Inhaled Oxygen as a Quantitative Intravascular MRI Contrast Agent

Increasing the fraction of inspired oxygen (FiO2) generates MR contrast by two distinct mechanisms: increased T2 from deoxyhemoglobin dilution in venous compartments (blood oxygenation level-dependent effect or BOLD) and reduced T­1 from paramagnetic molecular oxygen dissolved in blood plasma and tissues. Many research and clinical applications using hyperoxic contrast have recently emerged, including delineating ischemic stroke penumbra, oxygen delivery to tumors, and functional MRI data calibration. However, quantitative measurements using this contrast agent depend on the precise knowledge of its effects on the MR signal – of which there remain many crucial missing pieces. This thesis aims to obtain a more quantitative understanding of intravascular hyperoxic contrast in vivo, with the hope of increasing its precision and utility. Specifically, our work focuses on the following areas: (1) paramagnetic effects of molecular oxygen BOLD and arterial spin labeling (ASL) data, (2) degree and temporal characteristics of hyperoxia-induced reductions in cerebral blood flow (CBF), (3) use of oxygen in quantitative measurements of metabolism, and (4) biophysical mechanisms of hyperoxic T1 contrast. In Chapter 2, the artifactual influence of paramagnetic molecular oxygen on BOLD-modulated hyperoxic gas studies is characterized as a function of static field strength, and we show that optimum reduction in FiO2 mitigates this effect while maintaining BOLD contrast. Since ASL measurements are highly sensitive to arterial blood T­1 (T1a), the value of T1a in vivo is determined as a function of arterial oxygen partial pressure in Chapter 3. The effect of both the degree and duration of hyperoxic exposure on absolute CBF are quantified using simultaneous ASL and in vivo T1a measurements, as described in Chapter 4. In Chapter 5, hyperoxic gas calibration of BOLD/ASL data is used to measure cerebral oxygen metabolism in a hypermetabolic swine model, with our results comparing favorably to 17O2 measurements of absolute metabolism. In Chapter 6, a model to describe the relationship between CBF, oxygen consumption, and hyperoxic T1 reduction is developed, which allows for a more rigorous physiological interpretation of these data. Taken together, this work represents several important steps towards making hyperoxia a more quantitative MRI contrast agent for research and clinical applications

Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

ImportanceLess than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant.ObjectiveTo determine the relative effectiveness and safety of 3 common alternate treatments for MDD.Design, setting, and participantsFrom December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks.InterventionsSwitch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase).Main outcomes and measuresThe primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects.ResultsAmong 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain.Conclusions and relevanceAmong a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach.Trial registrationclinicaltrials.gov Identifier: NCT01421342