Tuned exchange imaging: Can the filter exchange imaging pulse sequence be adapted for applications with thin slices and restricted diffusion?

Filter exchange imaging (FEXI) is a double diffusion-encoding (DDE) sequence that is specifically sensitive to exchange between sites with different apparent diffusivities. FEXI uses a diffusion-encoding filtering block followed by a detection block at varying mixing times to map the exchange rate. Long mixing times enhance the sensitivity to exchange, but they pose challenges for imaging applications that require a stimulated echo sequence with crusher gradients. Thin imaging slices require strong crushers, which can introduce significant diffusion weighting and bias exchange rate estimates. Here, we treat the crushers as an additional encoding block and consider FEXI as a triple diffusion-encoding sequence. This allows the bias to be corrected in the case of multi-Gaussian diffusion, but not easily in the presence of restricted diffusion. Our approach addresses challenges in the presence of restricted diffusion and relies on the ability to independently gauge sensitivities to exchange and restricted diffusion for arbitrary gradient waveforms. It follows two principles: (i) the effects of crushers are included in the forward model using signal cumulant expansion; and (ii) timing parameters of diffusion gradients in filter and detection blocks are adjusted to maintain the same level of restriction encoding regardless of the mixing time. This results in the tuned exchange imaging (TEXI) protocol. The accuracy of exchange mapping with TEXI was assessed through Monte Carlo simulations in spheres of identical sizes and gamma-distributed sizes, and in parallel hexagonally packed cylinders. The simulations demonstrate that TEXI provides consistent exchange rates regardless of slice thickness and restriction size, even with strong crushers. However, the accuracy depends on b-values, mixing times, and restriction geometry. The constraints and limitations of TEXI are discussed, including suggestions for protocol adaptations. Further studies are needed to optimize the precision of TEXI and assess the approach experimentally in realistic, heterogeneous substrates.

Corrigendum to "Test-retest analysis of cerebral oxygen extraction estimates in healthy volunteers: Comparison of methods based on quantitative susceptibility mapping and dynamic susceptibility contrast magnetic resonance imaging" [Heliyon 8(12) (December 2022) e12364].

[This corrects the article DOI: 10.1016/j.heliyon.2022.e12364.].

Diffusion MRI with free gradient waveforms on a high-performance gradient system: Probing restriction and exchange in the human brain.

The dependence of the diffusion MRI signal on the diffusion time carries signatures of restricted diffusion and exchange. Here we seek to highlight these signatures in the human brain by performing experiments using free gradient waveforms designed to be selectively sensitive to the two effects. We examine six healthy volunteers using both strong and ultra-strong gradients (80, 200 and 300 mT/m). In an experiment featuring a large set of 150 gradient waveforms with different sensitivities to restricted diffusion and exchange, our results reveal unique and different time-dependence signatures in grey and white matter. Grey matter was characterised by both restricted diffusion and exchange and white matter predominantly by restricted diffusion. Exchange in grey matter was at least twice as fast as in white matter, across all subjects and all gradient strengths. The cerebellar cortex featured relatively short exchange times (115 ms). Furthermore, we show that gradient waveforms with tailored designs can be used to map exchange in the human brain. We also assessed the feasibility of clinical applications of the method used in this work and found that the exchange-related contrast obtained with a 25-minute protocol at 300 mT/m was preserved in a 4-minute protocol at 300 mT/m and a 10-minute protocol at 80 mT/m. Our work underlines the utility of free waveforms for detecting time dependence signatures due to restricted diffusion and exchange in vivo, which may potentially serve as a tool for studying diseased tissue.

Diffusion MRI with free gradient waveforms on a high-performance gradient system: Probing restriction and exchange in the human brain.

The dependence of the diffusion MRI signal on the diffusion time carries signatures of restricted diffusion and exchange. Here we seek to highlight these signatures in the human brain by performing experiments using free gradient waveforms that are selectively sensitive to the two effects. We examine six healthy volunteers using both strong and ultra-strong gradients (80, 200 and 300 mT/m). In an experiment featuring a large set of gradient waveforms with different sensitivities to restricted diffusion and exchange (150 samples), our results reveal unique time-dependence signatures in grey and white matter, where the former is characterised by both restricted diffusion and exchange and the latter predominantly exhibits restricted diffusion. Furthermore, we show that gradient waveforms with independently varying sensitivities to restricted diffusion and exchange can be used to map exchange in the human brain. We consistently find that exchange in grey matter is at least twice as fast as in white matter, across all subjects and all gradient strengths. The shortest exchange times observed in this study were in the cerebellar cortex (115 ms). We also assess the feasibility of future clinical applications of the method used in this work, where we find that the grey-white matter exchange contrast obtained with a 25-minute 300 mT/m protocol is preserved by a 4-minute 300 mT/m and a 10-minute 80 mT/m protocol. Our work underlines the utility of free waveforms for detecting time-dependence signatures due to restricted diffusion and exchange in vivo, which may potentially serve as a tool for studying diseased tissue.

Diffusion MRI with pulsed and free gradient waveforms: Effects of restricted diffusion and exchange.

Monitoring time dependence with diffusion MRI yields observables sensitive to compartment sizes (restricted diffusion) and membrane permeability (water exchange). However, restricted diffusion and exchange have opposite effects on the diffusion-weighted signal, which can lead to errors in parameter estimates. In this work, we propose a signal representation that incorporates the effects of both restricted diffusion and exchange up to second order in b-value and is compatible with gradient waveforms of arbitrary shape. The representation features mappings from a gradient waveform to two scalars that separately control the sensitivity to restriction and exchange. We demonstrate that these scalars span a two-dimensional space that can be used to choose waveforms that selectively probe restricted diffusion or exchange, eliminating the correlation between the two phenomena. We found that waveforms with specific but unconventional shapes provide an advantage over conventional pulsed and oscillating gradient acquisitions. We also show that parametrization of waveforms into a two-dimensional space can be used to understand protocols from other approaches that probe restricted diffusion and exchange. For example, we found that the variation of mixing time in filter-exchange imaging corresponds to variation of our exchange-weighting scalar at a fixed value of the restriction-weighting scalar. The proposed signal representation was evaluated using Monte Carlo simulations in identical parallel cylinders with hexagonal and random packing as well as parallel cylinders with gamma-distributed radii. Results showed that the approach is sensitive to sizes in the interval 4-12 µm and exchange rates in the simulated range of 0 to 20 s - 1 , but also that there is a sensitivity to the extracellular geometry. The presented theory constitutes a simple and intuitive description of how restricted diffusion and exchange influence the signal as well as a guide to protocol design capable of separating the two effects.

Non-parametric deconvolution using Bézier curves for quantification of cerebral perfusion in dynamic susceptibility contrast MRI.

OBJECTIVE: Deconvolution is an ill-posed inverse problem that tends to yield non-physiological residue functions R(t) in dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI). In this study, the use of Bézier curves is proposed for obtaining physiologically reasonable residue functions in perfusion MRI. MATERIALS AND METHODS: Cubic Bézier curves were employed, ensuring R(0) = 1, bounded-input, bounded-output stability and a non-negative monotonically decreasing solution, resulting in 5 parameters to be optimized. Bézier deconvolution (BzD), implemented in a Bayesian framework, was tested by simulation under realistic conditions, including effects of arterial delay and dispersion. BzD was also applied to DSC-MRI data from a healthy volunteer. RESULTS: Bézier deconvolution showed robustness to different underlying residue function shapes. Accurate perfusion estimates were observed, except for boxcar residue functions at low signal-to-noise ratio. BzD involving corrections for delay, dispersion, and delay with dispersion generally returned accurate results, except for some degree of cerebral blood flow (CBF) overestimation at low levels of each effect. Maps of mean transit time and delay were markedly different between BzD and block-circulant singular value decomposition (oSVD) deconvolution. DISCUSSION: A novel DSC-MRI deconvolution method based on Bézier curves was implemented and evaluated. BzD produced physiologically plausible impulse response, without spurious oscillations, with generally less CBF underestimation than oSVD.

Test-retest analysis of cerebral oxygen extraction estimates in healthy volunteers: comparison of methods based on quantitative susceptibility mapping and dynamic susceptibility contrast magnetic resonance imaging.

Background: Estimation of the oxygen extraction fraction (OEF) by quantitative susceptibility mapping (QSM) magnetic resonance imaging (MRI) is promising but requires systematic evaluation. Extraction of OEF-related information from the tissue residue function in dynamic susceptibility contrast MRI (DSC-MRI) has also been proposed. In this study, whole-brain OEF repeatability was investigated, as well as the relationships between QSM-based OEF and DSC-MRI-based parameters, i.e., mean transit time (MTT) and an oxygen extraction index, referred to as apparent OEF (AOEF). Method: Test-retest data were obtained from 20 healthy volunteers at 3 T. QSM maps were reconstructed from 3D gradient-echo MRI phase data, using morphology-enabled dipole inversion. DSC-MRI was accomplished using gradient-echo MRI at a temporal resolution of 1.24 s. Results: The whole-brain QSM-based OEF was (40.4±4.8) % and, in combination with a previously published cerebral blood flow (CBF) estimate, this corresponds to a cerebral metabolic rate of oxygen level of CMRO2 = 3.36 ml O2/min/100 g. The intra-class correlation coefficient [ICC(2,1)] for OEF test-retest data was 0.73. The MTT-versus-OEF and AOEF-versus-OEF relationships showed correlation coefficients of 0.61 (p = 0.004) and 0.52 (p = 0.019), respectively. Discussion: QSM-based OEF showed a convincing absolute level and good test-retest results in terms of the ICC. Moderate to good correlations between QSM-based OEF and DSC-MRI-based parameters were observed. The present results constitute an indicator of the level of robustness that can be achieved without applying extraordinary resources in terms of MRI equipment, imaging protocol, QSM reconstruction, and OEF analysis.

Mathematical modelling of the synergistic combination of radiotherapy and indoleamine-2,3-dioxygenase (IDO) inhibitory immunotherapy against glioblastoma.

OBJECTIVE: Recent research has shown that combining radiotherapy and immunotherapy can counteract the ability of cancer to evade and suppress the native immune system. To optimise the synergy of the combined therapies, factors such as radiation dose and fractionation must be considered, alongside numerous parameters resulting from the complexity of cancer-immune system interactions. It is instructive to use mathematical models to tackle this problem. METHODS: In this work, we adapted a model primarily to describe the synergistic effect between single-fraction radiotherapy and immunotherapy (1-methyl tryptophan) observed in previous experiments with glioblastoma-carrying rats. We also showed how the model can be used to generate hypotheses on the outcome of other treatment fractionation schemes. RESULTS: The model successfully reproduced the results of the experiments. Moreover, it provided support for the hypothesis that, for a given biologically effective dose, the efficacy of the combination therapy and the synergy between the two therapies are favoured by the administration of radiotherapy in a hypofractionated regime. Furthermore, for a double-fraction irradiation regimen, the synergy is favoured by a short time interval between the treatment fractions. CONCLUSION: It was concluded that the model could be fitted to reproduce the experimental data well within its uncertainties. It was also demonstrated that the fitted model can be used to form hypotheses to be validated by further pre-clinical experiments. Advances in knowledge: The results of this work support the hypothesis that the synergetic action of combined radiotherapy and immunotherapy is favoured by using a hypofractionated radiation treatment regimen, given over a short time interval.