Marta Varela

Development of BOLD signal hemodynamic responses in the human brain

In the rodent brain the hemodynamic response to a brief external stimulus changes significantly during development. Analogous changes in human infants would complicate the determination and use of the hemodynamic response function (HRF) for functional magnetic resonance imaging (fMRI) in developing populations. We aimed to characterize HRF in human infants before and after the normal time of birth using rapid sampling of the Blood Oxygen Level Dependent (BOLD) signal. A somatosensory stimulus and an event related experimental design were used to collect data from 10 healthy adults, 15 sedated infants at term corrected post menstrual age (PMA) (median 41 + 1 weeks), and 10 preterm infants (median PMA 34 + 4 weeks). A positive amplitude HRF waveform was identified across all subject groups, with a systematic maturational trend in terms of decreasing time-to-peak and increasing positive peak amplitude associated with increasing age. Application of the age-appropriate HRF models to fMRI data significantly improved the precision of the fMRI analysis. These findings support the notion of a structured development in the brains response to stimuli across the last trimester of gestation and beyond.

Superconductivity depression in ultrathin YBa2Cu3O7−δ layers in La0.7Ca0.3MnO3/YBa2Cu3O7−δ superlattices

We report on the depression of the superconducting critical temperature of ultrathin YBa2Cu3O7 (YBCO) layers, when their thickness is reduced in the presence of La0.7Ca0.3MnO3 (LCMO) magnetic layers in [LCMO (15 unit cells)/YBCO (N unit cells)] superlattices. The thickness of the manganite layer is kept at 15 unit cells and the YBCO thickness is varied between N=12 and N=1 unit cells. The structural analysis, using x-ray diffraction and electron microscopy, shows sharp interfaces with little structural disorder. While a critical temperature, TC=85 K, is found for 12 YBCO unit cells, superconductivity is completely suppressed for YBCO layer thickness below 3 unit cells. The possible interaction between superconductivity and magnetism is investigated.

A method for rapid in vivo measurement of blood T1

We present a technique to measure the longitudinal relaxation time constant of venous blood (T1b) in vivo in a few seconds. The MRI sequence consists of a thick‐slab adiabatic inversion, followed by a series of slice‐selective excitations and single‐shot echo planar imaging readouts. The time intervals between excitations were chosen so that blood in macroscopic vessels is fully refreshed between excitations, making the blood signal follow an unperturbed inversion recovery curve. Static tissue, which experiences the inversion and all excitation pulses, quickly reaches a steady state at a low signal as a result of partial saturation. This allows blood‐filled voxels to be discriminated from those containing static tissue, and to be fitted voxel‐by‐voxel to a simple inversion recovery model. The sequence was tested on a flow phantom with the proposed method, yielding T1 values consistent to within 3% of those obtained using a conventional inversion recovery sequence with a spin‐echo readout. The method was applied to seven adult volunteers and 18 neonates. The blood T1 of the neonates (1799 ± 206 ms; range, 1393–2035 ms) was found to be more variable than that of adults (1717 ± 39 ms; range, 1662–1779 ms). A linear correlation between the inverse of T1b and the haematocrit was established in 12 neonates (R2 = 0.90). Copyright

Evolution and pharmacological modulation of the arrhythmogenic wave dynamics in canine pulmonary vein model

Aims Atrial fibrillation (AF), the commonest cardiac arrhythmia, has been strongly linked with arrhythmogenic sources near the pulmonary veins (PVs), but underlying mechanisms are not fully understood. We aim to study the generation and sustenance of wave sources in a model of the PV tissue. Methods and results A previously developed biophysically detailed three-dimensional canine atrial model is applied. Effects of AF-induced electrical remodelling are introduced based on published experimental data, as changes of ion channel currents (ICaL, IK1, Ito, and IKur), the action potential (AP) and cell-to-cell coupling levels. Pharmacological effects are introduced by blocking specific ion channel currents. A combination of electrical heterogeneity (AP tissue gradients of 5–12 ms) and anisotropy (conduction velocities of 0.75–1.25 and 0.21–0.31 m/s along and transverse to atrial fibres) can results in the generation of wave breaks in the PV region. However, a long wavelength (171 mm) prevents the wave breaks from developing into re-entry. Electrical remodelling leads to decreases in the AP duration, conduction velocity and wavelength (to 49 mm), such that re-entry becomes sustained. Pharmacological effects on the tissue heterogeneity and vulnerability (to wave breaks and re-entry) are quantified to show that drugs that increase the wavelength and stop re-entry (IK1 and IKur blockers) can also increase the heterogeneity (AP gradients of 26–27 ms) and the likelihood of wave breaks. Conclusion Biophysical modelling reveals large conduction block areas near the PVs, which are due to discontinuous fibre arrangement enhanced by electrical heterogeneity. Vulnerability to re-entry in such areas can be modulated by pharmacological interventions.

Heterogeneous and anisotropic integrative model of pulmonary veins: computational study of arrhythmogenic substrate for atrial fibrillation

Mechanisms underlying the genesis of re-entrant substrate for the most common cardiac arrhythmia, atrial fibrillation (AF), are not well understood. In this study, we develop a multi-scale three-dimensional computational model that integrates cellular electrophysiology of the left atrium (LA) and pulmonary veins (PVs) with the respective tissue geometry and fibre orientation. The latter is reconstructed in unique detail from high-resolution (approx. 70 μm) contrast micro-computed tomography data. The model is used to explore the mechanisms of re-entry initiation and sustenance in the PV region, regarded as the primary source of high-frequency electrical activity in AF. Simulations of the three-dimensional model demonstrate that an initial break-down of normal electrical excitation wave-fronts can be caused by the electrical heterogeneity between the PVs and LA. High tissue anisotropy is then responsible for the slow conduction and generation of a re-entrant circuit near the PVs. Evidence of such circuits has been seen clinically in AF patients. Our computational study suggests that primarily the combination of electrical heterogeneity and conduction anisotropy between the PVs and LA tissues leads to the generation of a high-frequency (approx. 10 Hz) re-entrant source near the PV sleeves, thus providing new insights into the arrhythmogenic mechanisms of excitation waves underlying AF.

MONSTIR II: A 32-channel, multispectral, time-resolved optical tomography system for neonatal brain imaging

We detail the design, construction and performance of the second generation UCL time-resolved optical tomography system, known as MONSTIR II. Intended primarily for the study of the newborn brain, the system employs 32 source fibres that sequentially transmit picosecond pulses of light at any four wavelengths between 650 and 900 nm. The 32 detector channels each contain an independent photo-multiplier tube and temporally correlated photon-counting electronics that allow the photon transit time between each source and each detector position to be measured with high temporal resolution. The systems response time, temporal stability, cross-talk, and spectral characteristics are reported. The efficacy of MONSTIR II is demonstrated by performing multi-spectral imaging of a simple phantom.

Mean cerebral blood flow measurements using phase contrast MRI in the first year of life.

Alterations in cerebral blood flow (CBF) are believed to be linked to many of the neurological pathologies that affect neonates and small infants. CBF measurements are nonetheless often difficult to perform in this population, as many techniques rely on radioactive tracers or other invasive methods. In this study, mean global CBF was measured in 21 infants under the age of one, using non‐invasive MRI techniques adapted to the neonatal population. Mean CBF was computed as the ratio of blood flow delivered to the brain (measured using phase contrast MRI) and brain volume (computed by segmenting anatomical MR images). Tests in adult volunteers and repeated measurements showed the flow measurements using the proposed method to be both accurate and reproducible. It was also found that cardiac gating need not be employed in infants with no known cardiac pathology.

Cerebral blood flow measurements in infants using look–locker arterial spin labeling

To measure cerebral blood flow (CBF) using Look–Locker arterial spin labeling (ASL) in children under 1 year of age and to investigate the advantages of using subject‐specific estimates of ASL model parameters in this population.

The role of myocardial wall thickness in atrial arrhythmogenesis.

Changes in the structure and electrical behaviour of the left atrium are known to occur with conditions that predispose to atrial fibrillation (AF) and in response to prolonged periods of AF. We review the evidence that changes in myocardial thickness in the left atrium are an important part of this pathological remodelling process. Autopsy studies have demonstrated changes in the thickness of the atrial wall between patients with different clinical histories. Comparison of the reported tissue dimensions from pathological studies provides an indication of normal ranges for atrial wall thickness. Imaging studies, most commonly done using cardiac computed tomography, have demonstrated that these changes may be identified non-invasively. Experimental evidence using isolated tissue preparations, animal models of AF, and computer simulations proves that the three-dimensional tissue structure will be an important determinant of the electrical behaviour of atrial tissue. Accurately identifying the thickness of the atrial may have an important role in the non-invasive assessment of atrial structure. In combination with atrial tissue characterization, a comprehensive assessment of the atrial dimensions may allow prediction of atrial electrophysiological behaviour and in the future, guide radiofrequency delivery in regions based on their tissue thickness.

Atrial Heterogeneity Generates Re-entrant Substrate during Atrial Fibrillation and Anti-arrhythmic Drug Action: Mechanistic Insights from Canine Atrial Models

Anti-arrhythmic drug therapy is a frontline treatment for atrial fibrillation (AF), but its success rates are highly variable. This is due to incomplete understanding of the mechanisms of action of specific drugs on the atrial substrate at different stages of AF progression. We aimed to elucidate the role of cellular, tissue and organ level atrial heterogeneities in the generation of a re-entrant substrate during AF progression, and their modulation by the acute action of selected anti-arrhythmic drugs. To explore the complex cell-to-organ mechanisms, a detailed biophysical models of the entire 3D canine atria was developed. The model incorporated atrial geometry and fibre orientation from high-resolution micro-computed tomography, region-specific atrial cell electrophysiology and the effects of progressive AF-induced remodelling. The actions of multi-channel class III anti-arrhythmic agents vernakalant and amiodarone were introduced in the model by inhibiting appropriate ionic channel currents according to experimentally reported concentration-response relationships. AF was initiated by applied ectopic pacing in the pulmonary veins, which led to the generation of localized sustained re-entrant waves (rotors), followed by progressive wave breakdown and rotor multiplication in both atria. The simulated AF scenarios were in agreement with observations in canine models and patients. The 3D atrial simulations revealed that a re-entrant substrate was typically provided by tissue regions of high heterogeneity of action potential duration (APD). Amiodarone increased atrial APD and reduced APD heterogeneity and was more effective in terminating AF than vernakalant, which increased both APD and APD dispersion. In summary, the initiation and sustenance of rotors in AF is linked to atrial APD heterogeneity and APD reduction due to progressive remodelling. Our results suggest that anti-arrhythmic strategies that increase atrial APD without increasing its dispersion are effective in terminating AF.