of macrovascular blood flow, water diffusion, muscle cross sectional area (i.e. acute macroscopic muscle swelling), and intracellular water fraction measured using MRI.
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http://dx.doi.org/10.1152/japplphysiol.01012.2020DOI Listing
June 2021

Neuroplasticity induced by general anaesthesia: study protocol for a randomised cross-over clinical trial exploring the effects of sevoflurane and propofol on the brain - A 3-T magnetic resonance imaging study of healthy volunteers.

Trials 2020 Sep 22;21(1):805. Epub 2020 Sep 22.

Department of Neuroanaesthesiology, The Neuroscience Centre, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark.

Background: Although used extensively worldwide, the effects of general anaesthesia on the human brain remain largely elusive. Moreover, general anaesthesia may contribute to serious conditions or adverse events such as postoperative cognitive dysfunction and delirium. To understand the basic mechanisms of general anaesthesia, this project aims to study and compare possible de novo neuroplastic changes induced by two commonly used types of general anaesthesia, i.e. inhalation anaesthesia by sevoflurane and intravenously administered anaesthesia by propofol. In addition, we wish to to explore possible associations between neuroplastic changes, neuropsychological adverse effects and subjective changes in fatigue and well-being.

Methods: This is a randomised, participant- and assessor-blinded, cross-over clinical trial. Thirty healthy volunteers (male:female ratio 1:1) will be randomised to general anaesthesia by either sevoflurane or propofol. Multimodal magnetic resonance imaging (MRI) of the brain will be performed before and after general anaesthesia and repeated after 1 and 8 days. Each magnetic resonance imaging session will be accompanied by cognitive testing and questionnaires on fatigue and well-being. After a wash-out period of 4 weeks, the volunteers will receive the other type of anaesthetic (sevoflurane or propofol), followed by the same series of tests. Primary outcomes: changes in T1-weighted 3D anatomy and diffusion tensor imaging.

Secondary Outcomes: changes in resting-state functional magnetic resonance imaging, fatigue, well-being, cognitive function, correlations between magnetic resonance imaging findings and the clinical outcomes (questionnaires and cognitive function). Exploratory outcomes: changes in cerebral perfusion and oxygen metabolism, lactate, and response to visual stimuli.

Discussion: To the best of our knowledge, this is the most extensive and advanced series of studies with head-to-head comparison of two widely used methods for general anaesthesia. Recruitment was initiated in September 2019.

Trial Registration: Approved by the Research Ethics Committee in the Capital Region of Denmark, ref. H-18028925 (6 September 2018). EudraCT and Danish Medicines Agency: 2018-001252-35 (23 March 2018). www.clinicaltrials.gov , ID: NCT04125121 . Retrospectively registered on 10 October 2019.
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http://dx.doi.org/10.1186/s13063-020-04468-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506820PMC
September 2020

Physiological responses of human skeletal muscle to acute blood flow restricted exercise assessed by multimodal MRI.

J Appl Physiol (1985) 2020 10 27;129(4):748-759. Epub 2020 Aug 27.

Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Important physiological quantities for investigating muscle hypertrophy include blood oxygenation, cell swelling, and changes in blood flow. The purpose of this study was to compare the acute changes of these parameters in human skeletal muscle induced by low-load (20% 1-RM) blood flow-restricted (BFR-20) knee extensor exercise compared with free-flow work-matched (FF-20) and free-flow 50% 1-RM (FF-50) knee extensor exercise using multimodal magnetic resonance imaging (MRI). Subjects ( = 11) completed acute exercise sessions for each exercise mode in an MRI scanner, where interleaved measures of muscle (indicator of edema), [Formula: see text] (indicator of deoxyhemoglobin), macrovascular blood flow, and diffusion were performed before, between sets, and after the final set for each exercise protocol. BFR-20 exercise resulted in larger acute decreases in R and greater increases in cross-sectional area than FF-20 and FF-50 ( < 0.01). Blood oxygenation decreased between sets during BFR-20, as indicated by a 13.6% increase in [Formula: see text] values ( < 0.01)), whereas they remained unchanged for FF-20 and decreased during FF-50 exercise. Quadriceps blood flow between sets was highest for the heavier load (FF-50), averaging 305 mL/min, and lowest for BFR-20 at 123 ± 73 mL/min until post-exercise cuff release, where blood flow rates in BFR-20 exceeded both FF protocols ( < 0.01). Acute changes in diffusion rates were similar for all exercise protocols. This study was able to differentiate the acute exercise response of selected physiological factors associated with skeletal muscle hypertrophy. Marked differences in these parameters were found to exist between BFR and FF exercise conditions, which contribute to explain the anabolic potential of low-load blood flow restricted muscle exercise. Acute changes in blood flow, diffusion, blood oxygenation, cross-sectional area, and the "T shift" are evaluated in human skeletal muscle in response to blood flow-restricted (BFR) and conventional free-flow knee extensor exercise performed in an MRI scanner. The acute physiological response to exercise was dependent on the magnitude of load and the application of BFR. Physiological variables changed markedly and established a steady state rapidly after the first of four exercise sets.
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http://dx.doi.org/10.1152/japplphysiol.00171.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654733PMC
October 2020

Visual stimuli induce serotonin release in occipital cortex: A simultaneous positron emission tomography/magnetic resonance imaging study.

Hum Brain Mapp 2020 11 19;41(16):4753-4763. Epub 2020 Aug 19.

Neurobiology Research Unit and NeuroPharm, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Endogenous serotonin (5-HT) release can be measured noninvasively using positron emission tomography (PET) imaging in combination with certain serotonergic radiotracers. This allows us to investigate effects of pharmacological and nonpharmacological interventions on brain 5-HT levels in living humans. Here, we study the neural responses to a visual stimulus using simultaneous PET/MRI. In a cross-over design, 11 healthy individuals were PET/MRI scanned with the 5-HT receptor radioligand [ C]AZ10419369, which is sensitive to changes in endogenous 5-HT. During the last part of the scan, participants either viewed autobiographical images with positive valence (n = 11) or kept their eyes closed (n = 7). The visual stimuli increased cerebral blood flow (CBF) in the occipital cortex, as measured with pseudo-continuous arterial spin labeling. Simultaneously, we found decreased 5-HT receptor binding in the occipital cortex (-3.6 ± 3.6%), indicating synaptic 5-HT release. Using a linear regression model, we found that the change in 5-HT receptor binding was significantly negatively associated with change in CBF in the occipital cortex (p = .004). For the first time, we here demonstrate how cerebral 5-HT levels change in response to nonpharmacological stimuli in humans, as measured with PET. Our findings more directly support a link between 5-HT signaling and visual processing and/or visual attention.
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http://dx.doi.org/10.1002/hbm.25156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555083PMC
November 2020

Intradural artery dilation during experimentally induced migraine attacks.

Pain 2021 01;162(1):176-183

Department of Neurology, Danish Headache Center, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

The middle meningeal artery is a proposed surrogate marker for activation of trigeminal nociceptors during migraine. Previous studies focused on the extracranial part of the artery; hence, vasoreactivity in the intradural arteries during migraine is unknown. Thirty-four patients with migraine without aura were given sildenafil on one day and calcitonin gene-related peptide on another in double-blind crossover fashion. Patients were scanned with 3.0 T MR angiography before drug administration and again 6 hours later during induced attacks of migraine. We measured circumference of the intradural segment of the middle meningeal artery before and during induced migraine attacks. The middle cerebral and superficial temporal arteries were also examined. Fourteen patients had attacks during the second scan after both study drugs and 11 had a migraine after either one or the other, resulting in a total of 39 attacks included in the final analysis. Mean circumference of the intradural middle meningeal artery at baseline was 3.18 mm with an increase of 0.11 mm during attacks (P = 0.005), corresponding to a relative dilation of 3.6% [95% CI: 1.4%-5.7%]. Middle cerebral artery dilated by 9.4% [95% CI: 7.1%-11.7%] and superficial temporal artery by 2.3% [95% CI: 0.2%-4.4%]. Our study shows that the intradural middle meningeal artery and the middle cerebral artery are dilated during migraine induced by calcitonin gene-related peptide as well as sildenafil. We propose that intradural vasculature is affected by migraine-driven activation of trigeminal afferents during migraine attacks.
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http://dx.doi.org/10.1097/j.pain.0000000000002008DOI Listing
January 2021

Glutamate levels and perfusion in pons during migraine attacks: A 3T MRI study using proton spectroscopy and arterial spin labeling.

J Cereb Blood Flow Metab 2021 03 19;41(3):604-616. Epub 2020 May 19.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Glostrup, Denmark.

Migraine is a complex disorder, involving peripheral and central brain structures, where mechanisms and site of attack initiation are an unresolved puzzle. While abnormal pontine neuronal activation during migraine attacks has been reported, exact implication of this finding is unknown. Evidence suggests an important role of glutamate in migraine, implying a possible association of pontine hyperactivity to increased glutamate levels. Migraine without aura patients were scanned during attacks after calcitonin gene-related peptide and sildenafil in a double-blind, randomized, double-dummy, cross-over design, on two separate study days, by proton magnetic resonance spectroscopy and pseudo-continuous arterial spin labeling at 3T. Headache characteristics were recorded until 24 h after drug administrations. Twenty-six patients were scanned during migraine, yielding a total of 41 attacks. Cerebral blood flow increased in dorsolateral pons, ipsilateral to pain side during attacks, compared to outside attacks (13.6%, p = 0.009). Glutamate levels in the same area remained unchanged during attacks (p = 0.873), while total creatine levels increased (3.5%, p = 0.041). In conclusion, dorsolateral pontine activation during migraine was not associated with higher glutamate levels. However, the concurrently increased total creatine levels may suggest an altered energy metabolism, which should be investigated in future studies to elucidate the role of pons in acute migraine.
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http://dx.doi.org/10.1177/0271678X20906902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922760PMC
March 2021

Cerebrovascular effects of endothelin-1 investigated using high-resolution magnetic resonance imaging in healthy volunteers.

J Cereb Blood Flow Metab 2020 08 9;40(8):1685-1694. Epub 2019 Sep 9.

Department of Neurology, Danish Headache Center, Rigshospitalet Glostrup, Glostrup, Denmark.

Endothelin-1 (ET-1) is a highly potent vasoconstrictor peptide released from vascular endothelium. ET-1 plays a major role in cerebrovascular disorders and likely worsens the outcome of acute ischaemic stroke and aneurismal subarachnoid haemorrhage through vasoconstriction and cerebral blood flow (CBF) reduction. Disorders that increase the risk of stroke, including hypertension, diabetes mellitus, and acute myocardial infarction, are associated with increased plasma levels of ET-1. The in vivo human cerebrovascular effects of systemic ET-1 infusion have not previously been investigated. In a two-way crossover, randomized, double-blind design, we used advanced 3 tesla MRI methods to investigate the effects of high-dose intravenous ET-1 on intra- and extracranial artery circumferences, global and regional CBF, and cerebral metabolic rate of oxygen (CMRO) in 14 healthy volunteers. Following ET-1 infusion, we observed a 14% increase of mean arterial blood pressure, a 5% decrease of middle cerebral artery (MCA) circumference, but no effects on extracerebral arteries and no effects on CBF or CMRO. Collectively, the findings indicate MCA constriction secondarily to blood pressure increase and not due to a direct vasoconstrictor effect of ET-1. We suggest that, as opposed to ET-1 in the subarachnoid space, intravascular ET-1 does not exert direct cerebrovascular effects in humans.
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http://dx.doi.org/10.1177/0271678X19874295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370364PMC
August 2020

Comparison of simultaneous arterial spin labeling MRI and O-HO PET measurements of regional cerebral blood flow in rest and altered perfusion states.

J Cereb Blood Flow Metab 2020 08 9;40(8):1621-1633. Epub 2019 Sep 9.

Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen, Denmark.

Arterial spin labelling (ASL) is a non-invasive magnetic resonance imaging (MRI) technique that may provide fully quantitative regional cerebral blood flow (rCBF) images. However, before its application in clinical routine, ASL needs to be validated against the clinical gold standard, O-HO positron emission tomography (PET). We aimed to compare the two techniques by performing simultaneous quantitative ASL-MRI and O-HO-PET examinations in a hybrid PET/MRI scanner. Duplicate rCBF measurements were performed in healthy young subjects ( = 14) in rest, during hyperventilation, and after acetazolamide (post-ACZ), yielding 63 combined PET/MRI datasets in total. Average global CBF by ASL-MRI and O-HO-PET was not significantly different in any state (40.0 ± 6.5 and 40.6 ± 4.1 mL/100 g/min, respectively in rest, 24.5 ± 5.1 and 23.4 ± 4.8 mL/100 g/min, respectively, during hyperventilation, and 59.1 ± 10.4 and 64.7 ± 10.0 mL/100 g/min, respectively, post-ACZ). Overall, strong correlation between the two methods was found across all states (slope = 1.01, R= 0.82), while the correlations within individual states and of reactivity measures were weaker, in particular in rest (R= 0.05,  = 0.03). Regional distribution was similar, although ASL yielded higher perfusion and absolute reactivity in highly vascularized areas. In conclusion, ASL-MRI and O-HO-PET measurements of rCBF are highly correlated across different perfusion states, but with variable correlation within and between hemodynamic states, and systematic differences in regional distribution.
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http://dx.doi.org/10.1177/0271678X19874643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370368PMC
August 2020

Correction to: Ultra-high field MR angiography in human migraine models: a 3.0 T/7.0 T comparison study.

J Headache Pain 2019 May 28;20(1):62. Epub 2019 May 28.

Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Valdemar Hansens Vej 5, 2600, Glostrup, Denmark.

After publication of the original article [1], the authors have notified us that an updated version of Figures 1, 2 and 3 should have been published. The incorrect and revised figures can be found below.
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http://dx.doi.org/10.1186/s10194-019-1014-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734446PMC
May 2019

Investigating macrophage-mediated inflammation in migraine using ultrasmall superparamagnetic iron oxide-enhanced 3T magnetic resonance imaging.

Cephalalgia 2019 Oct 19;39(11):1407-1420. Epub 2019 May 19.

Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Copenhagen, Denmark.

Background: Initiating mechanisms of migraine headache remain poorly understood and a biomarker of migraine does not exist. Inflammation pertaining to the wall of cerebral arteries and brain parenchyma has been suggested to play a role in migraine pathophysiology.

Objective: We conducted the first experimental human study to investigate macrophage-mediated inflammation as a possible biomarker of migraine.

Methods: Using ultrasmall superparamagnetic iron oxide (USPIO)-enhanced 3T magnetic resonance imaging (MRI), we investigated the presence of macrophages in cerebral artery walls and in brain parenchyma of patients with migraine without aura. We used the phosphodiesterase-3-inhibitor cilostazol as an experimental migraine trigger, and investigated both patients who received sumatriptan treatment, and patients who did not. To validate our use of USPIO-enhanced MRI, we included a preclinical mouse model with subcutaneous capsaicin injection in the trigeminal V1 area. The study is registered at ClinicalTrials.gov with the identifier NCT02549898.

Results: A total of 28 female patients with migraine without aura underwent a baseline MRI scan, ingested cilostazol, developed a migraine-like attack, and underwent an USPIO-enhanced MRI scan > 24 hours after intravenous administration of USPIO. Twelve patients treated their attack with 6 mg s.c. sumatriptan, while the remaining 16 patients received no migraine-specific rescue medication. The preclinical model confirmed that USPIO-enhanced MRI detects macrophage-mediated inflammation. In patients, however, migraine attacks were not associated with increased USPIO signal on the pain side of the head compared to the non-pain side.

Conclusion: Our findings suggest that migraine without aura is not associated with macrophage-mediated inflammation specific to the head pain side.
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http://dx.doi.org/10.1177/0333102419848122DOI Listing
October 2019

Ultra-high field MR angiography in human migraine models: a 3.0 T/7.0 T comparison study.

J Headache Pain 2019 May 6;20(1):48. Epub 2019 May 6.

Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Valdemar Hansens Vej 5, 2600, Glostrup, Denmark.

Background: Sildenafil and calcitonin gene-related peptide both dilate the intradural segments of the middle meningeal artery measured with 3.0 tesla (T) MR angiography. Here we hypothesized that an increase in field strength to 7.0 T and concomitant enhanced voxel resolution would lower variance in measurements of dilation in the intradural middle meningeal artery.

Methods: Five subjects completed two sessions at respectively 3.0 T and 7.0 T. Each session comprised MR angiography scans once before and twice after administration of sildenafil, calcitonin gene-related peptide or placebo in a three-way, crossover, double-blind, placebo-controlled design.

Results: Standard deviations of arterial circumference revealed no difference between 3.0 T and 7.0 T measurements (p = 0.379). We found a decrease in standard deviation from our original angiography analysis software (QMra) to a newer (LAVA) software package (p < 0.001). Furthermore, we found that the dilation after sildenafil and calcitonin gene-related peptide were comparable between 3.0 T and 7.0 T.

Conclusions: Our findings suggest no gain from the increase in voxel resolution but cemented dilatory findings from earlier. The implemented software update improved variance in circumference measurements in the intradural middle meningeal artery, which should be exploited in future studies.

Trial Registration: The study is part of a parent study, which is registered at ClinicalTrials.gov ( NCT03143465 ).
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http://dx.doi.org/10.1186/s10194-019-0996-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734314PMC
May 2019

Higher physiological vulnerability to hypoxic exposure with advancing age in the human brain.

J Cereb Blood Flow Metab 2020 02 12;40(2):341-353. Epub 2018 Dec 12.

Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital Rigshospitalet, Glostrup, Denmark.

The aging brain is associated with atrophy along with functional and metabolic changes. In this study, we examined age-related changes in resting brain functions and the vulnerability of brain physiology to hypoxic exposure in humans in vivo. Brain functions were examined in 81 healthy humans (aged 18-62 years) by acquisitions of gray and white matter volumes, cerebral blood flow, cerebral oxygen consumption, and concentrations of lactate, N-acetylaspartate, and glutamate+glutamine using magnetic resonance imaging and spectroscopy. We observed impaired cerebral blood flow reactivity in response to inhalation of hypoxic air (p = 0.029) with advancing age along with decreased cerebral oxygen consumption (p = 0.036), and increased lactate concentration (p = 0.009), indicating tissue hypoxia and impaired metabolism. Diminished resilience to hypoxia and consequently increased vulnerability to metabolic stress could be a key part of declining brain health with age. Furthermore, we observed increased resting cerebral lactate concentration with advancing age (p = 0.007), which might reflect inhibited brain clearance of waste products.
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http://dx.doi.org/10.1177/0271678X18818291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985989PMC
February 2020

Phase contrast mapping MRI measurements of global cerebral blood flow across different perfusion states - A direct comparison with O-HO positron emission tomography using a hybrid PET/MR system.

J Cereb Blood Flow Metab 2019 12 11;39(12):2368-2378. Epub 2018 Sep 11.

Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Phase-contrast mapping (PCM) magnetic resonance imaging (MRI) provides easy-access non-invasive quantification of global cerebral blood flow (gCBF) but its accuracy in altered perfusion states is not established. We aimed to compare paired PCM MRI and O-HO positron emission tomography (PET) measurements of gCBF in different perfusion states in a single scanning session. Duplicate combined gCBF PCM-MRI and O-HO PET measurements were performed in the resting condition, during hyperventilation and after acetazolamide administration (post-ACZ) using a 3T hybrid PET/MR system. A total of 62 paired gCBF measurements were acquired in 14 healthy young male volunteers. Average gCBF in resting state measured by PCM-MRI and O-HO PET were 58.5 ± 10.7 and 38.6 ± 5.7 mL/100 g/min, respectively, during hyperventilation 33 ± 8.6 and 24.7 ± 5.8 mL/100 g/min, respectively, and post-ACZ 89.6 ± 27.1 and 57.3 ± 9.6 mL/100 g/min, respectively. On average, gCBF measured by PCM-MRI was 49% higher compared to O-HO PET. A strong correlation between the two methods across all states was observed (R = 0.72,  < 0.001). Bland-Altman analysis suggested a perfusion dependent relative bias resulting in higher relative difference at higher CBF values. In conclusion, measurements of gCBF by PCM-MRI in healthy volunteers show a strong correlation with O-HO PET, but are associated with a large and non-linear perfusion-dependent difference.
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http://dx.doi.org/10.1177/0271678X18798762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890999PMC
December 2019

Altered somatosensory neurovascular response in patients with Becker muscular dystrophy.

Brain Behav 2018 06 24;8(6):e00985. Epub 2018 Apr 24.

Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet Glostrup, University of Copenhagen, Glostrup, Denmark.

Introduction: Patients with dystrophinopathies show low levels of neuronal nitric oxide synthase (nNOS), due to reduced or absent dystrophin expression, as nNOS is attached to the dystrophin-associated protein complex. Deficient nNOS function leads to functional ischemia during muscle activity. Dystrophin-like proteins with nNOS attached have also been identified in the brain. This suggests that a mechanism of cerebral functional ischemia with attenuation of normal activation-related vascular response may cause changes in brain function.

Methods: The aim of this study was to investigate whether the brain response of patients with Becker muscular dystrophy (BMD) is dysfunctional compared to that of healthy controls. To investigate a potential change in brain activation response in patients with BMD, median nerve somatosensory evoked stimulation, with stimulation durations of 2, 4, and 10 s, was performed while recording electroencephalography and blood oxygen level-dependent (BOLD) functional magnetic resonance imaging.

Results: Results in 14 male patients with BMD (36.2 ± 9.9 years) were compared with those of 10 healthy controls (34.4 ± 10.9 years). Compared to controls, the patients with BMD showed sustained cortical electrical activity and a significant smaller BOLD activation in contralateral primary somatosensory cortex and bilaterally in secondary somatosensory cortex. In addition, significant activation differences were found after long duration (10 s) stimuli in thalamus.

Conclusion: An altered neurovascular response in patients with BMD may increase our understanding of neurovascular coupling and the pathogenesis related to dystrophinopathy and nNOS.
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http://dx.doi.org/10.1002/brb3.985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991560PMC
June 2018

Sildenafil and calcitonin gene-related peptide dilate intradural arteries: A 3T MR angiography study in healthy volunteers.

Cephalalgia 2019 02 5;39(2):264-273. Epub 2018 Jul 5.

1 Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: Sildenafil and calcitonin gene-related peptide are vasoactive substances that induce migraine attacks in patients. The intradural arteries are thought to be involved, but these have never been examined in vivo. Sildenafil is the only migraine-inducing compound for which cephalic, extracranial artery dilation is not reported. Here, we investigate the effects of sildenafil and calcitonin gene-related peptide on the extracranial and intradural parts of the middle meningeal artery.

Methods: In a double-blind, randomized, three-way crossover, placebo-controlled head-to-head comparison study, MR-angiography was recorded in healthy volunteers at baseline and twice after study drug (sildenafil/ calcitonin gene-related peptide/saline) administration. Circumferences of extracranial and intradural middle meningeal artery segments were measured using semi-automated analysis software. The area under the curve for circumference change was compared using paired t-tests between study days.

Results: Twelve healthy volunteers completed the study. The area under the curve was significantly larger on both the sildenafil and the calcitonin gene-related peptide day in the intradural middle meningeal artery (calcitonin gene-related peptide, p = 0.013; sildenafil, p = 0.027) and the extracranial middle meningeal artery (calcitonin gene-related peptide, p = 0.0003; sildenafil, p = 0.021), compared to placebo. Peak intradural middle meningeal artery dilation was 9.9% (95% CI [2.9-16.9]) after sildenafil (T) and 12.5% (95% CI [8.1-16.8]) after calcitonin gene-related peptide (T). Peak dilation of the extracranial middle meningeal artery after calcitonin gene-related peptide (T) was 15.7% (95% CI [11.2-20.1]) and 18.9% (95% CI [12.8-24.9]) after sildenafil (T).

Conclusion: An important novel finding is that both sildenafil and calcitonin gene-related peptide dilate intradural arteries, supporting the notion that all known pharmacological migraine triggers dilate cephalic vessels. We suggest that intradural artery dilation is associated with headache induced by calcitonin gene-related peptide and sildenafil.
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http://dx.doi.org/10.1177/0333102418787336DOI Listing
February 2019

Interindividual and regional relationship between cerebral blood flow and glucose metabolism in the resting brain.

J Appl Physiol (1985) 2018 10 5;125(4):1080-1089. Epub 2018 Jul 5.

Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen , Denmark.

Studies of the resting brain measurements of cerebral blood flow (CBF) show large interindividual and regional variability, but the metabolic basis of this variability is not fully established. The aim of the present study was to reassess regional and interindividual relationships between cerebral perfusion and glucose metabolism in the resting brain. Regional quantitative measurements of CBF and cerebral metabolic rate of glucose (CMR) were obtained in 24 healthy young men using dynamic [O]HO and [F]fluorodeoxyglucose positron emission tomography (PET). Magnetic resonance imaging measurements of global oxygen extraction fraction (gOEF) and metabolic rate of oxygen ([Formula: see text]) were obtained by combined susceptometry-based sagittal sinus oximetry and phase contrast mapping. No significant interindividual associations between global CBF, global CMR, and [Formula: see text] were observed. Linear mixed-model analysis showed a highly significant association of CBF with CMR regionally. Compared with neocortex significantly higher CBF values than explained by CMR were demonstrated in infratentorial structures, thalami, and mesial temporal cortex, and lower values were found in the striatum and cerebral white matter. The present study shows that absolute quantitative global CBF measurements appear not to be a valid surrogate measure of global cerebral glucose or oxygen consumption, and further demonstrates regionally variable relationship between perfusion and glucose metabolism in the resting brain that could suggest regional differences in energy substrate metabolism. NEW & NOTEWORTHY Using method-independent techniques the study cannot confirm direct interindividual correlations of absolute global values of perfusion with oxygen or glucose metabolism in the resting brain, and absolute global perfusion measurements appear not to be valid surrogate measures of cerebral metabolism. The ratio of both perfusion and oxygen delivery to glucose metabolism varies regionally, also when accounting for known methodological regional bias in quantification of glucose metabolism.
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http://dx.doi.org/10.1152/japplphysiol.00276.2018DOI Listing
October 2018

Impaired cerebrovascular reactivity in obstructive sleep apnea: a case-control study.

Sleep Med 2018 03 15;43:7-13. Epub 2017 Nov 15.

Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Rigshospitalet, Glostrup, Denmark; Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark.

Objective: Obstructive sleep apnea (OSA) is an independent risk factor for stroke. Little is known about the cerebrovascular hemodynamic changes during apnea. Hypercapnia occurs in apneas and hypopneas, and a reduced cerebral vasodilatory response to CO could compromise the cerebral blood flow (CBF). Therefore, we aimed to evaluate whether the apnea-hypopnea index (AHI) affected the cerebrovascular response to CO.

Methods: A total of 11 patients with OSA were compared to 16 controls. We assessed the cerebrovascular responses with arterial spin labeling (ASL) and blood oxygen level-dependent (BOLD) magnetic resonance imaging during hypercapnia or breath-holding tasks.

Results: The CBF response to CO was impaired with increasing AHI (average CBF: p = 0.018; gray matter: p = 0.038; white matter: p = 0.045), that is, increased OSA severity. When comparing the OSA patients to the control subjects, the OSA patients had a significantly reduced CO response of the white matter CBF (p = 0.04). However, the BOLD response to CO and the breath-holding task did not show any significant differences between OSA patients and control subjects.

Conclusion: The cerebrovascular CO reactivity, measured by the CBF, was impaired with increasing AHI, that is, OSA severity. These findings may add to the understanding of the increased stroke risk found in OSA patients.
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http://dx.doi.org/10.1016/j.sleep.2017.10.010DOI Listing
March 2018

No evidence for direct effects of recombinant human erythropoietin on cerebral blood flow and metabolism in healthy humans.

J Appl Physiol (1985) 2018 04 11;124(4):1107-1116. Epub 2018 Jan 11.

Department of Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen , Copenhagen , Denmark.

Erythropoietin (EPO) is expressed in human brain tissue, but its exact role is unknown. EPO may improve the efficiency of oxidative metabolism and has neuroprotective properties against hypoxic injuries in animal models. We aimed to investigate the effect of recombinant human EPO (rHuEPO) administration on healthy cerebral metabolism in humans during normoxia and during metabolic stress by inhalation of 10% O hypoxic air. Twenty-four healthy men participated in a two-arm double-blind placebo-controlled trial. rHuEPO was administered as a low dose (5,000 IU) over 4 wk ( n = 12) or as a high dose (500 IU·kg body wt·day) for three consecutive days ( n = 12). Global cerebral blood flow (CBF) and metabolic rate of glucose (CMR) were measured with positron emission tomography. CBF, metabolic rate of oxygen ([Formula: see text]), and cerebral lactate concentration were measured by magnetic resonance imaging and spectroscopy. Low-dose treatment increased hemoglobin and was associated with a near-significant decrease in CBF during baseline normoxia. High-dose treatment caused no change in CBF. Neither treatment had an effect on normoxia CMR, [Formula: see text], or lactate concentration or an effect on the cerebral metabolic response to inhalation of hypoxic air. In conclusion, the study found no evidence for a direct effect of rHuEPO on cerebral metabolism. NEW & NOTEWORTHY We demonstrate with magnetic resonance imaging and positron emission tomography that administration of erythropoietin does not have a substantial direct effect on healthy human resting cerebral blood flow or effect on cerebral glucose and oxygen metabolism. Also, administration of erythropoietin did not have a direct effect on the metabolic response to acute hypoxic stress in healthy humans, and a suggested neuroprotective effect from erythropoietin is therefore likely not a direct effect of erythropoietin on cerebral metabolism.
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http://dx.doi.org/10.1152/japplphysiol.00869.2017DOI Listing
April 2018

Hybrid PET/MRI imaging in healthy unsedated newborn infants with quantitative rCBF measurements using O-water PET.

J Cereb Blood Flow Metab 2019 05 15;39(5):782-793. Epub 2018 Jan 15.

1 Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

In this study, a new hybrid PET/MRI method for quantitative regional cerebral blood flow (rCBF) measurements in healthy newborn infants was assessed and the low values of rCBF in white matter previously obtained by arterial spin labeling (ASL) were tested. Four healthy full-term newborn subjects were scanned in a PET/MRI scanner during natural sleep after median intravenous injection of 14 MBq O-water. Regional CBF was quantified using a one-tissue-compartment model employing an image-derived input function (IDIF) from the left ventricle. PET rCBF showed the highest values in the thalami, mesencephalon and brain stem and the lowest in cortex and unmyelinated white matter. The average global CBF was 17.8 ml/100 g/min. The average frontal and occipital unmyelinated white matter CBF was 10.3 ml/100 g/min and average thalamic CBF 31.3 ml/100 g/min. The average white matter/thalamic ratio CBF was 0.36, significantly higher than previous ASL data. The rCBF ASL measurements were all unsuccessful primarily owing to subject movement. In this study, we demonstrated for the first time, a minimally invasive PET/MRI method using low activity O-water PET for quantitative rCBF assessment in unsedated healthy newborn infants and found a white/grey matter CBF ratio similar to that of the adult human brain.
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http://dx.doi.org/10.1177/0271678X17751835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501508PMC
May 2019

Safety and EEG data quality of concurrent high-density EEG and high-speed fMRI at 3 Tesla.

PLoS One 2017 26;12(5):e0178409. Epub 2017 May 26.

Department of Neurology, University of New Mexico, Albuquerque, NM, United States of America.

Purpose: Concurrent EEG and fMRI is increasingly used to characterize the spatial-temporal dynamics of brain activity. However, most studies to date have been limited to conventional echo-planar imaging (EPI). There is considerable interest in integrating recently developed high-speed fMRI methods with high-density EEG to increase temporal resolution and sensitivity for task-based and resting state fMRI, and for detecting interictal spikes in epilepsy. In the present study using concurrent high-density EEG and recently developed high-speed fMRI methods, we investigate safety of radiofrequency (RF) related heating, the effect of EEG on cortical signal-to-noise ratio (SNR) in fMRI, and assess EEG data quality.

Materials And Methods: The study compared EPI, multi-echo EPI, multi-band EPI and multi-slab echo-volumar imaging pulse sequences, using clinical 3 Tesla MR scanners from two different vendors that were equipped with 64- and 256-channel MR-compatible EEG systems, respectively, and receive only array head coils. Data were collected in 11 healthy controls (3 males, age range 18-70 years) and 13 patients with epilepsy (8 males, age range 21-67 years). Three of the healthy controls were scanned with the 256-channel EEG system, the other subjects were scanned with the 64-channel EEG system. Scalp surface temperature, SNR in occipital cortex and head movement were measured with and without the EEG cap. The degree of artifacts and the ability to identify background activity was assessed by visual analysis by a trained expert in the 64 channel EEG data (7 healthy controls, 13 patients).

Results: RF induced heating at the surface of the EEG electrodes during a 30-minute scan period with stable temperature prior to scanning did not exceed 1.0° C with either EEG system and any of the pulse sequences used in this study. There was no significant decrease in cortical SNR due to the presence of the EEG cap (p > 0.05). No significant differences in the visually analyzed EEG data quality were found between EEG recorded during high-speed fMRI and during conventional EPI (p = 0.78). Residual ballistocardiographic artifacts resulted in 58% of EEG data being rated as poor quality.

Conclusion: This study demonstrates that high-density EEG can be safely implemented in conjunction with high-speed fMRI and that high-speed fMRI does not adversely affect EEG data quality. However, the deterioration of the EEG quality due to residual ballistocardiographic artifacts remains a significant constraint for routine clinical applications of concurrent EEG-fMRI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178409PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446172PMC
September 2017

Brain capillary transit time heterogeneity in healthy volunteers measured by dynamic contrast-enhanced T -weighted perfusion MRI.

J Magn Reson Imaging 2017 06 12;45(6):1809-1820. Epub 2016 Oct 12.

Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Glostrup, Denmark.

Purpose: Capillary transit time heterogeneity, measured as CTH, may set the upper limit for extraction of substances in brain tissue, e.g., oxygen. The purpose of this study was to investigate the feasibility of dynamic contrast-enhanced T weighted MRI (DCE-MRI) at 3 Tesla (T), in estimating CTH based on a gamma-variate model of the capillary transit time distribution. In addition, we wanted to investigate if a subtle increase of the blood-brain barrier permeability can be incorporated into the model, still allowing estimation of CTH.

Materials And Methods: Twenty-three healthy subjects were scanned at 3.0T MRI system applying DCE-MRI and using a gamma-variate model to estimate CTH as well as cerebral blood flow (CBF), cerebral blood volume (CBV), and permeability of the blood-brain barrier, measured as the influx constant K . For proof of principle we also investigated three patients with recent thromboembolic events and a patient with a high grade brain tumor.

Results: In the healthy subjects, we found a narrow symmetric delta-like capillary transit time distribution in basal ganglia gray matter with median CTH of 0.93 s and interquartile range of 1.33 s. The corresponding residue impulse response function was compatible with the adiabatic tissue homogeneity model. In two patients with complete occlusion of the internal carotid artery and in the patient with a brain tumor CTH was increased with values up to 6 s in the affected brain tissue, with an exponential like residue impulse response function.

Conclusion: Our results open the possibility of characterizing brain perfusion by the capillary transit time distribution using DCE-MRI, theoretically a determinant of efficient blood to brain transport of important substances.

Level Of Evidence: 2 J. MAGN. RESON. IMAGING 2017;45:1809-1820.
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http://dx.doi.org/10.1002/jmri.25488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484282PMC
June 2017

Comparison of global cerebral blood flow measured by phase-contrast mapping MRI with O-H O positron emission tomography.

J Magn Reson Imaging 2017 03 13;45(3):692-699. Epub 2016 Sep 13.

Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital Rigshospitalet Blegdamsvej, Copenhagen, Denmark.

Purpose: To compare mean global cerebral blood flow (CBF) measured by phase-contrast mapping magnetic resonance imaging (PCM MRI) and by O-H O positron emission tomography (PET) in healthy subjects. PCM MRI is increasingly being used to measure mean global CBF, but has not been validated in vivo against an accepted reference technique.

Materials And Methods: Same-day measurements of CBF by O-H O PET and subsequently by PCM MRI were performed on 22 healthy young male volunteers. Global CBF by PET was determined by applying a one-tissue compartment model with measurement of the arterial input function. Flow was measured in the internal carotid and vertebral arteries by a noncardiac triggered PCM MRI sequence at 3T. The measured flow was normalized to total brain weight determined from a volume-segmented 3D T -weighted anatomical MR-scan.

Results: Mean CBF was 34.9 ± 3.4 mL/100 g/min measured by O-H O PET and 57.0 ± 6.8 mL/100 g/min measured by PCM MRI. The measurements were highly correlated (P = 0.0008, R  = 0.44), although values obtained by PCM MRI were higher compared to O-H O PET (absolute and relative differences were 22.0 ± 5.2 mL/100 g/min and 63.4 ± 14.8%, respectively).

Conclusion: This study confirms the use of PCM MRI for quantification of global CBF, but also that PCM MRI systematically yields higher values relative to O-H O PET, probably related to methodological bias.

Level Of Evidence: 3 J. Magn. Reson. Imaging 2017;45:692-699.
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http://dx.doi.org/10.1002/jmri.25442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324556PMC
March 2017

Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy.

Neurotherapeutics 2017 01;14(1):182-190

Lundbeck Foundation Center for Neurovascular signalling (LUCENS), Rigshospitalet Glostrup, University of Copenhagen, Glostrup, Denmark.

Patients suffering from Becker muscular dystrophy (BMD) have dysfunctional dystrophin proteins and are deficient in neuronal nitric oxide synthase (nNOS) in muscles. This causes functional ischemia and contributes to muscle wasting. Similar functional ischemia may be present in brains of patients with BMD, who often have mild cognitive impairment, and nNOS may be important for the regulation of the microvascular circulation in the brain. We hypothesized that treatment with sildenafil, a phosphodiesterase type 5 inhibitor that potentiates nitric oxide responses, would augment both the blood oxygen level-dependent (BOLD) response and cerebral blood flow (CBF) in patients with BMD. Seventeen patients (mean ± SD age 38.5 ± 10.8 years) with BMD were included in this randomized, double-blind, placebo-controlled, crossover trial. Twelve patients completed the entire study. Effects of sildenafil were assessed by 3 T magnetic resonance (MR) scanning, evoked potentials, somatosensory task-induced BOLD functional MR imaging, regional and global perfusion, and angiography before and after 4 weeks of sildenafil, 20 mg (Revatio in gelatine capsules, oral, 3 times daily), or placebo treatment. Sildenafil increased the event-related sensory and visual BOLD response compared with placebo (p < 0.01). However, sildenafil did not alter CBF, measured by MR phase contrast mapping, or the arterial diameter of the middle cerebral artery, measured by MR angiography. We conclude that nNOS may play a role in event-related neurovascular responses. Further studies in patients with BMD may help clarify the roles of dystrophin and nNOS in neurovascular coupling in general, and in patients with BMD in particular.
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http://dx.doi.org/10.1007/s13311-016-0467-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233618PMC
January 2017

Evidence of a Christmas spirit network in the brain: functional MRI study.

BMJ 2015 Dec 16;351:h6266. Epub 2015 Dec 16.

Functional Imaging Unit and Department of Clinical Physiology, Nuclear Medicine and PET, Rigshopitalet, Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark

Objective: To detect and localise the Christmas spirit in the human brain.

Design: Single blinded, cross cultural group study with functional magnetic resonance imaging (fMRI).

Setting: Functional imaging unit and department of clinical physiology, nuclear medicine and PET in Denmark.

Participants: 10 healthy people from the Copenhagen area who routinely celebrate Christmas and 10 healthy people living in the same area who have no Christmas traditions.

Main Outcome Measures: Brain activation unique to the group with Christmas traditions during visual stimulation with images with a Christmas theme.

Methods: Functional brain scans optimised for detection of the blood oxygen level dependent (BOLD) response were performed while participants viewed a series of images with Christmas themes interleaved with neutral images having similar characteristics but containing nothing that symbolises Christmas. After scanning, participants answered a questionnaire about their Christmas traditions and the associations they have with Christmas. Brain activation maps from scanning were analysed for Christmas related activation in the "Christmas" and "non-Christmas" groups individually. Subsequently, differences between the two groups were calculated to determine Christmas specific brain activation.

Results: Significant clusters of increased BOLD activation in the sensory motor cortex, the premotor and primary motor cortex, and the parietal lobule (inferior and superior) were found in scans of people who celebrate Christmas with positive associations compared with scans in a group having no Christmas traditions and neutral associations. These cerebral areas have been associated with spirituality, somatic senses, and recognition of facial emotion among many other functions.

Conclusions: There is a "Christmas spirit network" in the human brain comprising several cortical areas. This network had a significantly higher activation in a people who celebrate Christmas with positive associations as opposed to a people who have no Christmas traditions and neutral associations. Further research is necessary to understand this and other potential holiday circuits in the brain. Although merry and intriguing, these findings should be interpreted with caution.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681765PMC
http://dx.doi.org/10.1136/bmj.h6266DOI Listing
December 2015

Acute hypoxia increases the cerebral metabolic rate - a magnetic resonance imaging study.

J Cereb Blood Flow Metab 2016 06 2;36(6):1046-58. Epub 2015 Oct 2.

Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Glostrup, Denmark Institute of Clinical Medicine, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

The aim of the present study was to examine changes in cerebral metabolism by magnetic resonance imaging of healthy subjects during inhalation of 10% O2 hypoxic air. Hypoxic exposure elevates cerebral perfusion, but its effect on energy metabolism has been less investigated. Magnetic resonance imaging techniques were used to measure global cerebral blood flow and the venous oxygen saturation in the sagittal sinus. Global cerebral metabolic rate of oxygen was quantified from cerebral blood flow and arteriovenous oxygen saturation difference. Concentrations of lactate, glutamate, N-acetylaspartate, creatine and phosphocreatine were measured in the visual cortex by magnetic resonance spectroscopy. Twenty-three young healthy males were scanned for 60 min during normoxia, followed by 40 min of breathing hypoxic air. Inhalation of hypoxic air resulted in an increase in cerebral blood flow of 15.5% (p = 0.058), and an increase in cerebral metabolic rate of oxygen of 8.5% (p = 0.035). Cerebral lactate concentration increased by 180.3% ([Formula: see text]), glutamate increased by 4.7% ([Formula: see text]) and creatine and phosphocreatine decreased by 15.2% (p[Formula: see text]). The N-acetylaspartate concentration was unchanged (p = 0.36). In conclusion, acute hypoxia in healthy subjects increased perfusion and metabolic rate, which could represent an increase in neuronal activity. We conclude that marked changes in brain homeostasis occur in the healthy human brain during exposure to acute hypoxia.
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http://dx.doi.org/10.1177/0271678X15606460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904346PMC
June 2016

Positron emission tomography/magnetic resonance hybrid scanner imaging of cerebral blood flow using (15)O-water positron emission tomography and arterial spin labeling magnetic resonance imaging in newborn piglets.

J Cereb Blood Flow Metab 2015 Nov 10;35(11):1703-10. Epub 2015 Jun 10.

Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Abnormality in cerebral blood flow (CBF) distribution can lead to hypoxic-ischemic cerebral damage in newborn infants. The aim of the study was to investigate minimally invasive approaches to measure CBF by comparing simultaneous (15)O-water positron emission tomography (PET) and single TI pulsed arterial spin labeling (ASL) magnetic resonance imaging (MR) on a hybrid PET/MR in seven newborn piglets. Positron emission tomography was performed with IV injections of 20 MBq and 100 MBq (15)O-water to confirm CBF reliability at low activity. Cerebral blood flow was quantified using a one-tissue-compartment-model using two input functions: an arterial input function (AIF) or an image-derived input function (IDIF). The mean global CBF (95% CI) PET-AIF, PET-IDIF, and ASL at baseline were 27 (23; 32), 34 (31; 37), and 27 (22; 32) mL/100 g per minute, respectively. At acetazolamide stimulus, PET-AIF, PET-IDIF, and ASL were 64 (55; 74), 76 (70; 83) and 79 (67; 92) mL/100 g per minute, respectively. At baseline, differences between PET-AIF, PET-IDIF, and ASL were 22% (P<0.0001) and -0.7% (P=0.9). At acetazolamide, differences between PET-AIF, PET-IDIF, and ASL were 19% (P=0.001) and 24% (P=0.0003). In conclusion, PET-IDIF overestimated CBF. Injected activity of 20 MBq (15)O-water had acceptable concordance with 100 MBq, without compromising image quality. Single TI ASL was questionable for regional CBF measurements. Global ASL CBF and PET CBF were congruent during baseline but not during hyperperfusion.
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http://dx.doi.org/10.1038/jcbfm.2015.139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635240PMC
November 2015

Effect of sildenafil on skeletal and cardiac muscle in Becker muscular dystrophy.

Ann Neurol 2014 Oct 15;76(4):550-7. Epub 2014 Jul 15.

Neuromuscular Research Unit and Department of Neurology, Rigshospitalet, University Hospital Glostrup, University of Copenhagen, Copenhagen, Denmark.

Objective: Patients with Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy lack neuronal nitric oxide synthase (nNOS). nNOS mediates physiological sympatholysis, thus ensuring adequate blood supply to working muscle. In mice lacking dystrophin, restoration of nNOS effects by a phosphodiesterase 5 (PDE5) inhibitor (sildenafil) improves skeletal and cardiac muscle performance. Sildenafil also improves blood flow in patients with BMD. We therefore hypothesized that sildenafil would improve blood flow, maximal work capacity, and heart function in patients with BMD.

Methods: A randomized, double-blind, placebo-controlled crossover design with two 4-week periods of treatment, separated by 2-week washout was used. We assessed brachial artery blood flow during maximal handgrip exercise, 6-minute walk test, maximal oxidative capacity, and life quality; cardiac function was evaluated by magnetic resonance imaging (MRI) at rest and during maximal handgrip exercise. Muscle nNOS and PDE5 were tested with Western blotting in 5 patients.

Results: Sixteen patients completed all skeletal muscle evaluations, and 13 completed the cardiac MRI investigations. Sildenafil had no effect on any of the outcome parameters. No serious adverse effects were recorded. PDE5 and nNOS were deficient in 5 of 5 biopsies.

Interpretation: Despite positive evidence from animal models of dystrophinopathy and physiological findings in patients with BMD, this double-blind, placebo-controlled clinical study showed no effect of sildenafil on blood flow, maximal work capacity, and heart function in adults with BMD. This discrepancy may be explained by a significant downregulation of PDE5 in muscle.
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http://dx.doi.org/10.1002/ana.24216DOI Listing
October 2014
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