Radiation enhancement using focussed ultrasound-stimulated microbubbles for breast cancer: A Phase 1 clinical trial.

BACKGROUND: Preclinical studies have demonstrated that tumour cell death can be enhanced 10- to 40-fold when radiotherapy is combined with focussed ultrasound-stimulated microbubble (FUS-MB) treatment. The acoustic exposure of microbubbles (intravascular gas microspheres) within the target volume causes bubble cavitation, which induces perturbation of tumour vasculature and activates endothelial cell apoptotic pathways responsible for the ablative effect of stereotactic body radiotherapy. Subsequent irradiation of a microbubble-sensitised tumour causes rapid increased tumour death. The study here presents the mature safety and efficacy outcomes of magnetic resonance (MR)-guided FUS-MB (MRgFUS-MB) treatment, a radioenhancement therapy for breast cancer. METHODS AND FINDINGS: This prospective, single-center, single-arm Phase 1 clinical trial included patients with stages I-IV breast cancer with in situ tumours for whom breast or chest wall radiotherapy was deemed adequate by a multidisciplinary team (clinicaltrials.gov identifier: NCT04431674). Patients were excluded if they had contraindications for contrast-enhanced MR or microbubble administration. Patients underwent 2 to 3 MRgFUS-MB treatments throughout radiotherapy. An MR-coupled focussed ultrasound device operating at 800 kHz and 570 kPa peak negative pressure was used to sonicate intravenously administrated microbubbles within the MR-guided target volume. The primary outcome was acute toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Secondary outcomes were tumour response at 3 months and local control (LC). A total of 21 female patients presenting with 23 primary breast tumours were enrolled and allocated to intervention between August/2020 and November/2022. Three patients subsequently withdrew consent and, therefore, 18 patients with 20 tumours were included in the safety and LC analyses. Two patients died due to progressive metastatic disease before 3 months following treatment completion and were excluded from the tumour response analysis. The prescribed radiation doses were 20 Gy/5 fractions (40%, n = 8/20), 30 to 35 Gy/5 fractions (35%, n = 7/20), 30 to 40 Gy/10 fractions (15%, n = 3/20), and 66 Gy/33 fractions (10%, n = 2/20). The median follow-up was 9 months (range, 0.3 to 29). Radiation dermatitis was the most common acute toxicity (Grade 1 in 16/20, Grade 2 in 1/20, and Grade 3 in 2/20). One patient developed grade 1 allergic reaction possibly related to microbubbles administration. At 3 months, 18 tumours were evaluated for response: 9 exhibited complete response (50%, n = 9/18), 6 partial response (33%, n = 6/18), 2 stable disease (11%, n = 2/18), and 1 progressive disease (6%, n = 1/18). Further follow-up of responses indicated that the 6-, 12-, and 24-month LC rates were 94% (95% confidence interval [CI] [84%, 100%]), 88% (95% CI [75%, 100%]), and 76% (95% CI [54%, 100%]), respectively. The study's limitations include variable tumour sizes and dose fractionation regimens and the anticipated small sample size typical for a Phase 1 clinical trial. CONCLUSIONS: MRgFUS-MB is an innovative radioenhancement therapy associated with a safe profile, potentially promising responses, and durable LC. These results warrant validation in Phase 2 clinical trials. TRIAL REGISTRATION: clinicaltrials.gov, identifier NCT04431674.

Chemical Exchange Saturation Transfer MRI: What Neuro-Oncology Clinicians Need To Know.

Chemical exchange saturation transfer (CEST) is a relatively novel magnetic resonance imaging (MRI) technique with an image contrast designed for in vivo measurement of certain endogenous molecules with protons that are exchangeable with water protons, such as amide proton transfer commonly used for neuro-oncology applications. Recent technological advances have made it feasible to implement CEST on clinical grade scanners within practical acquisition times, creating new opportunities to integrate CEST in clinical workflow. In addition, the majority of CEST applications used in neuro-oncology are performed without the use gadolinium-based contrast agents which are another appealing feature of this technique. This review is written for clinicians involved in neuro-oncologic care (nonphysicists) as the target audience explaining what they need to know as CEST makes its way into practice. The purpose of this article is to (1) review the basic physics and technical principles of CEST MRI, and (2) review the practical applications of CEST in neuro-oncology.

Diffusion-weighted imaging on an MRI-linear accelerator to identify adversely prognostic tumour regions in glioblastoma during chemoradiation.

BACKGROUND AND PURPOSE: Survival in glioblastoma might be extended by escalating the radiotherapy dose to treatment-resistant tumour and adapting to tumour changes. Diffusion-weighted imaging (DWI) on MRI-linear accelerators (MR-Linacs) could be used to identify a dose escalation target, but its prognostic value must be demonstrated. The purpose of this study was to determine whether MR-Linac DWI can assess treatment response in glioblastoma and whether changes in DWI show greater prognostic value than changes in the contrast-enhancing gross tumour volume (GTV). MATERIALS AND METHODS: Seventy-five patients with glioblastoma were treated with chemoradiotherapy, of which 32 were treated on a 1.5 T MRI-linear accelerator (MR-Linac). Patients were imaged with simulation MRI scanners (MR-sim) at treatment planning and weeks 2, 4, and 10 after treatment start. Twenty-eight patients had additional MR-Linac DWI sequences. Cox modelling was used to evaluate the correlation of overall and progression-free survival (OS and PFS) with clinical variables and volumetric changes in the GTV and low-ADC regions (ADC < 1.25 µm2/ms within GTV). RESULTS: In total, 479 MR-Linac DWI and 289 MR-sim DWI datasets were analyzed. MR-Linac low-ADC changes between weeks 2 and 5 inclusive were prognostic for OS (hazard ratio lower limits ≥ 1.2, p-values ≤ 0.02). MR-sim low-ADC changes showed greater correlation with OS and PFS than GTV changes (e.g., OS hazard ratio at week 2 was 3.4 (p <0.001) for low-ADC versus 2.0 (p = 0.022) for GTV). CONCLUSION: MR-Linac DWI can measure low-ADC tumour volumes that correlate with OS and PFS better than contrast-enhancing GTV. Low-ADC regions could serve as dose escalation targets.

Age-associated change in pyruvate metabolism investigated with hyperpolarized 13 C-MRI of the human brain.

In this study, hyperpolarized 13 C MRI (HP-13 C MRI) was used to investigate changes in the uptake and metabolism of pyruvate with age. Hyperpolarized 13 C-pyruvate was administered to healthy aging individuals (N = 35, ages 21-77) and whole-brain spatial distributions of 13 C-lactate and 13 C-bicarbonate production were measured. Linear mixed-effects regressions were performed to compute the regional percentage change per decade, showing a significant reduction in both normalized 13 C-lactate and normalized 13 C-bicarbonate production with age: - 7 % ± 2 % per decade for 13 C-lactate and - 9 % ± 4 % per decade for 13 C-bicarbonate. Certain regions, such as the right medial precentral gyrus, showed greater rates of change while the left caudate nucleus had a flat 13 C-lactate versus age and a slightly increasing 13 C-bicarbonate versus age. The results show that both the production of lactate (visible as 13 C-lactate signal) as well as the consumption of monocarboxylates to make acetyl-CoA (visible as 13 C-bicarbonate signal) decrease with age and that the rate of change varies by brain region.

Chemical Exchange Saturation Transfer MRI for Differentiating Radiation Necrosis From Tumor Progression in Brain Metastasis-Application in a Clinical Setting.

BACKGROUND: High radiation doses of stereotactic radiosurgery (SRS) for brain metastases (BM) can increase the likelihood of radiation necrosis (RN). Advanced MRI sequences can improve the differentiation between RN and tumor progression (TP). PURPOSE: To use saturation transfer MRI methods including chemical exchange saturation transfer (CEST) and magnetization transfer (MT) to distinguish RN from TP. STUDY TYPE: Prospective cohort study. SUBJECTS: Seventy patients (median age 60; 73% females) with BM (75 lesions) post-SRS. FIELD STRENGTH/SEQUENCE: 3-T, CEST imaging using low/high-power (saturation B1  = 0.52 and 2.0 µT), quantitative MT imaging using B1  = 1.5, 3.0, and 5.0 µT, WAter Saturation Shift Referencing (WASSR), WAter Shift And B1 (WASABI), T1 , and T2 mapping. All used gradient echoes except T2 mapping (gradient and spin echo). ASSESSMENT: Voxel-wise metrics included: magnetization transfer ratio (MTR); apparent exchange-dependent relaxation (AREX); MTR asymmetry; normalized MT exchange rate and pool size product; direct water saturation peak width; and the observed T1 and T2 . Regions of interests (ROIs) were manually contoured on the post-Gd T1 w. The mean (of median ROI values) was compared between groups. Clinical outcomes were determined by clinical and radiologic follow-up or histopathology. STATISTICAL TESTS: t-Test, univariable and multivariable logistic regression, receiver operating characteristic, and area under the curve (AUC) with sensitivity/specificity values with the optimal cut point using the Youden index, Akaike information criterion (AIC), Cohen's d. P < 0.05 with Bonferroni correction was considered significant. RESULTS: Seven metrics showed significant differences between RN and TP. The high-power MTR showed the highest AUC of 0.88, followed by low-power MTR (AUC = 0.87). The combination of low-power CEST scans improved the separation compared to individual parameters (with an AIC of 70.3 for low-power MTR/AREX). Cohen's d effect size showed that the MTR provided the largest effect sizes among all metrics. DATA CONCLUSION: Significant differences between RN and TP were observed based on saturation transfer MRI. EVIDENCE LEVEL: 3 Technical Efficacy: Stage 2.

High grade glioma radiation therapy on a high field 1.5 Tesla MR-Linac - workflow and initial experience with daily adapt-to-position (ATP) MR guidance: A first report.

Purpose: This study reports the workflow and initial clinical experience of high grade glioma (HGG) radiotherapy on the 1.5 T MR-Linac (MRL), with a focus on the temporal variations of the tumor and feasibility of multi-parametric image (mpMRI) acquisition during routine treatment workflow. Materials and methods: Ten HGG patients treated with radiation within the first year of the MRL's clinical operation, between October 2019 and August 2020, were identified from a prospective database. Workflow timings were recorded and online adaptive plans were generated using the Adapt-To-Position (ATP) workflow. Temporal variation within the FLAIR hyperintense region (FHR) was assessed by the relative FHR volumes (n = 281 contours) and migration distances (maximum linear displacement of the volume). Research mpMRIs were acquired on the MRL during radiation and changes in selected functional parameters were investigated within the FHR. Results: All patients completed radiotherapy to a median dose of 60 Gy (range, 54-60 Gy) in 30 fractions (range, 30-33), receiving a total of 287 fractions on the MRL. The mean in-room time per fraction with or without post-beam research imaging was 42.9 minutes (range, 25.0-69.0 minutes) and 37.3 minutes (range, 24.0-51.0 minutes), respectively. Three patients (30%) required re-planning between fractions 9 to 12 due to progression of tumor and/or edema identified on daily MRL imaging. At the 10, 20, and 30-day post-first fraction time points 3, 3, and 4 patients, respectively, had a FHR volume that changed by at least 20% relative to the first fraction. Research mpMRIs were successfully acquired on the MRL. The median apparent diffusion coefficient (ADC) within the FHR and the volumes of FLAIR were significantly correlated when data from all patients and time points were pooled (R=0.68, p<.001). Conclusion: We report the first clinical series of HGG patients treated with radiotherapy on the MRL. The ATP workflow and treatment times were clinically acceptable, and daily online MRL imaging triggered adaptive re-planning for selected patients. Acquisition of mpMRIs was feasible on the MRL during routine treatment workflow. Prospective clinical outcomes data is anticipated from the ongoing UNITED phase 2 trial to further refine the role of MR-guided adaptive radiotherapy.

Early alterations in brain glucose metabolism and vascular function in a transgenic rat model of Alzheimer's disease.

Alteration in brain metabolism predates clinical onset of Alzheimer's Disease (AD). Realizing its potential as an early diagnostic marker, however, requires understanding how early AD metabolic dysregulation manifests on non-invasive brain imaging. We presently utilized magnetic resonance imaging and spectroscopy to map glucose and ketone metabolic profiles and image cerebrovascular function in a rat model of early stage AD - 9-month-old TgF344-AD (TgAD) rats - and their age-matched non-transgenic (nTg) littermates. Compared to the nTg rats, TgAD rats displayed attenuation in global cerebral and hippocampal vasoreactivity to hypercapnia, by 49 ± 17% and 58 ± 19%, respectively, while their functional hyperemia to somatosensory stimulation diminished by 69 ± 5%. To assess brain glucose uptake, rats were fasted overnight and then challenged with an intravenous infusion of 2-deoxy-D-glucose (2DG). Compared to their non-transgenic littermates, TgAD rats exhibited 99 ± 10% and 52 ± 5% smaller glucose uptake in the entorhinal cortex and the hippocampus, respectively. Moreover, hippocampal glucose uptake reduction in male TgAD rats compared to the nTg was 54 ± 36% greater than the reduction seen in female TgAD rats. TgAD rats also showed a 59 ± 42% increase in total choline level in the hippocampus, suggesting increased membrane turnover. In combination with our earlier findings of impaired electrophysiological metrics at this early stage of AD pathology progression, our findings suggest that subtle neuronal function alterations that would be difficult to assess in a clinical population may be accompanied by MRI-detectable changes in brain glucose metabolism and cerebrovascular function.

Skull phantom-based methodology to validate MRI co-registration accuracy for Gamma Knife radiosurgery.

PURPOSE: Target localization, for stereotactic radiosurgery (SRS) treatment with Gamma Knife, has become increasingly reliant on the co-registration between the planning MRI and the stereotactic cone-beam computed tomography (CBCT). Validating image registration between modalities would be particularly beneficial when considering the emergence of novel functional and metabolic MRI pulse sequences for target delineation. This study aimed to develop a phantom-based methodology to quantitatively compare the co-registration accuracy of the standard clinical imaging protocol to a representative MRI sequence that was likely to fail co-registration. The comparative methodology presented in this study may serve as a useful tool to evaluate the clinical translatability of novel MRI sequences. METHODS: A realistic human skull phantom with fiducial marker columns was designed and manufactured to fit into a typical MRI head coil and the Gamma Knife patient positioning system. A series of "optimized" 3D MRI sequences-T1 -weighted Dixon, T1 -weighted fast field echo (FFE), and T2 -weighted fluid-attenuated inversion recovery (FLAIR)-were acquired and co-registered to the CBCT. The same sequences were "compromised" by reconstructing without geometric distortion correction and re-collecting with lower signal-to-noise-ratio (SNR) to simulate a novel MRI sequence with poor co-registration accuracy. Image similarity metrics-structural similarity (SSIM) index, mean squared error (MSE), and peak SNR (PSNR)-were used to quantitatively compare the co-registration of the optimized and compromised MR images. RESULTS: The ground truth fiducial positions were compared to positions measured from each optimized image volume revealing a maximum median geometric uncertainty of 0.39 mm (LR), 0.92 mm (AP), and 0.13 mm (SI) between the CT and CBCT, 0.60 mm (LR), 0.36 mm (AP), and 0.07 mm (SI) between the CT and T1 -weighted Dixon, 0.42 mm (LR), 0.23 mm (AP), and 0.08 mm (SI) between the CT and T1 -weighted FFE, and 0.45 mm (LR), 0.19 mm (AP), and 1.04 mm (SI) between the CT and T2 -weighted FLAIR. Qualitatively, pairs of optimized and compromised image slices were compared using a fusion image where separable colors were used to differentiate between images. Quantitatively, MSE was the most predictive and SSIM the second most predictive metric for evaluating co-registration similarity. A clinically relevant threshold of MSE, SSIM, and/or PSNR may be defined beyond which point an MRI sequence should be rejected for target delineation based on its dissimilarity to an optimized sequence co-registration. All dissimilarity thresholds calculated using correlation coefficients with in-plane geometric uncertainty would need to be defined on a sequence-by-sequence basis and validated with patient data. CONCLUSION: This study utilized a realistic skull phantom and image similarity metrics to develop a methodology capable of quantitatively assessing whether a modern research-based MRI sequence can be co-registered to the Gamma Knife CBCT with equal or less than equal accuracy when compared to a clinically accepted protocol.

Continuous Ingestion of Lacticaseibacillus rhamnosus JB-1 during Chronic Stress Ensures Neurometabolic and Behavioural Stability in Rats.

The intestinal microbiome composition and dietary supplementation with psychobiotics can result in neurochemical alterations in the brain, which are possible due to the presence of the brain-gut-microbiome axis. In the present study, magnetic resonance spectroscopy (MRS) and behavioural testing were used to evaluate whether treatment with Lacticaseibacillus rhamnosus JB-1 (JB­1) bacteria alters brain metabolites' levels and behaviour during continuous exposure to chronic stress. Twenty Wistar rats were subjected to eight weeks of a chronic unpredictable mild stress protocol. Simultaneously, half of them were fed with JB-1 bacteria, and the second half was given a daily placebo. Animals were examined at three-time points: before starting the stress protocol and after five and eight weeks of stress onset. In the elevated plus maze behavioural test the placebo group displayed increased anxiety expressed by almost complete avoidance of exploration, while the JB-1 dietary supplementation mitigated anxiety which resulted in a longer exploration time. Hippocampal MRS measurements demonstrated a significant decrease in glutamine + glutathione concentration in the placebo group compared to the JB-1 bacteria-supplemented group after five weeks of stress. With the progression of stress the decrease of glutamate, glutathione, taurine, and macromolecular concentrations were observed in the placebo group as compared to baseline. The level of brain metabolites in the JB-1-supplemented rats were stable throughout the experiment, with only the taurine level decreasing between weeks five and eight of stress. These data indicated that the JB-1 bacteria diet might stabilize levels of stress-related neurometabolites in rat brain and could prevent the development of anxiety/depressive-like behaviour.

Review and consensus recommendations on clinical APT-weighted imaging approaches at 3T: Application to brain tumors.

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.

Accuracy and precision of apparent diffusion coefficient measurements on a 1.5 T MR-Linac in central nervous system tumour patients.

BACKGROUND AND PURPOSE: MRI linear accelerators (MR-Linacs) may allow treatment adaptation to be guided by quantitative MRI including diffusion-weighted imaging (DWI). The aim of this study was to evaluate the accuracy and precision of apparent diffusion coefficient (ADC) measurements from DWI on a 1.5 T MR-Linac in patients with central nervous system (CNS) tumours through comparison with a diagnostic scanner. MATERIALS AND METHODS: CNS patients were treated using a 1.5 T Elekta Unity MR-Linac. DWI was acquired during MR-Linac treatment and on a Philips Ingenia 1.5 T. The agreement between the two scanners on median ADC over the gross tumour/clinical target volumes (GTV/CTV) and in brain regions (white/grey matter, cerebrospinal fluid (CSF)) was computed. Repeated scans were used to estimate ADC repeatability. Daily changes in ADC over the GTV of high-grade gliomas were characterized from MR-Linac scans. RESULTS: DWI from 59 patients was analyzed. MR-Linac ADC measurements showed a small bias relative to Ingenia measurements in white matter, grey matter, GTV, and CTV (bias: -0.05 ± 0.03, -0.08 ± 0.05, -0.1 ± 0.1, -0.08 ± 0.07 µm2/ms). ADC differed substantially in CSF (bias: -0.5 ± 0.3 µm2/ms). The repeatability of MR-Linac ADC over white/grey matter was similar to previous reports (coefficients of variation for median ADC: 1.4%/1.8%). MR-Linac ADC changes in the GTV were detectable. CONCLUSIONS: It is possible to obtain ADC measurements in the brain on a 1.5 T MR-Linac that are comparable to those of diagnostic-quality scanners. This technical validation study adds to the foundation for future studies that will correlate brain tumour ADC with clinical outcomes.

Saturation transfer MRI is sensitive to neurochemical changes in the rat brain due to chronic unpredictable mild stress.

Chemical exchange saturation transfer (CEST) MRI was performed for the evaluation of cerebral metabolic changes in a rat model of depressive-like disease induced by chronic unpredictable mild stress (CUMS). CEST Z-spectra were acquired on a 7 T MRI with two saturation B1 amplitudes (0.5 and 0.75 µT) to measure the magnetization transfer ratio (MTR), CEST and relayed nuclear Overhauser effect (rNOE). Cerebral cortex and hippocampus were examined in two groups of animals: healthy control (n = 10) and stressed (n = 14), the latter of which was exposed to eight weeks of the CUMS protocol. The stressed group Z-spectrum parameters, primarily MTRs, were significantly lower than in controls, at all selected frequency offsets (3.5, 3.0, 2.0, - 3.2, - 3.6 ppm) in the cortex (the largest difference of ~ 3.5% at - 3.6 ppm, p = 0.0005) and the hippocampus (MTRs measured with a B1 = 0.5 µT). The hippocampal rNOE contributions decreased significantly in the stressed brains. Glutamate concentration (assessed using ELISA) and MTR at 3 ppm correlated positively in both brain regions. GABA concentration also correlated positively with CEST contributions in both cerebral areas, while such correlation with MTR was positive in hippocampus, and nonsignificant in cortex. Results indicate that CEST is sensitive to neurometabolic changes following chronic stress exposure.

Probiotics, Prebiotics and Postbiotics on Mitigation of Depression Symptoms: Modulation of the Brain-Gut-Microbiome Axis.

The brain-gut-microbiome axis is a bidirectional communication pathway between the gut microbiota and the central nervous system. The growing interest in the gut microbiota and mechanisms of its interaction with the brain has contributed to the considerable attention given to the potential use of probiotics, prebiotics and postbiotics in the prevention and treatment of depressive disorders. This review discusses the up-to-date findings in preclinical and clinical trials regarding the use of pro-, pre- and postbiotics in depressive disorders. Studies in rodent models of depression show that some of them inhibit inflammation, decrease corticosterone level and change the level of neurometabolites, which consequently lead to mitigation of the symptoms of depression. Moreover, certain clinical studies have indicated improvement in mood as well as changes in biochemical parameters in patients suffering from depressive disorders.

Chemical exchange saturation transfer MRI in central nervous system tumours on a 1.5 T MR-Linac.

PURPOSE: To describe the implementation and initial results of using Chemical Exchange Saturation Transfer (CEST) for monitoring patients with central nervous system (CNS) tumours treated using a 1.5 tesla MR-guided radiotherapy system. METHODS: CNS patients were treated with up to 30 fractions (total dose up to 60 Gy) using a 1.5 T Elekta Unity MR-Linac. CEST scans were obtained in 54 subjects at one or more time points during treatment. CEST metrics, including the amide magnetization transfer ratio (MTRAmide), nuclear Overhauser effect (NOE) MTR (MTRNOE) and asymmetry, were quantified in phantoms and CNS patients. The signal was investigated between tumour and white matter, across time, and across disease categories including high- and low-grade tumours. RESULTS: The gross tumour volume (GTV) exhibited lower MTRAmide and MTRNOE and higher asymmetry compared to contralateral normal appearing white matter. Signal changes in the GTV during fractionated radiotherapy were observed. There were differences between high- and low-grade tumours, with higher CEST asymmetry associated with higher grade disease. CONCLUSION: CEST MRI using a 1.5 T MR-Linac was demonstrated to be feasible for in vivo imaging of CNS tumours. CEST images showed tumour/white-matter contrast, temporal CEST signal changes, and associations with tumour grade. These results show promise for the eventual goal of using metabolic imaging to inform the design of adaptive radiotherapy protocols.

A strategy to prevent a temperature-induced MRI artifact in warm liquid phantoms due to convection currents.

MRI phantom studies often fail to mimic the temperature of the human body, which can negatively impact accuracy. An artifact induced by increasing temperature in liquid phantoms was observed, presenting a significant challenge to temperature-controlled experiments. In this study we characterize and provide a solution to eliminate this temperature-induced MRI artifact. Low concentration (0.5-2.5 mM) agar phantoms were prepared. Utilizing a temperature-controlled phantom holder, T1 - and T2 -weighted structural images were acquired at 7 T along with quantitative B0 , B1 , T1 , T2 and ADC maps at both 25 and 37°C. Additionally, computer simulations were conducted to demonstrate the fluid flow and thermal flux patterns in water to provide an insight into the origins of the artifact. Evidence from computer simulation and quantitative MRI strongly suggest the artifact was caused by heat transfer in the form of natural convection leading to structured patterns of signal loss in MR images. The artifact was present up to agar concentrations of 1.5 mM (T1 = 3068 ± 16 ms, T2 = 1052 ± 20 ms, ADC = 2.29 ± 0.36 × 10-3 mm2 /s at 25°C; T1 = 3928 ± 44 ms, T2 = 1122 ± 24 ms, ADC = 2.64 ± 0.49 × 10-3 mm2 /s at 37°C), above which point increased sample viscosity no longer allows for convection currents, thereby eliminating the artifact. The methodology described in this work simplifies quantitative MR acquisition of liquid phantoms at physiological temperature by suppressing convection currents with relatively small changes to intrinsic MR parameters (T1 increased by 1.4% and T2 decreased by 17% for 1.5 mM agar at 25°C).

Quantitative CEST and MT at 1.5T for monitoring treatment response in glioblastoma: early and late tumor progression during chemoradiation.

PURPOSE: Quantitative MRI (qMRI) was performed using a 1.5T protocol that includes a novel chemical exchange saturation transfer/magnetization transfer (CEST/MT) approach. The purpose of this prospective study was to determine if qMRI metrics at baseline, at the 10th and 20th fraction during a 30 fraction/6 week standard chemoradiation (CRT) schedule, and at 1 month following treatment could be an early indicator of response for glioblastoma (GBM). METHODS: The study included 51 newly diagnosed GBM patients. Four regions-of-interest (ROI) were analyzed: (i) the radiation defined clinical target volume (CTV), (ii) radiation defined gross tumor volume (GTV), (iii) enhancing-tumor regions, and (iv) FLAIR-hyperintense regions. Quantitative CEST, MT, T1 and T2 parameters were compared between those patients progressing within 6.9 months (early), and those progressing after CRT (late), using mixed modelling. Exploratory predictive modelling was performed to identify significant predictors of early progression using a multivariable LASSO model. RESULTS: Results were dependent on the specific tumor ROI analyzed and the imaging time point. The baseline CEST asymmetry within the CTV was significantly higher in the early progression cohort. Other significant predictors included the T2 of the MT pools (for semi-solid at fraction 20 and water at 1 month after CRT), the exchange rate (at fraction 20) and the MGMT methylation status. CONCLUSIONS: We observe the potential for multiparametric qMRI, including a novel pulsed CEST/MT approach, to show potential in distinguishing early from late progression GBM cohorts. Ultimately, the goal is to personalize therapeutic decisions and treatment adaptation based on non-invasive imaging-based biomarkers.

Saturation transfer properties of tumour xenografts derived from prostate cancer cell lines 22Rv1 and DU145.

Histopathology is currently the most reliable tool in assessing the aggressiveness and prognosis of solid tumours. However, developing non-invasive modalities for tumour evaluation remains crucial due to the side effects and complications caused by biopsy procedures. In this study, saturation transfer MRI was used to investigate the microstructural and metabolic properties of tumour xenografts in mice derived from the prostate cancer cell lines 22Rv1 and DU145, which express different aggressiveness. The magnetization transfer (MT) and chemical exchange saturation transfer (CEST) effects, which are associated with the microstructural and metabolic properties in biological tissue, respectively, were analyzed quantitatively and compared amongst different tumour types and regions. Histopathological staining was performed as a reference. Higher cellular density and metabolism expressed in more aggressive tumours (22Rv1) were associated with larger MT and CEST effects. High collagen content in the necrotic regions might explain their higher MT effects compared to tumour regions.

Dietary supplementation with Lactobacillus rhamnosus JB-1 restores brain neurochemical balance and mitigates the progression of mood disorder in a rat model of chronic unpredictable mild stress.

Major depressive disorder is a stress-related disease associated with brain metabolic dysregulation in the glutamine-glutamate/γ-aminobutyric acid (Gln-Glu/GABA) cycle. Recent studies have demonstrated that microbiome-gut-brain interactions have the potential to influence mental health. The hypothesis of this study was that Lactobacillus rhamnosus JB-1 (LR-JB1™) dietary supplementation has a positive impact on neuro-metabolism which can be quantified in vivo using magnetic resonance spectroscopy (MRS). A rat model of depressive-like disorder, chronic unpredictable mild stress (CUMS), was used. Baseline comparisons of MRS and behavior were obtained in a control group and in a stressed group subjected to CUMS. Of the 22 metabolites measured using MRS, stressed rats had significantly lower concentrations of GABA, glutamate, glutamine + glutathione, glutamate + glutamine, total creatine, and total N-acetylaspartate (tNAA). Stressed rats were then separated into 2 groups and supplemented with either LR-JB1™ or placebo and re-evaluated after 4 weeks of continued CUMS. The LR-JB1™ microbiotic diet restored these metabolites to levels previously observed in controls, while the placebo diet resulted in further significant decrease of glutamate, total choline, and tNAA. LR-JB1™ treated animals also exhibited calmer and more relaxed behavior, as compared with placebo treated animals. In summary, significant cerebral biochemical downregulation of major brain metabolites following prolonged stress were measured in vivo using MRS, and these decreases were reversed using a microbiotic dietary supplement of LR-JB1™, even in the presence of continued stress, which also resulted in a reduction of stress-induced behavior in a rat model of depressive-like disorder.

An Automated Segmentation Pipeline for Intratumoural Regions in Animal Xenografts Using Machine Learning and Saturation Transfer MRI.

Saturation transfer MRI can be useful in the characterization of different tumour types. It is sensitive to tumour metabolism, microstructure, and microenvironment. This study aimed to use saturation transfer to differentiate between intratumoural regions, demarcate tumour boundaries, and reduce data acquisition times by identifying the imaging scheme with the most impact on segmentation accuracy. Saturation transfer-weighted images were acquired over a wide range of saturation amplitudes and frequency offsets along with T1 and T2 maps for 34 tumour xenografts in mice. Independent component analysis and Gaussian mixture modelling were used to segment the images and identify intratumoural regions. Comparison between the segmented regions and histopathology indicated five distinct clusters: three corresponding to intratumoural regions (active tumour, necrosis/apoptosis, and blood/edema) and two extratumoural (muscle and a mix of muscle and connective tissue). The fraction of tumour voxels segmented as necrosis/apoptosis quantitatively matched those calculated from TUNEL histopathological assays. An optimal protocol was identified providing reasonable qualitative agreement between MRI and histopathology and consisting of T1 and T2 maps and 22 magnetization transfer (MT)-weighted images. A three-image subset was identified that resulted in a greater than 90% match in positive and negative predictive value of tumour voxels compared to those found using the entire 24-image dataset. The proposed algorithm can potentially be used to develop a robust intratumoural segmentation method.

In vitro characterization of the serotonin biosynthesis pathway by CEST MRI.

PURPOSE: The diagnosis of monoamine-related psychiatric disorders is based on the phenomenological evaluation of symptoms and behavior by trained clinicians. The CEST technique can be sensitive to monoamines such as serotonin. This study quantifies the CEST properties of the compounds in the serotonin biosynthesis pathway with the goal of developing noninvasive techniques aimed at advancing the diagnostic assessment of serotonin dysfunction. METHODS: Saturation transfer-weighted images of L-tryptophan, 5-hydroxytryptophan, serotonin, 5-hydroxyindoleacetic acid, and melatonin phantoms were acquired over a range of saturation amplitudes and frequency offsets along with observed T1 , T2 , and B1 efficiency maps at physiological temperature and pH of 5.5, 6.7, and 7.4. The CEST and MT data were fitted to a three-pool Bloch-McConnell model of exchange to estimate the model parameters. RESULTS: At a pH of 5.5, tryptophan, 5-hydroxytryptophan and serotonin exhibited significant CEST contrast at resonance frequency offset, Δω between 2.64 ppm and 2.71 ppm, and magnetization transfer ratio asymmetry amplitudes up to 20% per 30 mM. At a pH of 7.4, all molecules exhibited significant CEST contrast between 5.11 ppm and 5.47 ppm, and magnetization transfer ratio asymmetry amplitudes up to 9.5% per 30 mM. At a pH of 6.7, all studied compounds except melatonin exhibited a CEST peak from each of the preceding two pHs. CONCLUSION: At a pH of 5.5, tryptophan, 5-hydroxytryptophan, and serotonin CEST contrast originates from the NH3+ side chain, whereas at a pH of 7.4, CEST contrast is due to the chemical exchange between water and the NH proton on the indole ring. The data in this study could be used to inform future investigations aimed at detecting and measuring in vivo serotonin.