Purpose: As the field of CEST grows, various novel preparation periods using different parameters are being introduced. At the same time, large, multisite clinical studies require clearly defined protocols, especially across different vendors. Here, we propose a CEST definition standard using the open Pulseq format for a shareable, simple, and exact definition of CEST protocols. Methods: We present the benefits of such a standard in three ways: (1) an open database on GitHub, where fully defined, human-readable CEST protocols can be shared; (2) an open-source Bloch-McConnell simulation to test and optimize CEST preparation periods in silico; and (3) a hybrid MR sequence that plays out the CEST preparation period and can be combined with any existing readout module. Results: The exact definition of the CEST preparation period, in combination with the flexible simulation, leads to a good match between simulations and measurements. The standard allowed finding consensus on three amide proton transfer–weighted protocols that could be compared in healthy subjects and a tumor patient. In addition, we could show coherent multisite results for a sophisticated CEST method, highlighting the benefits regarding protocol sharing and reproducibility. Conclusion: With Pulseq-CEST, we provide a straightforward approach to standardize, share, simulate, and measure different CEST preparation schemes, which are inherently completely defined.

Brain pH is thought to be important in epilepsy. The regulation of brain pH is, however, still poorly understood in animal models of chronic seizures (SZ) as well as in patients with intractable epilepsy. We used chemical exchange saturation transfer (CEST) MRI to noninvasively determine if the pH is alkaline shifted in a rodent model of the mesial temporal lobe (MTL) epilepsy with chronic SZ. Taking advantage of its high spatial resolution, we determined the pH values in specific brain regions believed to be important in this model produced by lithium-pilocarpine injection. All animals developed status epilepticus within 90 min after the lithium-pilocarpine administration, but one animal died within 24 hrs. All the surviving animals developed chronic SZ during the first 2 months. After SZ developed, brain pH was determined in the pilocarpine and control groups (n = 8 each). Epileptiform activity was documented in six pilocarpine rats with scalp EEG. The brain pH was estimated using two methods based on magnetization transfer asymmetry and amide proton transfer ratio. The pH was alkaline shifted in the pilocarpine rats (one outlier excluded) compared to the controls in the hippocampus (7.29 vs 7.17, t-test, p < 0.03) and the piriform cortex (7.34 vs. 7.06, p < 0.005), marginally more alkaline in the thalamus (7.13 vs. 7.01, p < 0.05), but not in the cerebral cortex (7.18 vs. 7.08, p > 0.05). Normalizing the brain pH may lead to an effective non-surgical method for treating intractable epilepsy as it is known that SZ can be eliminated by lowering the pH.

Purpose: To develop fast multi-slice apparent T1 (T1app) mapping for accurate cerebral blood flow (CBF) quantification with arterial spin labeling (ASL) MRI. Methods: Fast multi-slice T1app was measured using a modified inversion recovery echo planar imaging (EPI) sequence with simultaneous application of ASL tagging radiofrequency (RF) and gradient pulses. The fast multi-slice T1app measurement was compared with the single-slice T1app imaging approach, repeated per slice. CBF was assessed in healthy adult Wistar rats (N = 5) and rats with acute stroke 24 hours after a transient middle cerebral artery occlusion (N = 5). Results: The fast multi-slice T1app measurement was in good agreement with that of a single-slice T1app imaging approach (Lin's concordance correlation coefficient = 0.92). CBF calculated using T1app reasonably accounted for the finite labeling RF duration, whereas the routine T1-normalized ASL MRI underestimated the CBF, particularly at short labeling durations. In acute stroke rats, the labeling time and the CBF difference (ΔCBF) between the contralateral normal area and the ischemic lesion were significantly correlated when using T1-normalized perfusion calculation (R = 0.844, P =.035). In comparison, T1app-normalized ΔCBF had little labeling time dependence based on the linear regression equation of ΔCBF = −0.0247*τ + 1.579 mL/g/min (R = −0.352, P =.494). Conclusions: Our study found fast multi-slice T1app imaging improves the accuracy and reproducibility of CBF measurement.

Recently, there has been a lot of interest in the neuroimaging community in exploring fMRI time-series measures of local neuronal activity and excitation/inhibition (E/I) balance in the brain. In this preliminary study we probed the sensitivity of widely used sample entropy (SE) measure at multiple scales to controlled alteration of the brain's E/I balance in non-human primates (NHPs) with a well-characterized sub-anesthetic ketamine infusion fMRI model. We found that SE failed to detect the expected changes in E/I balance induced by ketamine. Subsequently, noticing that the complexity in the time series contributing SE could be dominated by non-neuronal noise in this experimental setting, we developed a new time-series measure called restricted sample entropy (RSE) by restricting SE estimations to regular portions of the fMRI time-series. RSE was able to adequately reflect the increased excitatory activity engendered by disinhibition of glutamergic neurons, through sub-anesthetic ketamine infusion. These results show that RSE is potentially a powerful tool for examining local neural activity, E/I balance, and alterations in brain state.

Purpose: CEST MRI omega plot quantifies the labile proton fraction ratio (fr) and exchange rate (ksw), yet it assumes long RF saturation time (Ts) and relaxation delay (Td). Our study aimed to test if a quasi–steady-state (QUASS) CEST analysis that accounts for the effect of finite Ts and Td could improve the accuracy of CEST MRI quantification. Methods: We modeled the MRI signal evolution using a typical CEST EPI sequence. The signal relaxes toward its thermal equilibrium following the bulk water relaxation rate during Td, and then toward its CEST steady state following the spin-lock relaxation rate during Ts from which the QUASS CEST effect is derived. Both fr and ksw were solved from simulated conventional apparent CEST and QUASS CEST MRI. We also performed MRI experiments from a Cr-gel phantom under serially varied Ts and Td times from 1.5 to 7.5 s. Results: Simulation showed that, although ksw could be slightly overestimated (3%-15%) for the range of Ts and Td, fr could be substantially underestimated by as much as 67%. In contrast, the QUASS solution provided accurate ksw and fr determination within 2%. The CEST MRI experiments confirmed that the QUASS solution enabled robust quantification of ksw and fr, superior over the omega plot analysis based on the conventional apparent CEST MRI measurements. Conclusions: The QUASS CEST MRI algorithm corrects the effect of finite Ts and Td times on CEST measurements, thereby allowing robust and accurate CEST quantification.

Amide proton transfer-weighted (APTw) MR imaging shows promise as a biomarker of brain tumor status. Currently used APTw MRI pulse sequences and protocols vary substantially among different institutes, and there are no agreed-on standards in the imaging community. Therefore, the results acquired from different research centers are difficult to compare, which hampers uniform clinical application and interpretation. This paper reviews current clinical APTw imaging approaches and provides a rationale for optimized APTw brain tumor imaging at 3 T, including specific recommendations for pulse sequences, acquisition protocols, and data processing methods. We expect that these consensus recommendations will become the first broadly accepted guidelines for APTw imaging of brain tumors on 3 T MRI systems from different vendors. This will allow more medical centers to use the same or comparable APTw MRI techniques for the detection, characterization, and monitoring of brain tumors, enabling multi-center trials in larger patient cohorts and, ultimately, routine clinical use.

Purpose: CEST MRI is sensitive to dilute proteins/peptides and microenvironmental properties yet susceptible to magnetic field inhomogeneity. We aimed to develop a high-resolution field map-based CEST intravoxel inhomogeneity correction (CIVIC) algorithm for CEST Z-spectral imaging. Methods: The proposed CIVIC approach treats the intravoxel inhomogeneity as a point spread function and applies the deconvolution algorithm to reconstruct the original Z-spectrum. We simulated the effect of B0 field inhomogeneity on CEST measurement and tested the efficacy of the proposed CIVIC algorithm. We also performed CEST MRI on a dual-pH Creatine-gel phantom under varied field homogeneity conditions and compared the CEST MRI contrast-to-noise ratio from the raw Z-spectrum, water saturation shift referencing, and the proposed CIVIC methods. Results: The numerical simulation showed that the CIVIC algorithm remains effective even in the case of symmetric field dispersion with a 0 mean shift. The experimental results confirmed that the proposed CIVIC method substantially improves the CEST MRI contrast-to-noise ratio under different field homogeneity conditions. Conclusion: Our study established a new intravoxel B0 inhomogeneity correction algorithm, promising to facilitate CEST spectral imaging in challenging experimental conditions.

Chemical exchange saturation transfer (CEST) MRI, versatile for detecting endogenous mobile proteins and tissue pH, has proved valuable in tumor imaging. However, CEST MRI scans are often performed under non-equilibrium conditions, which confound tissue characterization. This study proposed a quasi-steady-state (QUASS) CEST MRI algorithm to standardize fast and accurate tumor imaging at 3 T. The CEST signal evolution was modeled by longitudinal relaxation rate during relaxation delay (Td) and spinlock relaxation during RF saturation time (Ts), from which the QUASS CEST effect is derived. Numerical simulation and human MR imaging experiments (7 healthy volunteers and 19 tumor patients) were conducted at 3 T to compare the CEST measurements obtained under two representative experimental conditions. In addition, amide proton transfer (APT), combined magnetization transfer (MT) and nuclear overhauser enhancement (NOE) effects, and direct water saturation were isolated using a 3-pool Lorentzian fitting in white matter and gray matter of healthy volunteers and for patients in the contralateral normal-appearing white matter and tumor regions. Finally, the student's t-test was performed between conventional and QUASS CEST measurements. The routine APT and combined MT & NOE measures significantly varied with Ts and Td (P < .001) and were significantly smaller than the corresponding QUASS indices (P < .001). In contrast, the results from the QUASS reconstruction showed little dependence on the scan protocol (P > .05), indicating the accuracy and robustness of QUASS CEST MRI for tumor imaging. To summarize, the QUASS CEST reconstruction algorithm enables fast and accurate tumor CEST imaging at 3 T, promising to expedite and standardize clinical CEST MRI.

Imaging has played a vital role in our mechanistic understanding of acute ischemia and the management of acute stroke patients. The most recent DAWN and DEFUSE-3 trials showed that endovascular therapy could be extended to a selected group of late-presenting stroke patients with the aid of imaging. Although perfusion and diffusion MRI have been commonly used in stroke imaging, the approximation of their mismatch as the penumbra is oversimplified, particularly in the era of endovascular therapy. Briefly, the hypoperfusion lesion includes the benign oligemia that does not proceed to infarction. Also, with prompt and effective reperfusion therapy, a portion of the diffusion lesion is potentially reversible. Therefore, advanced imaging that provides improved ischemic tissue characterization may enable new experimental stroke therapeutics and eventually further individualize stroke treatment upon translation to the clinical setting. Specifically, pH imaging captures tissue of altered metabolic state that demarcates the hypoperfused lesion into ischemic penumbra and benign oligemia, which remains promising to define the ischemic penumbra’s outer boundary. On the other hand, diffusion kurtosis imaging (DKI) differentiates the most severely damaged and irreversibly injured diffusion lesion from the portion of diffusion lesion that is potentially reversible, refining the inner boundary of the penumbra. Altogether, the development of advanced imaging has the potential to not only transform the experimental stroke research but also aid clinical translation and patient management.

Purpose: To characterize and minimize the magnetization transfer (MT) effect in MR fingerprinting (MRF) relaxation measurements with a 2-pool (2P) MT model of multiple tissue types. Theory and Methods: Semisolid MT effect in MRF was modeled using 2P Bloch-McConnell equations. The combinations of MT parameters of multiple tissues (white [WM] and gray matter [GM]) were used to build the MRF dictionary. Both 1-pool (1P) and 2P models were simulated to characterize the dependence on MT. Relaxations measured using MRF with spin-echo saturation-recovery (SR) or inversion-recovery preparations were compared with conventional SR-prepared T1 and multiple spin-echo T2 measurements. The simulations results were validated with phantoms and brain tissue samples. Results: The MRF signal was different from the 1P and 2P models. 1P MRF produced significantly (P <.05) underestimated T1 in WM (20-30%) and GM (7-10%), while 2P MRF measured consistent T1 and T2 in both WM and GM with conventional measurements (pairwise test P >.1; correlated P <.05). Simulations showed that SR-prepared MRF measuring T1 had much less errors against the variation of the macromolecular fraction. Compared with inversion-recovery preparation, SR-prepared MRF produced higher relaxation correlations (R > 0.9) with conventional measurements in both WM and GM across samples, suggesting that SR-prepared MRF was less sensitive to the compositive effect of multiple MT parameters variations. Conclusions: 2P MRF using a combination of MT parameters for multiple tissue types can measure consistent relaxations with conventional methods. With the 2P models, SR-prepared MRF would provide an option for robust relaxation measurement under heterogeneous MT.