Ulrich Lindberg

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

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.

Acute hypoxia increases the cerebral metabolic rate – a magnetic resonance imaging study:

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% ( p < 10 - 6 ), glutamate increased by 4.7% ( p < 10 - 4 ) and creatine and phosphocreatine decreased by 15.2% (p < 10 - 3 ). 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.

Positron Emission Tomography/Magnetic Resonance Hybrid Scanner Imaging of Cerebral Blood Flow Using 15O-Water Positron Emission Tomography and Arterial Spin Labeling Magnetic Resonance Imaging in Newborn Piglets

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 15O-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 15O-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 15O-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.

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

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.

Brain capillary transit time heterogeneity in healthy volunteers measured by dynamic contrast‐enhanced T1‐weighted perfusion MRI

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 T1 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.

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

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.

Hybrid PET/MRI imaging in healthy unsedated newborn infants with quantitative rCBF measurements using 15O-water PET

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 15O-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 15O-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.

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

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 (CMRglc) were obtained in 24 healthy young men using dynamic [15O]H2O and [18F]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 CMRglc, and [Formula: see text] were observed. Linear mixed-model analysis showed a highly significant association of CBF with CMRglc regionally. Compared with neocortex significantly higher CBF values than explained by CMRglc 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.

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

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 curveBaseline-120min 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 (T30min) and 12.5% (95% CI [8.1–16.8]) after calcitonin gene-related peptide (T30min). Peak dilation of the extracranial middle meningeal artery after calcitonin gene-related peptide (T30min) was 15.7% (95% CI [11.2–20.1]) and 18.9% (95% CI [12.8–24.9]) after sildenafil (T120min). 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.

Altered somatosensory neurovascular response in patients with Becker muscular dystrophy

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.