Efficient total variation algorithm for fetal brain MRI reconstruction.

Fetal MRI reconstruction aims at finding a high-resolution image given a small set of low-resolution images. It is usually modeled as an inverse problem where the regularization term plays a central role in the reconstruction quality. Literature has considered several regularization terms s.a. Dirichlet/Laplacian energy, Total Variation (TV)- based energies and more recently non-local means. Although TV energies are quite attractive because of their ability in edge preservation, standard explicit steepest gradient techniques have been applied to optimize fetal-based TV energies. The main contribution of this work lies in the introduction of a well-posed TV algorithm from the point of view of convex optimization. Specifically, our proposed TV optimization algorithm or fetal reconstruction is optimal w.r.t. the asymptotic and iterative convergence speeds O(1/n2) and O(1/√ε), while existing techniques are in O(1/n2) and O(1/√ε). We apply our algorithm to (1) clinical newborn data, considered as ground truth, and (2) clinical fetal acquisitions. Our algorithm compares favorably with the literature in terms of speed and accuracy.

Expression of dual angiogenic/neurogenic growth factors in human primary brain tumors.

Brain tumors, benign or malignant, are characterized by a very high degree of vascularization. Recent accumulating evidence suggests that during development the neuronal wiring follows the same routes as the vasculature and that these two systems may share some of the same factors for guidance. Thus, expression of dual angiogenic/neurogenic growth factors was evaluated by in situ hybridization in human primary brain tumors of three different types, i.e., astrocytomas, oligodendrogliomas, and ependymomas, of increasing grades, in relation with the grade and type of the tumor. For this evaluation we selected vascular endothelial growth factor (VEGF-A) and its receptors VEGF-R1 and VEGF-R2 and the neuropilins 1 and 2 (NRP-1 and NRP-2), which have proangiogenic properties, platelet-derived growth factor (PDGF) receptor-beta (PDGF-Rβ), which is required for the functional maturation of blood vessels, the ephrins and their Eph receptors, angiotensinogen (AGT) and thrombospondin-2 (TSP-2), which have potential antiangiogenic properties, and netrin-1 (Net-1), which regulates vascular architecture. We show that the expression of the VEGF-NRP system, PDGF-Rβ, TSP-2, AGT, and Net-1 are differentially regulated, either increased or decreased, in relation with the type and grade of the tumor, whereas regulation of the ephrinB system does not seem to be relevant in these human brain tumors.

Optimized MEGA-SPECIAL for in vivo glutamine detection in the rat brain at 14.1 T.

Glutamine has multiple roles in brain metabolism and its concentration can be altered in various pathological conditions. An accurate knowledge of its concentration is therefore highly desirable to monitor and study several brain disorders in vivo. However, in recent years, several MRS studies have reported conflicting glutamine concentrations in the human brain. A recent hypothesis for explaining these discrepancies is that a short T2 component of the glutamine signal may impact on its quantification at long echo times. The present study therefore aimed to investigate the impact of acquisition parameters on the quantified glutamine concentration using two different acquisition techniques, SPECIAL at ultra-short echo time and MEGA-SPECIAL at moderate echo time. For this purpose, MEGA-SPECIAL was optimized for the first time for glutamine detection. Based on the very good agreement of the glutamine concentration obtained between the two measurements, it was concluded that no impact of a short T2 component of the glutamine signal was detected.

Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury.

OBJECTIVES: We have sought to develop an automated methodology for the continuous updating of optimal cerebral perfusion pressure (CPPopt) for patients after severe traumatic head injury, using continuous monitoring of cerebrovascular pressure reactivity. We then validated the CPPopt algorithm by determining the association between outcome and the deviation of actual CPP from CPPopt. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Neurosciences critical care unit of a university hospital. PATIENTS: A total of 327 traumatic head-injury patients admitted between 2003 and 2009 with continuous monitoring of arterial blood pressure and intracranial pressure. MEASUREMENTS AND MAIN RESULTS: Arterial blood pressure, intracranial pressure, and CPP were continuously recorded, and pressure reactivity index was calculated online. Outcome was assessed at 6 months. An automated curve fitting method was applied to determine CPP at the minimum value for pressure reactivity index (CPPopt). A time trend of CPPopt was created using a moving 4-hr window, updated every minute. Identification of CPPopt was, on average, feasible during 55% of the whole recording period. Patient outcome correlated with the continuously updated difference between median CPP and CPPopt (chi-square=45, p<.001; outcome dichotomized into fatal and nonfatal). Mortality was associated with relative "hypoperfusion" (CPP<CPPopt), severe disability with "hyperperfusion" (CPP>CPPopt), and favorable outcome was associated with smaller deviations of CPP from the individualized CPPopt. While deviations from global target CPP values of 60 mm Hg and 70 mm Hg were also related to outcome, these relationships were less robust. CONCLUSIONS: Real-time CPPopt could be identified during the recording time of majority of the patients. Patients with a median CPP close to CPPopt were more likely to have a favorable outcome than those in whom median CPP was widely different from CPPopt. Deviations from individualized CPPopt were more predictive of outcome than deviations from a common target CPP. CPP management to optimize cerebrovascular pressure reactivity should be the subject of future clinical trial in severe traumatic head-injury patients.

Parenchymal brain oxygen monitoring in the neurocritical care unit.

Patients admitted to the neurocritical care unit (NCCU) often have serious conditions that can be associated with high morbidity and mortality. Pharmacologic agents or neuroprotectants have disappointed in the clinical environment. Current NCCU management therefore is directed toward identification, prevention, and treatment of secondary cerebral insults that evolve over time and are known to aggravate outcome. This strategy is based on a variety of monitoring techniques including use of intraparenchymal monitors. This article reviews parenchymal brain oxygen monitors, including the available technologies, practical aspects of use, the physiologic rationale behind their use, and patient management based on brain oxygen.

Single spin-echo T 2 relaxation times of cerebral metabolites at 14.1 T in the in vivo rat brain.

OBJECT: To determine the single spin-echo T 2 relaxation times of uncoupled and J-coupled metabolites in rat brain in vivo at 14.1 T and to compare these results with those previously obtained at 9.4 T. MATERIALS AND METHODS: Measurements were performed on five rats at 14.1 T using the SPECIAL sequence and TE-specific basis-sets for LCModel analysis. RESULTS AND CONCLUSION: The T 2 of singlets ranged from 98 to 148 ms and T 2 of J-coupled metabolites ranged from 72 ms (glutamate) to 97 ms (myo-inositol). When comparing the T 2s of the metabolites measured at 14.1 T with those previously measured at 9.4 T, a decreasing trend was found (p < 0.0001). We conclude that the modest shortening of T 2 at 14.1 T has a negligible impact on the sensitivity of the (1)H MRS when performed at TE shorter than 10 ms.

Age-related differences on event-related potentials and brain rhythm oscillations during working memory activation.

Previous functional imaging studies have pointed to the compensatory recruitment of cortical circuits in old age in order to counterbalance the loss of neural efficiency and preserve cognitive performance. Recent electroencephalographic (EEG) analyses reported age-related deficits in the amplitude of an early positive-negative working memory (PN(wm)) component as well as changes in working memory (WM)-load related brain oscillations during the successful performance of the n-back task. To explore the age-related differences of EEG activation in the face of increasing WM demands, we assessed the PN(wm) component area, parietal alpha event-related synchronization (ERS) as well as frontal theta ERS in 32 young and 32 elderly healthy individuals who successfully performed a highly WM demanding 3-back task. PN(wm) area increased with higher memory loads (3- and 2-back > 0-back tasks) in younger subjects. Older subjects reached the maximal values for this EEG parameter during the less WM demanding 0-back task. They showed a rapid development of an alpha ERS that reached its maximal amplitude at around 800 ms after stimulus onset. In younger subjects, the late alpha ERS occurred between 1,200 and 2,000 ms and its amplitude was significantly higher compared with elders. Frontal theta ERS culmination peak decreased in a task-independent manner in older compared with younger cases. Only in younger individuals, there was a significant decrease in the phasic frontal theta ERS amplitude in the 2- and 3-back tasks compared with the detection and 0-back tasks. These observations suggest that older adults display a rapid mobilization of their neural generators within the parietal cortex to manage very low demanding WM tasks. Moreover, they are less able to activate frontal theta generators during attentional tasks compared with younger persons.

Hand-disinfectant alcoholic vapors in incubators

Objective: To analyze the atmosphere inside incubators regarding alcoholic solvent such as isopropanol or ethanol which are commonly used in hand disinfecting solutions. Design: Observational. Setting: The third level neonatal unit of the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Patients: Nine neonates with median (range) gestational age of 29 4/7 (25 5/7-39 0/7) weeks and birth weight of 960 (550-3050) grams. All neonates were inside incubators. Interventions: Alcoholic vapors inside incubators were directly and cumulatively measured by photoionisation and gas chromatography respectively after absorption on a charcoal sampling tube. Results: Eleven studies (mean study time: 230 ± 19 minutes) were performed. Highly variable isopropanol/ethanol concentrations profiles were found inside incubators. Peak value for isopropanol was 1982 part per million and for ethanol was 906 part per million. Conclusions: Incubators' inner atmosphere can be highly polluted by alcohol vapors. To reduce them staff should respect long evaporation time between hands disinfection and manipulations inside incubators. The use of an ethanol-based disinfecting solution, because of its short evaporation time, could be favored. As alcohol vapor toxicity for neonate remains largely unknown, further studies could be welcome.

Genotype-phenotype interactions in primary dystonias revealed by differential changes in brain structure.

Our understanding of how genotype determines phenotype in primary dystonia is limited. Familial young-onset primary dystonia is commonly due to the DYT1 gene mutation. A critical question, given the 30% penetrance of clinical symptoms in DYT1 mutation carriers, is why the same genotype leads to differential clinical expression and whether non-DYT1 adult-onset primary dystonia, with and without family history share pathophysiological mechanisms with DYT1 dystonia. This study examines the relationship between dystonic phenotype and the DYT1 gene mutation by monitoring whole-brain structure using voxel-based morphometry. We acquired magnetic resonance imaging data of symptomatic and asymptomatic DYT1 mutation carriers, of non-DYT1 primary dystonia patients, with and without family history and control subjects with normal DYT1 alleles. By crossing the factors genotype and phenotype we demonstrate a significant interaction in terms of brain anatomy confined to the basal ganglia bilaterally. The explanation for this effect differs according to both gene and dystonia status: non-DYT1 adult-onset dystonia patients and asymptomatic DYT1 carriers have significantly larger basal ganglia compared to healthy subjects and symptomatic DYT1 mutation carriers. There is a significant negative correlation between severity of dystonia and basal ganglia size in DYT1 mutation carriers. We propose that differential pathophysiological and compensatory mechanisms lead to brain structure changes in non-DYT1 primary adult-onset dystonias and DYT1 gene carriers. Given the range of age of onset, there may be differential genetic modulation of brain development that in turn determines clinical expression. Alternatively, a DYT1 gene dependent primary defect of motor circuit development may lead to stress-induced remodelling of the basal ganglia and hence dystonia.

Targeting PI3KC2β Impairs Proliferation and Survival in Acute Leukemia, Brain Tumours and Neuroendocrine Tumours.

BACKGROUND: Eight human catalytic phosphoinositide 3-kinase (PI3K) isoforms exist which are subdivided into three classes. While class I isoforms have been well-studied in cancer, little is known about the functions of class II PI3Ks. MATERIALS AND METHODS: The expression pattern and functions of the class II PI3KC2β isoform were investigated in a panel of tumour samples and cell lines. RESULTS: Overexpression of PI3KC2β was found in subsets of tumours and cell lines from acute myeloid leukemia (AML), glioblastoma multiforme (GBM), medulloblastoma (MB), neuroblastoma (NB), and small cell lung cancer (SCLC). Specific pharmacological inhibitors of PI3KC2β or RNA interference impaired proliferation of a panel of human cancer cell lines and primary cultures. Inhibition of PI3KC2β also induced apoptosis and sensitised the cancer cells to chemotherapeutic agents. CONCLUSION: Together, these data show that PI3KC2β contributes to proliferation and survival in AML, brain tumours and neuroendocrine tumours, and may represent a novel target in these malignancies.

An immune-competent model of spontaneous breast cancer metastasis to the brain

In breast cancer, brain metastases are often seen as late complications of recurrent disease and represent a particularly serious condition, since there are limited therapeutic options and patients have an unfavorable prognosis. The frequency of brain metastases in breast cancer is currently on the rise. This might be due to the fact that adjuvant chemotherapeutic and targeted anticancer drugs, while they effectively control disease progression in the periphery, they only poorly cross the blood-brain barrier and do not reach effectively cancer cells disseminated in the brain. It is therefore of fundamental clinical relevance to investigate mechanisms involved in breast cancer metastasis to the brain. To date experimental models of breast cancer metastasis to the brain described in literature are based on the direct intracarotid or intracardiac injection of breast cancer cells. We recently established a brain metastasis breast cancer model in immunocompetent mice based on the orthotopic injection of 4T1 murine breast carcinoma cells in the mammary gland of syngeneic BALB/c mice. 4T1-derived tumors recapitulate the main steps of human breast cancer progression, including epithelial-to-mesenchymal transition, local invasion and metastatic spreading to lung and lymph nodes. 4T1 cells were engineered to stably express firefly Luciferase allowing noninvasive in vivo and ex vivo monitoring of tumor progression and metastatic spreading to target organs. Bioluminescence imaging revealed the appearance of spontaneous lesions to the lung and lymph nodes and, at a much lower frequency, to the brain. Brain metastases were confirmed by macroscopic and microscopic evaluation of the brains at necropsy. We then isolated brain metastatic cells, re-injected them orthotopically in new mice and isolated again lines from brain metastases. After two rounds of selection we obtained lines metastasizing to the brain with 100% penetrance (named 4T1-BM2 for Brain Metastasis, 2nd generation) compared to lines derived after two rounds of in vivo growth from primary tumors (4T1-T2) or from lung metastases (4T1-LM2). We are currently performing experiments to unravel differences in cell proliferation, adhesion, migration, invasion and survival of the 4T1-BM2 line relative to the 4T1-T2 and 4T1-LM2 lines. Initial results indicate that 4T1-BM2 cells are not more invasive or more proliferative in vitro and do not show a more mesenchymal phenotype. Our syngeneic (BALB/c) model of spontaneous breast carcinoma metastasis to the brain is a unique and clinically relevant model to unravel the mechanisms of metastatic breast cancer colonization of the brain. Genes identified in this model represent potentially clinically relevant therapeutic targets for the prevention and the treatment of brain metastases in breast cancer patients.

Creatine deficiency syndromes and the importance of creatine synthesis in the brain.

Creatine deficiency syndromes, due to deficiencies in AGAT, GAMT (creatine synthesis pathway) or SLC6A8 (creatine transporter), lead to complete absence or very strong decrease of creatine in CNS as measured by magnetic resonance spectroscopy. Brain is the main organ affected in creatine-deficient patients, who show severe neurodevelopmental delay and present neurological symptoms in early infancy. AGAT- and GAMT-deficient patients can be treated by oral creatine supplementation which improves their neurological status, while this treatment is inefficient on SLC6A8-deficient patients. While it has long been thought that most, if not all, of brain creatine was of peripheral origin, the past years have brought evidence that creatine can cross blood-brain barrier, however, only with poor efficiency, and that CNS must ensure parts of its creatine needs by its own endogenous synthesis. Moreover, we showed very recently that in many brain structures, including cortex and basal ganglia, AGAT and GAMT, while found in every brain cell types, are not co-expressed but are rather expressed in a dissociated way. This suggests that to allow creatine synthesis in these structures, guanidinoacetate must be transported from AGAT- to GAMT-expressing cells, most probably through SLC6A8. This new understanding of creatine metabolism and transport in CNS will not only allow a better comprehension of brain consequences of creatine deficiency syndromes, but will also contribute to better decipher creatine roles in CNS, not only in energy as ATP regeneration and buffering, but also in its recently suggested functions as neurotransmitter or osmolyte.

Increased plasma levels of N-terminal brain natriuretic peptide (NT-proBNP) in type 2 diabetic patients with vascular complications.

AIMS: The plasma levels of either brain natriuretic peptide (BNP) or the N-terminal fragment of the prohormone (NT-proBNP) have recently gained extreme importance as markers of myocardial dysfunction. Patients with type 2 diabetes are at high risk of developing cardiovascular complications. This study was aimed to assess whether plasma NT-proBNP levels are at similar levels in type 2 diabetics with or without overt cardiovascular diseases. METHODS: We assayed plasma NT-proBNP in 54 type 2 diabetics, 27 of whom had no overt macro- and/or microvascular complications, while the remaining ones had either or both. The same assay was carried out in 38 healthy control subjects age and sex matched as a group with the diabetics. RESULTS: Plasma NT-proBNP was higher in diabetics (median 121 pg/ml, interquartile range 50-240 pg/ml, ) than in those without complications (37 pg/ml, 21-54 pg/ml, P<0.01). Compared with the controls (55 pg/ml, 40-79 pg/ml), only diabetics with vascular complications had significantly increased plasma NT-proBNP levels (P<0.001). In the diabetics, coronary heart disease and nephropathy (defined according to urinary excretion of albumin) were each independently associated with elevated values of plasma NT-proBNP. CONCLUSIONS: In type 2 diabetes mellitus, patients with macro- and/or micro-vascular complications exhibit an elevation of plasma NT-proBNP levels compared to corresponding patients with no evidence of vascular disease. The excessive secretion of this peptide is independently associated with coronary artery disease and overt nephropathy. The measurement of circulating NT-proBNP concentration may therefore be useful to screen for the presence of macro- and/or microvascular disease.

Delayed Cyclic Activity Development on Early Amplitude-Integrated EEG in the Preterm Infant with Brain Lesions.

Background: Maturation of amplitude-integrated electroencephalogram (aEEG) activity is influenced by both gestational age (GA) and postmenstrual age. It is not fully known how this process is influenced by cerebral lesions. Objective: To compare early aEEG developmental changes between preterm newborns with different degrees of cerebral lesions on cranial ultrasound (cUS). Methods: Prospective cohort study on preterm newborns with GA <32.0 weeks, undergoing continuous aEEG recording during the first 84 h after birth. aEEG characteristics were qualitatively and quantitatively evaluated using pre-established criteria. Based on cUS findings three groups were formed: normal (n = 78), mild (n = 20), and severe cerebral lesions (n = 6). Linear mixed models for repeated measures were used to analyze aEEG maturational trajectories. Results: 104 newborns with a mean GA (range) 29.5 (24.4-31.7) weeks, and birth weight 1,220 (580-2,020) g were recruited. Newborns with severe brain lesions started with similar aEEG scores and tendentially lower aEEG amplitudes than newborns without brain lesions, and showed a slower development of the cyclic activity (p < 0.001), but a more rapid increase of the maximum and minimum aEEG amplitudes (p = 0.002 and p = 0.04). Conclusions: Preterm infants with severe cerebral lesions manifest a maturational delay in the aEEG cyclic activity already early after birth, but show a catch-up of aEEG amplitudes to that of newborns without cerebral lesions. Changes in the maturational aEEG pattern may be a marker of severe neurological lesions in the preterm infant.

In vivo 13C NMR spectroscopy and metabolic modeling in the brain: a practical perspective.

In vivo 13C NMR spectroscopy has the unique capability to measure metabolic fluxes noninvasively in the brain. Quantitative measurements of metabolic fluxes require analysis of the 13C labeling time courses obtained experimentally with a metabolic model. The present work reviews the ingredients necessary for a dynamic metabolic modeling study, with particular emphasis on practical issues.