Metabolic and physiologic magnetic resonance imaging in distinguishing true progression from pseudoprogression in patients with glioblastoma

Pseudoprogression (PsP) refers to treatment-related clinico-radiologic changes mimicking true progression (TP) that occurs in patients with glioblastoma (GBM), predominantly within the first 6 months after the completion of surgery and concurrent chemoradiation therapy (CCRT) with temozolomide. Accurate differentiation of TP from PsP is essential for making informed decisions on appropriate therapeutic intervention as well as for prognostication of these patients. Conventional neuroimaging findings are often equivocal in distinguishing between TP and PsP and present a considerable diagnostic dilemma to oncologists and radiologists. These challenges have emphasized the need for developing alternative imaging techniques that may aid in the accurate diagnosis of TP and PsP. In this review, we encapsulate the current state of knowledge in the clinical applications of commonly used metabolic and physiologic magnetic resonance (MR) imaging techniques such as diffusion and perfusion imaging and proton spectroscopy in distinguishing TP from PsP. We also showcase the potential of promising imaging techniques, such as amide proton transfer and amino acid-based positron emission tomography, in providing useful information about the treatment response. Additionally, we highlight the role of “radiomics”, which is an emerging field of radiology that has the potential to change the way in which advanced MR techniques are utilized in assessing treatment response in GBM patients. Finally, we present our institutional experiences and discuss future perspectives on the role of multiparametric MR imaging in identifying PsP in GBM patients treated with “standard-of-care” CCRT as well as novel/targeted therapies.     

Combining parallel detection of proton echo planar spectroscopic imaging (PEPSI) measurements with a data‐consistency constraint improves SNR

One major challenge of MRSI is the poor signal‐to‐noise ratio (SNR), which can be improved by using a surface coil array. Here we propose to exploit the spatial sensitivity of different channels of a coil array to enforce the k‐space data consistency (DC) in order to suppress noise and consequently to improve MRSI SNR. MRSI data were collected using a proton echo planar spectroscopic imaging (PEPSI) sequence at 3 T using a 32‐channel coil array and were averaged with one, two and eight measurements (avg‐1, avg‐2 and avg‐8). The DC constraint was applied using a regularization parameter λ of 1, 2, 3, 5 or 10. Metabolite concentrations were quantified using LCModel. Our results show that the suppression of noise by applying the DC constraint to PEPSI reconstruction yields up to 32% and 27% SNR gain for avg‐1 and avg‐2 data with λ = 5, respectively. According to the reported Cramer–Rao lower bounds, the improvement in metabolic fitting was significant (p < 0.01) when the DC constraint was applied with λ ≥ 2. Using the DC constraint with λ = 3 or 5 can minimize both root‐mean‐square errors and spatial variation for all subjects using the avg‐8 data set as reference values. Our results suggest that MRSI reconstructed with a DC constraint can save around 70% of scanning time to obtain images and spectra with similar SNRs using λ = 5. Copyright © 2015 John Wiley & Sons, Ltd.     

Accelerated echo planar J‐resolved spectroscopic imaging in prostate cancer: a pilot validation of non‐linear reconstruction using total variation and maximum entropy

The overlap of metabolites is a major limitation in one‐dimensional (1D) spectral‐based single‐voxel MRS and multivoxel‐based MRSI. By combining echo planar spectroscopic imaging (EPSI) with a two‐dimensional (2D) J‐resolved spectroscopic (JPRESS) sequence, 2D spectra can be recorded in multiple locations in a single slice of prostate using four‐dimensional (4D) echo planar J‐resolved spectroscopic imaging (EP‐JRESI). The goal of the present work was to validate two different non‐linear reconstruction methods independently using compressed sensing‐based 4D EP‐JRESI in prostate cancer (PCa): maximum entropy (MaxEnt) and total variation (TV). Twenty‐two patients with PCa with a mean age of 63.8 years (range, 46–79 years) were investigated in this study. A 4D non‐uniformly undersampled (NUS) EP‐JRESI sequence was implemented on a Siemens 3‐T MRI scanner. The NUS data were reconstructed using two non‐linear reconstruction methods, namely MaxEnt and TV. Using both TV and MaxEnt reconstruction methods, the following observations were made in cancerous compared with non‐cancerous locations: (i) higher mean (choline + creatine)/citrate metabolite ratios; (ii) increased levels of (choline + creatine)/spermine and (choline + creatine)/myo‐inositol; and (iii) decreased levels of (choline + creatine)/(glutamine + glutamate). We have shown that it is possible to accelerate the 4D EP‐JRESI sequence by four times and that the data can be reliably reconstructed using the TV and MaxEnt methods. The total acquisition duration was less than 13 min and we were able to detect and quantify several metabolites. Copyright © 2015 John Wiley & Sons, Ltd.     

Accelerated three‐dimensional cine phase contrast imaging using randomly undersampled echo planar imaging with compressed sensing reconstruction

The aim of this study was to implement and evaluate an accelerated three‐dimensional (3D) cine phase contrast MRI sequence by combining a randomly sampled 3D k‐space acquisition sequence with an echo planar imaging (EPI) readout. An accelerated 3D cine phase contrast MRI sequence was implemented by combining EPI readout with randomly undersampled 3D k‐space data suitable for compressed sensing (CS) reconstruction. The undersampled data were then reconstructed using low‐dimensional structural self‐learning and thresholding (LOST). 3D phase contrast MRI was acquired in 11 healthy adults using an overall acceleration of 7 (EPI factor of 3 and CS rate of 3). For comparison, a single two‐dimensional (2D) cine phase contrast scan was also performed with sensitivity encoding (SENSE) rate 2 and approximately at the level of the pulmonary artery bifurcation. The stroke volume and mean velocity in both the ascending and descending aorta were measured and compared between two sequences using Bland–Altman plots. An average scan time of 3 min and 30 s, corresponding to an acceleration rate of 7, was achieved for 3D cine phase contrast scan with one direction flow encoding, voxel size of 2 × 2 × 3 mm³, foot–head coverage of 6 cm and temporal resolution of 30 ms. The mean velocity and stroke volume in both the ascending and descending aorta were statistically equivalent between the proposed 3D sequence and the standard 2D cine phase contrast sequence. The combination of EPI with a randomly undersampled 3D k‐space sampling sequence using LOST reconstruction allows a seven‐fold reduction in scan time of 3D cine phase contrast MRI without compromising blood flow quantification. Copyright © 2014 John Wiley & Sons, Ltd.     

Density‐weighted concentric rings k‐space trajectory for 1H magnetic resonance spectroscopic imaging at 7 T

It has been shown that density‐weighted (DW) k‐space sampling with spiral and conventional phase encoding trajectories reduces spatial side lobes in magnetic resonance spectroscopic imaging (MRSI). In this study, we propose a new concentric ring trajectory (CRT) for DW‐MRSI that samples k‐space with a density that is proportional to a spatial, isotropic Hanning window. The properties of two different DW‐CRTs were compared against a radially equidistant (RE) CRT and an echo‐planar spectroscopic imaging (EPSI) trajectory in simulations, phantoms and in vivo experiments. These experiments, conducted at 7 T with a fixed nominal voxel size and matched acquisition times, revealed that the two DW‐CRT designs improved the shape of the spatial response function by suppressing side lobes, also resulting in improved signal‐to‐noise ratio (SNR). High‐quality spectra were acquired for all trajectories from a specific region of interest in the motor cortex with an in‐plane resolution of 7.5 × 7.5 mm² in 8 min 3 s. Due to hardware limitations, high‐spatial‐resolution spectra with an in‐plane resolution of 5 × 5 mm² and an acquisition time of 12 min 48 s were acquired only for the RE and one of the DW‐CRT trajectories and not for EPSI. For all phantom and in vivo experiments, DW‐CRTs resulted in the highest SNR. The achieved in vivo spectral quality of the DW‐CRT method allowed for reliable metabolic mapping of eight metabolites including N‐acetylaspartylglutamate, γ‐aminobutyric acid and glutathione with Cramér‐Rao lower bounds below 50%, using an LCModel analysis. Finally, high‐quality metabolic mapping of a whole brain slice using DW‐CRT was achieved with a high in‐plane resolution of 5 × 5 mm² in a healthy subject. These findings demonstrate that our DW‐CRT MRSI technique can perform robustly on MRI systems and within a clinically feasible acquisition time.     

Ultra-short echo time spectroscopic imaging in rats: implications for monitoring lipids in glioma gene therapy

We demonstrate the feasibility of using ultra-short echo time (TE = 2 ms) magnetic resonance spectroscopic imaging (MRSI) to detect intracranial mobile lipids in the rat brain. High-performance outer volume suppression and pre-localization were demonstrated in phantoms and by the total absence of signals arising from extra-cranial lipids in MRSI spectra from control rats. The sequence performance was tested on glioma-bearing BDIX rats. Fast-relaxing lipid signals were spatially varied within a glioma during herpes simplex virus thymidine kinase-mediated gene therapy, demonstrating the potential application of this method.     

MRSI‐based molecular imaging of therapy response to temozolomide in preclinical glioblastoma using source analysis

Characterization of glioblastoma (GB) response to treatment is a key factor for improving patients' survival and prognosis. MRI and magnetic resonance spectroscopic imaging (MRSI) provide morphologic and metabolic profiles of GB but usually fail to produce unequivocal biomarkers of response. The purpose of this work is to provide proof of concept of the ability of a semi‐supervised signal source extraction methodology to produce images with robust recognition of response to temozolomide (TMZ) in a preclinical GB model. A total of 38 female C57BL/6 mice were used in this study. The semi‐supervised methodology extracted the required sources from a training set consisting of MRSI grids from eight GL261 GBs treated with TMZ, and six control untreated GBs. Three different sources (normal brain parenchyma, actively proliferating GB and GB responding to treatment) were extracted and used for calculating nosologic maps representing the spatial response to treatment. These results were validated with an independent test set (7 control and 17 treated cases) and correlated with histopathology. Major differences between the responder and non‐responder sources were mainly related to the resonances of mobile lipids (MLs) and polyunsaturated fatty acids in MLs (0.9, 1.3 and 2.8 ppm). Responding tumors showed significantly lower mitotic (3.3 ± 2.9 versus 14.1 ± 4.2 mitoses/field) and proliferation rates (29.8 ± 10.3 versus 57.8 ± 5.4%) than control untreated cases. The methodology described in this work is able to produce nosological images of response to TMZ in GL261 preclinical GBs and suitably correlates with the histopathological analysis of tumors. A similar strategy could be devised for monitoring response to treatment in patients. Copyright © 2016 John Wiley & Sons, Ltd.     

3D spatially encoded and accelerated TE‐averaged echo planar spectroscopic imaging in healthy human brain

Several different pathologies, including many neurodegenerative disorders, affect the energy metabolism of the brain. Glutamate, a neurotransmitter in the brain, can be used as a biomarker to monitor these metabolic processes. One method that is capable of quantifying glutamate concentration reliably in several regions of the brain is TE‐averaged ¹H spectroscopic imaging. However, this type of method requires the acquisition of multiple TE lines, resulting in long scan durations. The goal of this experiment was to use non‐uniform sampling, compressed sensing reconstruction and an echo planar readout gradient to reduce the scan time by a factor of eight to acquire TE‐averaged spectra in three spatial dimensions. Simulation of glutamate and glutamine showed that the 2.2–2.4 ppm spectral region contained 95% glutamate signal using the TE‐averaged method. Peak integration of this spectral range and home‐developed, prior‐knowledge‐based fitting were used for quantitation. Gray matter brain phantom measurements were acquired on a Siemens 3 T Trio scanner. Non‐uniform sampling was applied retrospectively to these phantom measurements and quantitative results of glutamate with respect to creatine 3.0 (Glu/Cr) ratios showed a coefficient of variance of 16% for peak integration and 9% for peak fitting using eight‐fold acceleration. In vivo scans of the human brain were acquired as well and five different brain regions were quantified using the prior‐knowledge‐based algorithm. Glu/Cr ratios from these regions agreed with previously reported results in the literature. The method described here, called accelerated TE‐averaged echo planar spectroscopic imaging (TEA‐EPSI), is a significant methodological advancement and may be a useful tool for categorizing glutamate changes in pathologies where affected brain regions are not known a priori. Copyright © 2016 John Wiley & Sons, Ltd.     

Diffusion‐prepared stimulated‐echo turbo spin echo (DPsti‐TSE): An eddy current‐insensitive sequence for three‐dimensional high‐resolution and undistorted diffusion‐weighted imaging

In this study, we present a new three‐dimensional (3D), diffusion‐prepared turbo spin echo sequence based on a stimulated‐echo read‐out (DPsti‐TSE) enabling high‐resolution and undistorted diffusion‐weighted imaging (DWI). A dephasing gradient in the diffusion preparation module and rephasing gradients in the turbo spin echo module create stimulated echoes, which prevent signal loss caused by eddy currents. Near to perfect agreement of apparent diffusion coefficient (ADC) values between DPsti‐TSE and diffusion‐weighted echo planar imaging (DW‐EPI) was demonstrated in both phantom transient signal experiments and phantom imaging experiments. High‐resolution and undistorted DPsti‐TSE was demonstrated in vivo in prostate and carotid vessel wall. 3D whole‐prostate DWI was achieved with four b values in only 6 min. Undistorted ADC maps of the prostate peripheral zone were obtained at low and high imaging resolutions with no change in mean ADC values [(1.60 ± 0.10) × 10^?3 versus (1.60 ± 0.02) × 10^?3 mm²/s]. High‐resolution 3D DWI of the carotid vessel wall was achieved in 12 min, with consistent ADC values [(1.40 ± 0.23) × 10^?3 mm²/s] across different subjects, as well as slice locations through the imaging volume. This study shows that DPsti‐TSE can serve as a robust 3D diffusion‐weighted sequence and is an attractive alternative to the traditional two‐dimensional DW‐EPI approaches.     

A pilot validation of multi‐echo based echo‐planar correlated spectroscopic imaging in human calf muscles

A current limitation of MR spectroscopic imaging of multiple skeletal muscles is prolonged scan duration. A significant reduction in the total scan duration using the echo‐planar correlated spectroscopic imaging (EP‐COSI) sequence was accomplished using two bipolar readout trains with different phase‐encoded echoes for one of two spatial dimensions within a single repetition time (TR). The second bipolar readout was used for spatially encoding the outer k‐space, whereas the first readout was used for the central k‐space only. The performance of this novel sequence, called multi‐echo based echo‐planar correlated spectroscopic imaging (ME‐EPCOSI), was demonstrated by localizing specific key features in calf muscles and bone marrow of 11 healthy volunteers and five subjects with type 2 diabetes (T2D). A 3 T MRI–MRS scanner equipped with a transmit–receive extremity coil was used. Localization of the ME‐EPCOSI sequence was in good agreement with the earlier single‐readout based EP‐COSI sequence and the required scan time was reduced by a factor of two. In agreement with an earlier report using single‐voxel based 2D MRS, significantly increased unsaturated pools of intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) and decreased IMCL and EMCL unsaturation indices (UIs) were observed in the soleus and tibialis anterior muscle regions of subjects with T2D compared with healthy controls. In addition, significantly decreased choline content was observed in the soleus of T2D subjects compared with healthy controls. Multi‐voxel characterization of IMCL and EMCL ratios and UI in the calf muscle may be useful for the non‐invasive assessment of altered lipid metabolism in the pathophysiology of T2D. Copyright © 2014 John Wiley & Sons, Ltd.     

Non‐uniformly under‐sampled multi‐dimensional spectroscopic imaging in vivo: maximum entropy versus compressed sensing reconstruction

The four‐dimensional (4D) echo‐planar correlated spectroscopic imaging (EP‐COSI) sequence allows for the simultaneous acquisition of two spatial (k_y, k_x) and two spectral (t₂, t₁) dimensions in vivo in a single recording. However, its scan time is directly proportional to the number of increments in the k_y and t₁ dimensions, and a single scan can take 20–40 min using typical parameters, which is too long to be used for a routine clinical protocol. The present work describes efforts to accelerate EP‐COSI data acquisition by application of non‐uniform under‐sampling (NUS) to the k_y–t₁ plane of simulated and in vivo EP‐COSI datasets then reconstructing missing samples using maximum entropy (MaxEnt) and compressed sensing (CS). Both reconstruction problems were solved using the Cambridge algorithm, which offers many workflow improvements over other l₁‐norm solvers. Reconstructions of retrospectively under‐sampled simulated data demonstrate that the MaxEnt and CS reconstructions successfully restore data fidelity at signal‐to‐noise ratios (SNRs) from 4 to 20 and 5× to 1.25× NUS. Retrospectively and prospectively 4× under‐sampled 4D EP‐COSI in vivo datasets show that both reconstruction methods successfully remove NUS artifacts; however, MaxEnt provides reconstructions equal to or better than CS. Our results show that NUS combined with iterative reconstruction can reduce 4D EP‐COSI scan times by 75% to a clinically viable 5 min in vivo, with MaxEnt being the preferred method. Copyright © 2013 John Wiley & Sons, Ltd.     

Short-echo spectroscopic imaging combined with lactate editing in a single scan

A short-echo spectroscopic imaging sequence extended with a frequency-selective multiple-quantum- coherence technique (Sel-MQC) is presented. The method enables acquisition of a complete water-suppressed proton spectrum with a short echo time and filtering of the J-coupling metabolite, lactate, from co-resonant lipids in one scan. The purpose of the study was to validate this combined pulse sequence in vitro and in vivo. Measurements on phantoms confirmed the feasibility of the method, and, for a practical in vivo application, experiments were carried out on eight tumors from two different tumor models [UT-SCC-8 (n = 4) and SAS (n = 4)]. T(1)- and T(2)-weighted metabolite and lipid ratios were calculated, and the tumors showed different values in the central and outer regions. The ratio of the lipid methylene peak area (1.30 ppm) to choline peak area (3.20 ppm) was significantly (p < 0.01) different in the central tumor area between the two models, and lactate was detected in only three out of four tumors in the SAS tumor line. The present approach of combining short-echo spectroscopic imaging and lactate editing allows the characterization of tumor-specific metabolites such as choline, lipid methylene and methyl resonances as well as lactate in a single scan.     

Two‐dimensional spectroscopic imaging with combined free induction decay and long‐TE acquisition (FID echo spectroscopic imaging,FIDESI) for the detection of intramyocellular lipids in calf muscle at 7 T

The aim of this study was to introduce a two‐dimensional chemical shift imaging (2D CSI) sequence, with simultaneous acquisition of free induction decay (FID) and long TEs, for the detection and quantification of intramyocellular lipids (IMCLs) in the calf at 7 T. The feasibility of the new 2D CSI sequence, which acquires FID (acquisition delay, 1.3 ms) and an echo (long TE) in one measurement, was evaluated in phantoms and volunteers (n = 5): TR/TE*/TE = 800/1.3/156 ms; 48 × 48 matrix; field of view, 200 × 200 × 20 mm³; Hamming filter; no water suppression; measurement time, 22 min 2 s. The IMCL concentration and subcutaneous lipid contamination were assessed. Spectra in the tibialis anterior (TA), gastrocnemius (GM) and soleus (SOL) muscles were analyzed. The water signal from the FID acquisition was used as an internal concentration reference. In the spectra from subcutaneous adipose tissue (SUB) and bone marrow (BM), an unsaturation index (UI) of the vinyl‐H (5.3 ppm) to methyl‐CH₃ ratio, and a polyunsaturation index (pUI) of the diallylic‐H (2.77 ppm) to ‐CH₃ ratio, were calculated. Long‐TE spectra from muscles showed a simplified spectral pattern with well‐separated IMCL for several muscle groups in the same scan. The IMCL to water ratio was largest in SOL (0.66% ± 0.23%), and lower in GM (0.37% ± 0.14%) and TA (0.36% ± 0.12%). UI and pUI for SUB were 0.65 ± 0.06 and 0.18 ± 0.04, respectively, and for BM were 0.60 ± 0.16 and 0.18 ± 0.08, respectively. The new sequence, with the proposed name ‘free induction decay echo spectroscopic imaging’ (FIDESI), provides information on both specific lipid resonances and water signal from different tissues in the calf, with high spectral and spatial resolution, as well as minimal voxel bleeding and subcutaneous lipid contamination, in clinically acceptable measurement times. Copyright © 2014 John Wiley & Sons, Ltd.     

Quantitative three‐dimensional ultrashort echo time cones imaging of the knee joint with motion correction

Knee degeneration involves all the major tissues in the joint. However, conventional MRI sequences can only detect signals from long T2 tissues such as the superficial cartilage, with little signal from the deep cartilage, menisci, ligaments, tendons and bone. It is highly desirable to develop new sequences that can detect signal from all major tissues in the knee. We aimed to develop a comprehensive quantitative three‐dimensional ultrashort echo time (3D UTE) cones imaging protocol for a truly “whole joint” evaluation of knee degeneration. The protocol included 3D UTE cones actual flip angle imaging (3D UTE‐Cones‐AFI) for T₁ mapping, multiecho UTE‐Cones with fat suppression for T₂* mapping, UTE‐Cones with adiabatic T_1ρ (AdiabT_1ρ) preparation for AdiabT_1ρ mapping, and UTE‐Cones magnetization transfer (UTE‐Cones‐MT) for MT ratio (MTR) and modeling of macromolecular proton fraction (f). An elastix registration technique was used to compensate for motion during scans. Quantitative data analyses were performed on the registered data. Three knee specimens and 15 volunteers were evaluated at 3 T. The elastix motion correction algorithm worked well in correcting motion artifacts associated with relatively long scan times. Much improved curve fitting was achieved for all UTE‐Cones biomarkers with greatly reduced root mean square errors. The averaged T₁, T₂*, AdiabT_1ρ, MTR and f for knee joint tissues of 15 healthy volunteers were reported. The 3D UTE‐Cones quantitative imaging techniques (ie, T₁, T₂*, AdiabT_1ρ, MTR and MT modeling) together with elastix motion correction provide robust volumetric measurement of relaxation times, MTR and f of both short and long T₂ tissues in the knee joint.     

Imaging quality of PROPELLER diffusion‐weighted MR imaging and its diagnostic performance in distinguishing pleomorphic adenomas from Warthin tumors of the parotid gland

The aim of this study was to evaluate the imaging quality and diagnostic performance of fast spin echo diffusion‐weighted imaging with periodically rotated overlapping parallel lines with enhanced reconstruction (FSE‐PROP‐DWI) in distinguishing parotid pleomorphic adenoma (PMA) from Warthin tumor (WT). This retrospective study enrolled 44 parotid gland tumors from 34 patients, including 15 PMAs and 29 WTs with waived written informed consent. All participants underwent 1.5 T diffusion‐weighted imaging including FSE‐PROP‐DWI and single‐shot echo‐planar diffusion‐weighted imaging (SS‐EP‐DWI). After imaging resizing and registration among T2WI, FSE‐PROP‐DWI and SS‐EP‐DWI, imaging distortion was quantitatively analyzed by using the Dice coefficient. Signal‐to‐noise ratio and contrast‐to‐noise ratio were qualitatively evaluated. The mean apparent diffusion coefficient (ADC) of parotid gland tumors was calculated. Wilcoxon signed‐rank test was used for paired comparison between FSE‐PROP‐DWI versus SS‐EP‐DWI. Mann–Whitney U test was used for independent group comparison between PMAs versus WTs. Diagnostic performance was evaluated by receiver operating characteristics curve analysis. P < 0.05 was considered statistically significant. The Dice coefficient was statistically significantly higher on FSE‐PROP‐DWI than SS‐EP‐DWI for both tumors (P < 0.005). Mean ADC was statistically significantly higher in PMAs than WTs on both FSE‐PROP‐DWI and SS‐EP‐DWI (P < 0.005). FSE‐PROP‐DWI and SS‐EP‐DWI successfully distinguished PMAs from WTs with an AUC of 0.880 and 0.945, respectively (P < 0.05). Sensitivity, specificity, positive predictive value, negative predictive value and accuracy in diagnosing PMAs were 100%, 69.0%, 62.5%, 100% and 79.5% for FSE‐PROP‐DWI, and 100%, 82.8%, 75%, 100% and 88.6% for SS‐EP‐DWI, respectively. FSE‐PROP‐DWI is useful to distinguish parotid PMAs from WTs with less distortion of tumors but lower AUC than SS‐EP‐DWI.     

The quest for high spatial resolution diffusion‐weighted imaging of the human brain in vivo

Diffusion‐weighted imaging, a contrast unique to MRI, is used for assessment of tissue microstructure in vivo. However, this exquisite sensitivity to finer scales far above imaging resolution comes at the cost of vulnerability to errors caused by sources of motion other than diffusion motion. Addressing the issue of motion has traditionally limited diffusion‐weighted imaging to a few acquisition techniques and, as a consequence, to poorer spatial resolution than other MRI applications. Advances in MRI imaging methodology have allowed diffusion‐weighted MRI to push to ever higher spatial resolution. In this review we focus on the pulse sequences and associated techniques under development that have pushed the limits of image quality and spatial resolution in diffusion‐weighted MRI.