Nicolas Kunz

Assessing white matter microstructure of the newborn with multi-shell diffusion MRI and biophysical compartment models

Brain white matter connections have become a focus of major interest with important maturational processes occurring in newborns. To study the complex microstructural developmental changes in-vivo, it is imperative that non-invasive neuroimaging approaches are developed for this age-group. Multi-b-value diffusion weighted imaging data were acquired in 13 newborns, and the biophysical compartment diffusion models CHARMED-light and NODDI, providing new microstructural parameters such as intra-neurite volume fraction (νin) and neurite orientation dispersion index (ODI), were developed for newborn data. Comparative analysis was performed and twenty ROIs in the white matter were investigated. Diffusion tensor imaging and both biophysical compartment models highlighted the compact and oriented structure of the corpus-callosum with the highest FA and νin values and the smallest ODI values. We could clearly differentiate, using the FA, νin and ODI, the posterior and anterior internal capsule representing similar cellular structure but with different maturation (i.e. partially myelinated and absence of myelin, respectively). Late maturing regions (external capsule and periventricular crossroads of pathways) had lower νin values, but displayed significant differences in ODI. The compartmented models CHARMED-light and NODDI bring new indices corroborating the cellular architectures, with the lowest νin, reflecting the late maturation of areas with thin non-myelinated fibers, and with highest ODI indicating the presence of fiber crossings and fanning. The application of biophysical compartment diffusion models adds new insights to the brain white matter development in vivo.

Net increase of lactate and glutamate concentration in activated human visual cortex detected with magnetic resonance spectroscopy at 7 tesla

After the landmark studies reporting changes in the cerebral metabolic rate of glucose (CMRGlc) in excess of those in oxygen (CMRO2) during physiological stimulation, several studies have examined the fate of the extra carbon taken up by the brain, reporting a wide range of changes in brain lactate from 20% to 250%. The present study reports functional magnetic resonance spectroscopy measurements at 7 Tesla using the enhanced sensitivity to study a small cohort (n = 6). Small increases in lactate (19% ± 4%, P < 0.05) and glutamate (4% ± 1%, P < 0.001) were seen within the first 2 min of activation. With the exception of glucose (12% ± 5%, P < 0.001), no other metabolite concentration changes beyond experimental error were significantly observed. Therefore, the present study confirms that lactate and glutamate changes during physiological stimulation are small (i.e. below 20%) and shows that the increased sensitivity allows reproduction of previous results with fewer subjects. In addition, the initial rate of glutamate and lactate concentration increases implies an increase in CMRO2 that is slightly below that of CMRGlc during the first 1–2 min of activation.

Developmental and metabolic brain alterations in rats exposed to bisphenol A during gestation and lactation

In recent years, considerable research has focused on the biological effect of endocrine‐disrupting chemicals. Bisphenol A (BPA) has been implicated as an endocrine‐disrupting chemical (EDC) due to its ability to mimic the action of endogenous estrogenic hormones.

Connectivity and tissue microstructural alterations in right and left temporal lobe epilepsy revealed by diffusion spectrum imaging

Focal epilepsy is increasingly recognized as the result of an altered brain network, both on the structural and functional levels and the characterization of these widespread brain alterations is crucial for our understanding of the clinical manifestation of seizure and cognitive deficits as well as for the management of candidates to epilepsy surgery. Tractography based on Diffusion Tensor Imaging allows non-invasive mapping of white matter tracts in vivo. Recently, diffusion spectrum imaging (DSI), based on an increased number of diffusion directions and intensities, has improved the sensitivity of tractography, notably with respect to the problem of fiber crossing and recent developments allow acquisition times compatible with clinical application. We used DSI and parcellation of the gray matter in regions of interest to build whole-brain connectivity matrices describing the mutual connections between cortical and subcortical regions in patients with focal epilepsy and healthy controls. In addition, the high angular and radial resolution of DSI allowed us to evaluate also some of the biophysical compartment models, to better understand the cause of the changes in diffusion anisotropy. Global connectivity, hub architecture and regional connectivity patterns were altered in TLE patients and showed different characteristics in RTLE vs LTLE with stronger abnormalities in RTLE. The microstructural analysis suggested that disturbed axonal density contributed more than fiber orientation to the connectivity changes affecting the temporal lobes whereas fiber orientation changes were more involved in extratemporal lobe changes. Our study provides further structural evidence that RTLE and LTLE are not symmetrical entities and DSI-based imaging could help investigate the microstructural correlate of these imaging abnormalities.

Diffusion‐weighted spectroscopy: A novel approach to determine macromolecule resonances in short‐echo time 1H‐MRS

Quantification of short‐echo time proton magnetic resonance spectroscopy results in >18 metabolite concentrations (neurochemical profile). Their quantification accuracy depends on the assessment of the contribution of macromolecule (MM) resonances, previously experimentally achieved by exploiting the several fold difference in T1. To minimize effects of heterogeneities in metabolites T1, the aim of the study was to assess MM signal contributions by combining inversion recovery (IR) and diffusion‐weighted proton spectroscopy at high‐magnetic field (14.1 T) and short echo time (=8 msec) in the rat brain. IR combined with diffusion weighting experiments (with δ/Δ = 1.5/200 msec and b‐value = 11.8 msec/μm2) showed that the metabolite nulled spectrum (inversion time = 740 msec) was affected by residuals attributed to creatine, inositol, taurine, choline, N‐acetylaspartate as well as glutamine and glutamate. While the metabolite residuals were significantly attenuated by 50%, the MM signals were almost not affected (<8%). The combination of metabolite‐nulled IR spectra with diffusion weighting allows a specific characterization of MM resonances with minimal metabolite signal contributions and is expected to lead to a more precise quantification of the neurochemical profile. Magn Reson Med, 2010.

Diffusion tensor echo planar imaging using surface coil transceiver with a semiadiabatic RF pulse sequence at 14.1T.

Diffusion magnetic resonance studies of the brain are typically performed using volume coils. Although in human brain this leads to a near optimal filling factor, studies of rodent brain must contend with the fact that only a fraction of the head volume can be ascribed to the brain. The use of surface coil as transceiver increases Signal‐to‐Noise Ratio (SNR), reduces radiofrequency power requirements and opens the possibility of parallel transmit schemes, likely to allow efficient acquisition schemes, of critical importance for reducing the long scan times implicated in diffusion tensor imaging. This study demonstrates the implementation of a semiadiabatic echo planar imaging sequence (echo time = 40 ms, four interleaves) at 14.1T using a quadrature surface coil as transceiver. It resulted in artifact free images with excellent SNR throughout the brain. Diffusion tensor derived parameters obtained within the rat brain were in excellent agreement with reported values. Magn Reson Med, 2011.

Definition and quantification of acute inflammatory white matter injury in the immature brain by MRI/MRS at high magnetic field

Background:Lipopolysaccharide (LPS) injection in the corpus callosum (CC) of rat pups results in diffuse white matter injury similar to the main neuropathology of preterm infants. The aim of this study was to characterize the structural and metabolic markers of acute inflammatory injury by high-field magnetic resonance imaging (MRI) magnetic resonance spectroscopy (MRS) in vivo.Methods:Twenty-four hours after a 1-mg/kg injection of LPS in postnatal day 3 rat pups, diffusion tensor imaging and proton nuclear magnetic spectroscopy (1H NMR) were analyzed in conjunction to determine markers of cell death and inflammation using immunohistochemistry and gene expression.Results:MRI and MRS in the CC revealed an increase in lactate and free lipids and a decrease of the apparent diffusion coefficient. Detailed evaluation of the CC showed a marked apoptotic response assessed by fractin expression. Interestingly, the degree of reduction in the apparent diffusion coefficient correlated strongly with the natural logarithm of fractin expression, in the same region of interest. LPS injection further resulted in increased activated microglia clustered in the cingulum, widespread astrogliosis, and increased expression of genes for interleukin (IL)-1, IL-6, and tumor necrosis factor.Conclusion:This model was able to reproduce the typical MRI hallmarks of acute diffuse white matter injury seen in preterm infants and allowed the evaluation of in vivo biomarkers of acute neuropathology after inflammatory challenge.

Investigation of field and diffusion time dependence of the diffusion-weighted signal at ultrahigh magnetic fields

Over the last decade, there has been a significant increase in the number of high‐magnetic‐field MRI magnets. However, the exact effect of a high magnetic field strength (B0) on diffusion‐weighted MR signals is not yet fully understood. The goal of this study was to investigate the influence of different high magnetic field strengths (9.4 T and 14.1 T) and diffusion times (9, 11, 13, 15, 17 and 24 ms) on the diffusion‐weighted signal in rat brain white matter. At a short diffusion time (9 ms), fractional anisotropy values were found to be lower at 14.1 T than at 9.4 T, but this difference disappeared at longer diffusion times. A simple two‐pool model was used to explain these findings. The model describes the white matter as a first hindered compartment (often associated with the extra‐axonal space), characterized by a faster orthogonal diffusion and a lower fractional anisotropy, and a second restricted compartment (often associated with the intra‐axonal space), characterized by a slower orthogonal diffusion (i.e. orthogonal to the axon direction) and a higher fractional anisotropy. Apparent T2 relaxation time measurements of the hindered and restricted pools were performed. The shortening of the pseudo‐T2 value from the restricted compartment with B0 is likely to be more pronounced than the apparent T2 changes in the hindered compartment. This study suggests that the observed differences in diffusion tensor imaging parameters between the two magnetic field strengths at short diffusion time may be related to differences in the apparent T2 values between the pools. Copyright

Which prior knowledge? : Quantification of in vivo brain 13C MR spectra following 13C glucose infusion using AMARES

The recent developments in high magnetic field 13C magnetic resonance spectroscopy with improved localization and shimming techniques have led to important gains in sensitivity and spectral resolution of 13C in vivo spectra in the rodent brain, enabling the separation of several 13C isotopomers of glutamate and glutamine. In this context, the assumptions used in spectral quantification might have a significant impact on the determination of the 13C concentrations and the related metabolic fluxes. In this study, the time domain spectral quantification algorithm AMARES (advanced method for accurate, robust and efficient spectral fitting) was applied to 13C magnetic resonance spectroscopy spectra acquired in the rat brain at 9.4 T, following infusion of [1,6‐13C2] glucose. Using both Monte Carlo simulations and in vivo data, the goal of this work was: (1) to validate the quantification of in vivo 13C isotopomers using AMARES; (2) to assess the impact of the prior knowledge on the quantification of in vivo 13C isotopomers using AMARES; (3) to compare AMARES and LCModel (linear combination of model spectra) for the quantification of in vivo 13C spectra. AMARES led to accurate and reliable 13C spectral quantification similar to those obtained using LCModel, when the frequency shifts, J‐coupling constants and phase patterns of the different 13C isotopomers were included as prior knowledge in the analysis. Magn Reson Med, 2013.

Refined Analysis of Brain Energy Metabolism Using In Vivo Dynamic Enrichment of 13C Multiplets.

Carbon-13 nuclear magnetic resonance spectroscopy in combination with the infusion of 13C-labeled precursors is a unique approach to study in vivo brain energy metabolism. Incorporating the maximum information available from in vivo localized 13C spectra is of importance to get broader knowledge on cerebral metabolic pathways. Metabolic rates can be quantitatively determined from the rate of 13C incorporation into amino acid neurotransmitters such as glutamate and glutamine using suitable mathematical models. The time course of multiplets arising from 13C-13C coupling between adjacent carbon atoms was expected to provide additional information for metabolic modeling leading to potential improvements in the estimation of metabolic parameters. The aim of the present study was to extend two-compartment neuronal/glial modeling to include dynamics of 13C isotopomers available from fine structure multiplets in 13C spectra of glutamate and glutamine measured in vivo in rats brain at 14.1 T, termed bonded cumomer approach. Incorporating the labeling time courses of 13C multiplets of glutamate and glutamine resulted in elevated precision of the estimated fluxes in rat brain as well as reduced correlations between them.